INDEX

Abacavir, bioactivation, 4: 77–79 ABCB1 resistance, 2: 167 Abbreviated New Drug Application (ANDA), ABCC1, 2: 168 bioequivalence studies, 2: 464–465 ABCC2, 2: 168–169 ABC transporter superfamily: ABCG2, 2: 169 ABCB1 subfamily: multidrug resistance, 2: 169–170 cancer drug resistance, 2: 167 food-drug interactions, cruciferous vegetables, 4: pharmacogenetics, 4: 390–393 496 SNP effects, 2: 176–178 functional modulation: ABCC1 subfamily: adjuvant therapies, 2: 172–173 cancer drug resistance, 2: 168 molecular mechanisms, 2: 171–172 SNP effects, 2: 178 future research issues, 2: 181–182 ABCC1 subfamily, glutathione transport, 2: genetically modified animal models, 3: 165–166 666–667 ABCC2 subfamily, cancer drug resistance, 2: 168 genetic polymorphisms: ABCG2 subfamily: basic principles, 2: 174–176 cancer drug resistance, 2: 168 disease states, 2: 179–181 SNP effects, 2: 178 SNP effects: adverse drug reactions, 2: 171 ABCB1, 2: 176–178 biotransformation, 6: 7 ABCC1, 2: 178 “phase 3” activation, 6: 12–13 ABCG2, 2: 178–179 blood-brain barrier penetration, in vitro studies, 3: herb-drug interactions, 4: 500–501 574–576 in vivo human studies, 4: 504–505 classification, 2: 156–158 oral absorption mechanisms, bioavailability dietary supplement-drug interaction: studies, 2: 477–480 black cohosh, 4: 507 oral chemotherapeutic agents, intestinal ABCB1 Echinacea spp., 4: 509–510 efflux, 6: 503–506 garlic, 4: 512–513 overview, 2: 155–156 Ginkgo biloba, 4: 515–516 pediatric drug metabolism, 6: 560–562 ginseng, 4: 517–518 pharmacogenetics, 4: 390–393 goldenseal, 4: 520 plant secondary metabolites, 4: 488–494 kava kava, 4: 521–522 pregnancy drug metabolism and, 2: 938–945 milk thistle, 4: 527–528 protein structure and function, 2: 156, 159–161 piperine/black pepper, 4: 523–524 small molecule transport: St. Johns wort, 4: 532 glutathione, ABCC subfamily activity, 2: Schisandra spp., 4: 525–526 165–166 distribution mechanisms,COPYRIGHTED2: 125–128 substrate MATERIAL specificity, 2: 161–165 drug-drug interactions: vesicular drug accumulation, 2: 166 influence on, 2: 171 transcriptional regulation, 2: 173–174 orally administered drug absorption or vectorial transport, 2: 550–558 elimination, 6: 161–162 Abiraterone, oral chemotherapeutic agents, 6: 525 drug metabolism, 4: 641–645 Absolute bioavailability: drug resistance, 2: 167–170 calculation of, 2: 458–459 cancer drugs: defined, 2: 457

Encyclopedia of Drug Metabolism and Interactions, 6-Volume Set, First Edition. Edited by Alexander V. Lyubimov. © 2012 John Wiley & Sons, Inc. Published 2012 by John Wiley & Sons, Inc.

651 652 INDEX

Absolute quantification (AQUA) of protein platform, saw palmetto, 2: 822 proteomics analysis, 4: 323–325 Siberian ginseng, 2: 823 Absorption, distribution, metabolism, excretion US herb use, 2: 812–826 (ADME) studies: valerian, 2: 825 assays, 2: 20–33 distribution role in, 2: 107–108 in silico studies, 2: 20, 23–24 DNA microarrays, 3: 320–324 in vitro studies, 2: 24–32 drug discovery and development: cytochrome P450 enzymes: absorption, 2: 33–34 identification/mapping, 2: 28–29 CYP 450 inhibition, 3: 15 induction, 2: 30–31 distribution, 2: 34–35 inhibition, 2: 29–30 drug candidate selection: metabolism, 2: 25–28 extrinsic attenuating factors, 3: 52–53 permeability/transporters, 2: 24–25 intrinsic attenuating factors, 3: 52 reactive intermediate trapping, 2: 28 Lipinski’s “rule of five” and, 3: 47–54 solubility, 2: 24 natural products, 3: 54 transgenic mice, DDI prediction, 2: 31 Pajouhseh’s “rules,” central nervous system in vivo studies, 2: 32–33 compounds, 3: 48–49 cancer therapy: physicochemical properties, 3: 47–54 carboplatin and hyperbaric oxygenation, 2: research background, 3: 43–47 848–849 human metabolism studies, 3: 20–21 future research issues, 2: 849 hybrid mass spectrometry, 5: 180–181 irinotecan and UGTs, 2: 847–848 induction screening, 3: 14–15 letrozole, CYP2A6 and, 2: 843–844 lead optimization and identification, 2: 6-mercaptopurine, 2: 848 746–749 research background, 2: 841–842 metabolite identification, 3: 62–65 tamoxifen, CYP2D6, 2: 844–846 multiparameter optimization, 3: 70–71 tegafur, CYP2A6 and, 2: 842–843 oral drug requirements, 3: 8–10 thalidomide and CYP3A4/5, 2: 846–847 overview, 2: 33–36 thiopurine-S-methyltransferase, 2: 848 pharmacokinetics improvements, 3: 71–80 defined, 2: 4–6 plasma protein binding, 3: 16–17, 5: 658–660 dietary supplements: prodrug use and abuse, 3: 18–20 aloe, 2: 812–813 research background, 3: 3–6 bitter orange, 2: 813 in silico modeling, 3: 65–70 black cohosh, 2: 813–814 solubility, permeability, and metabolic stability, cranberry, 2: 814 3: 15–16 curcumin, 2: 814–815 stages of, 3: 4–6 danshen, 2: 815 target space properties, 3: 6–8 dong quai, 2: 815–816 tissue distribution, 3: 61–62 echinacea, 2: 816 in vitro-in vivo correlation, 3: 17–18 evening primrose oil, 2: 816 failures, DDI prediction, 2: 11–12 future research issues, 2: 825–826 in vitro studies, 3: 11–14 garlic, 2: 816–818 compound progression, 3: 11–13 ginger, 2: 8181 CYP induction, 3: 59 Gingko biloba, 2: 818–820 drug candidate selection, 3: 54–60 ginseng, 2: 813 drug-drug interactions, 3: 57–58 green tea, 2: 820 linear/nonlinear processes, 3: 13–14 herb-drug interactions: metabolic stability, 3: 55–57 assessment, 2: 807–809 permeability, 3: 55 CYP induction, 2: 812 phenotyping, 3: 57 CYP inhibition, 2: 811–812 plasma protein and tissue binding, 3: 59 transporter-associated absorption, 2: 809–811 transport assays, 3: 59–60 underlying mechanisms, 2: 809–812 in vivo studies, 3: 60–61 kava kava, 2: 820–821 drug-drug interactions, 2: 15–19 licorice, 2: 821 drug-metabolizing enzymes: milk thistle, 2: 821–822 induction, 2: 17–18 regulatory issues, 2: 796–807 inhibition, 2: 16–17 research background, 2: 793–796 transporter interaction, 2: 18 St. John’s wort, 2: 823–825 high-throughput screening assays, 6: 165–166 INDEX 653

plasma protein binding, 2: 18–19 in vitro studies, 2: 31–32 predictive studies, 6: 154–155 protein lysate array technologies, 3: 318 in vitro-in vivo correlation failures, 2: 11–12 quantitative whole-body autoradiography, 5: in vitro studies: 380–381 plasma protein binding, 2: 31–32 safety testing, stable metabolites, 3: 223–227 transgenic mice, DDI prediction, 2: 31 solubility and dissolution assessment, oral drug metabolism, 1: 32–33 absorption, research background, 3: 494–495 basic principles, 2: 247–256 toxicity studies, 2: 19 drug-metabolizing enzymes: metabolite prediction, 2: 14–15 induction, 2: 17–18 natural toxins: inhibition, 2: 16–17 aflatoxins, 2: 918–920 polymorphism of, 2: 19 α-aminitin, 2: 925–926 transporter interaction, 2: 18 aristolochic acid, 2: 920–922 early drug development, radiolabeled studies, 3: arsenic, 2: 922–923 110 germander, 2: 927 flavin-containing monooxygenases: Ibotenic acid and muscimol, 2: 925–926 academic drug development, 1: 281–283 pyrrolidizine alkaloids, 2: 926–927 overview, 1: 279–281 research background, 2: 917–918 future research issues, 2: 36 selenium, 2: 923–925 hepatic drug metabolism, 6: 312 translational drug discovery, 2: 745–746 high throughput quantitative mass spectrometry, Biopharmaceutical Drug Disposition mass analyzer tuning and selection, 5: Classification System, 2: 763–764 553–555 clearance concepts, 2: 761–763 human metabolites: LC-MS/MS advances, 2: 764–768 prediction, 2: 13–15 Simcyp predictions, 2: 763–764 safety testing, 2: 19–20 in vivo studies: human pharmacokinetic prediction, 2: 12–13 chimeric mouse model, 1: 54–55 hybrid mass spectrometry, drug discovery and current research, 3: 592–593 development, 5: 180–181 research background, 3: 592–593 mass balance studies, 2: 416–417 Absorption mechanisms. See also Oral absorption animal studies, 2: 418–420 defined, 2: 5 metabolic stability, 2: 10 dietary supplements, absorption effects, 2: MIST guidelines: 797–805 development plan modifications, 4: 208–210 distribution alterations, 2: 143 human carbon-14 study, 4: 215 drug discovery and development, 2: 33–34 industrial ADME research, 4: 206–207 early drug development, labeling issues, 3: 114 overview, 2: 3–4 hepatic drug metabolism, liver transplant patients, pharmacogenetics, 4: 378–379 6: 333 ADME-related genes, 4: 380 herb-drug interactions, transporter mechanisms, 2: drug transport proteins, 4: 389–393 809–811 pharmacokinetics data analysis and modeling: intestinal absorption: blood data, noncompartmental analysis, 2: ADME studies, 2: 5 602–603 alimentary canal, 2: 46–54 future research issues, 2: 633–634 absorption sites and barriers, 2: 52–54 plasma studies, 2: 608–633 protective and absorptive interfaces, 2: 50–52 radioactive dose recovery, 2: 600–602 anatomical and physical parameters, research renal clearance, 2: 603–606 background, 2: 45–46 research background, 2: 599–600 enterohepatic recirculation, 2: 72–73 urine data, 2: 603–607 future research issues, 2: 73 physicochemical properties, 2: 6–10 gastrointestinal tract: molecular weight and lipophilicity, 2: 6 motility and transit times, 2: 64–67 permeability, 2: 7–10 regional dimensions, 2: 60–64 solubility and dissolution, 2: 7 linear dimensions, 2: 60 physiologically-based pharmacokinetic modeling, relative surface areas, 2: 63–64 6: 585–594 surface areas, 2: 60–63 plasma protein binding, 2: 10–11 lumenal contents: drug discovery and development, 5: 658–660 bacterial flora and coprophagy, 2: 71 drug-drug interaction, 2: 18–19 bile and bile salts, 2: 70–71 654 INDEX

Absorption mechanisms. See also Oral absorption inflammation and, 3: 194–196 (Continued) hepatotoxicity, 3: 192–193 physicochemical characteristics, 2: 68–70 cytochrome P450 enzymes: vascularity, 2: 54–59 CYP2E, 1: 258–260 blood flow, 2: 54–55 dealkylation reactions, 4: 15–18 lymphatic flow, 2: 55–56 metabolic activation, 4: 34–37 segregation routes, 2: 56–59 drug-drug interactions, CYP-mediated induction, oral absorption: 4: 443–444 bioavailability studies, 2: 470–480 electrochemical liquid chromatography mass MDR1 impact on, 2: 90–91 spectrometry, reactive intermediates, 5: pharmacokinetics: 319–320 basic principles, 3: 72–80 food-drug interactions, cruciferous vegetables, 4: modeling, 2: 515, 6: 586–588 494–496 dermal absorption, 6: 588 hepatotoxicity: inhalation, 6: 588 drug-drug interactions, 4: 3–4 oral absorption, 6: 586–588 reactive intermediate formation, 4: 166–172 plasma studies, 2: 608–618 metabolic pathways, 4: 238–239 UGT enzymes, 6: 252–254 metabonomics analysis, 4: 290 in vivo studies, 2: 32–33 pediatric drug metabolism, hydrolytic metabolism, Absorptive transporters, distribution mechanisms, 2: 6: 550–551 129 phase I metabolism, soft drug development, 6: Absorptivity, MALDI-MS techniques, 5: 125 356–357 Academic drug development, flavin-containing prostaglandin H synthase bioactivation, 4: 80–81 monooxygenases, ADMET studies, 1: 281–283 sulfotransferases, drug-drug interactions, 1: 547 Accelerator mass spectrometry (AMS): UGT enzyme bioactivation, toxicity prevention, 6: bioavailability estimations, 2: 461–462 261–262 biotransformation pathway predictions, in vivo in vitro toxicity screening, hepatic drug human studies, 6: 197–198 metabolism, 4: 237–239 blood-brain barrier penetration, in vivo studies, 3: 2-Acetylaminofluorene (2-AAF): 571–572 glucuronidation, 4: 119–121 early drug development, clinical pharmacology, 3: sulfonation, 4: 124–126 102 N-Acetylation: mass balance studies, animal studies, 2: 426 metabolic pathways, 4: 105–108 metabolite identification, 3: 166 phase-II-enzyme-catalyzed xenobiotic conjugation, microdose studies, 5: 602–614 4: 126–129 biotransformation and conjugate formation, 5: aromatic amines-benzidine, 4: 128–129 612–613 aromatic hydrazines, 4: 127 carbon-14 measurement, 5: 604–606 Acetylcholinesterase, genetically modified animal drug discovery and development, 5: 606–610 studies, 3: 650–652 drug-ligand binding and subcellular localization, Acetylenes, cytochrome P450 catalytic cycle, 1: 5: 614 193–194 pharmacokinetics, 5: 611–612 Acetylhydrazine, isoniazid-induced toxicity, 4: 575 reactive metabolite determination, 5: 614 Acetyltransferase (ACT), intestinal metabolism, MIST guidelines, human studies, 4: 216 Caco-2/TC7 cell line comparisons, 3: 339–340 multiple analyte assays, MIST guidelines, 5: Acidic drugs: 498–500 distribution mechanisms, 2: 109–112 safety testing, stable metabolites, 3: 224–227 oral absorption, bioavailability studies, 2: ACE inhibitors, ADME studies, 2: 879–880 475–476 Acetaminophen (APAP): Acrolein, allyl alcohol bioactivation, 4: 75–76 age-dependent drug metabolism, CYP2E1 Action potential, pharmacodynamics mechanisms, expression, 4: 459–460 ion channels, 2: 688–689 bioactivation and oxidative stress, oxidative stress, Activator mechanisms, carboxylesterases, 1: 3: 192–198 434–438 cellular consequences, 3: 193–194 Active metabolites. See also Reactive metabolites circadian rhythm, 3: 197–198 bioequivalence studies, 2: 467 drug-induced liver injury: cytochrome P450: animal studies, inflammatory response, 3: bioactivation, 4: 18–23 196–197 consequences of formation, 4: 26–27 INDEX 655

identification of, 3: 124 amino acid conjugation, mitochondrial medium MIST guidelines, 2: 595 chain acyl-CoA synthetases, 1: 597–602 pharmacology, 1: 19 phase II metabolism, 2: 288–290 phase I metabolism, 6: 357–360 Acyl glucuronides: benzodiazepines, 6: 357 analysis and quantitation, 1: 471–472 codeine, 6: 358 bioactivation and oxidative stress, 3: 200–204 drug-metabolite-bioactivation continuum, 6: 355 reactive metabolites, 3: 201–203 tamoxifen, 6: 359–360 toxicity mechanisms, 3: 203–204 tramadol, 6: 358–359 phase-II-enzyme-catalyzed xenobiotic conjugation, Active oxygenating species, cytochrome P450 4: 109–118 catalytic cycle, 1: 186–188 safety testing: Active retroviral (ARV) therapy, allometric scaling reactive metabolites, 3: 233–237 pharmacokinetics, 2: 509–510 stable metabolites, 3: 225–227 Active site characterization: UGT biotransformation, toxicity studies, 6: cytosolic glutathione transferases, 1: 577–579 259–260 peptide and protein therapeutics, 2: 899–901 S-Acyl-glutathione thioester adducts, phase II metabolism, N-acetyltransferase, 2: carboxylic-acid-containing drugs, 4: 139–140 287–288 Adaptation, idiosyncratic drug-induced reactions, 4: UGT isoforms: 568–570 UGT1A1, 1: 474–475 Additivity, micellar electrokinetic chromatography, UGT1A3, 1: 476 5: 425 UGT1A4, 1: 478 Adenylate cyclase/cAMP system, pharmacodynamics UGT1A6, 1: 480–481 mechanisms, 2: 690 Adjuvant therapies, ABC protein function, 2: UGT1A8, 1: 483 172–173 UGT1A9, 1: 484–485 ADME studies. See Absorption, distribution, UGT1A10, 1: 486 metabolism, excretion (ADME) studies UGT2B4, 1: 488 Administration methods and formulation. See also UGT2B7, 1: 489, 491 Drug delivery systems UGT2B10, 1: 492–493 bioavailability, research background, 2: 457 UGT2B15, 1: 494–495 dose calculations and, 6: 612 UGT2B17, 1: 496 mass balance studies, animal studies, 2: 420–421 Active transport: oral bioavailability, 2: 82–83 pharmacogenetics, drug transport proteins, 4: β-Adrenergic blockade, ADME studies, 2: 876–878 389–393 Adulterants, phytochemicals, 4: 505–506 in vivo studies, renal clearance, 3: 609 Adverse drug reactions (ADRs). See also Activity-based biomarkers, pharmacodynamics Drug-induced liver injury (DILI); Idiosyncratic studies, 2: 701 adverse drug reactions (IADRs) Acute-phase proteins (APPs), drug-disease-drug ABC transporters, 2: 171 interactions: bioactivation: biomarkers, 4: 630 classification, 3: 180–181 chronic diseases, 4: 629–630 non-P450 enzymes, 4: 63–65 liver injury, 4: 628 oxidative stress, 3: 182–188 Acute-phase response (APR): biotransformation, UGTs, 6: 10–11 drug-disease-drug interactions, liver injury, 4: 628 cancer therapies: transcriptional regulation, 4: 649–650 clinical trial/post-market emergence, 3: 30–31 Acyclovir, phase I metabolism, 6: 362–363 miscellaneous toxicities, 3: 35–36 Acyl-adenylates, phase-II-enzyme-catalyzed preclinical studies and prediction of, 3: 37–38 xenobiotic conjugation, 4: 144 metabonomic analysis, 4: 292–293 Acyl-AMP intermediates, phase-II-enzyme-catalyzed microsomal epoxide hydrolase, 1: 401–402 xenobiotic conjugation, 4: 144 pediatric drug metabolism: Acyl-S-CoA formation: clearance and exposure mechanisms, 6: phase-II-enzyme-catalyzed xenobiotic conjugation, 562–563 4: 140–144 clinically relevant drug-drug interactions, 6: acyl-adenylates, 4: 144 563–566 S-acyl-coA thioesters, 4: 142–144 reactive intermediates, table of, 3: 178 synthetases, metabolic pathways, 4: 106–108 reactive metabolite bioactivation, 5: 627–630 Acyl coA synthetases (ACS): stereoselective metabolic activation, 4: 365–366 656 INDEX

Adverse effects, metabolite toxicity, 1: (Continued) age-dependent drug metabolism, 4: 464–465 Adverse effects, metabolite toxicity, 1: 19–20 bioactivation, 4: 75–79 Affinity, pharmacodynamics, 2: 695 abacavir, 4: 77–79 Afla-Guard compound, aflatoxin production and allyl alcohol, 4: 75–76 toxicity, 2: 919–920 felbamate, 4: 76–77 Aflatoxins, production and toxicity, 2: 918–920 extrahepatic metabolism, 2: 342–343 Afloqualone, glucuronosyltransferases and, 1: age and gender differences, 2: 350 141–143 genetically modified animal models, 3: 647–649 Age-dependent drug metabolism. See also Elderly; pediatric drug metabolism, 6: 549–550 Pediatric populations Alcoholism, hepatic drug metabolism: alcohol dehydrogenase, 4: 464–465 acute alcohol ingestion, 6: 322 aldehyde oxidase, 4: 465 chronic alcohol ingestion, 6: 322–323 carboxylesterases, 4: 466 drug disposition and elimination, 6: 323 cytochrome P450 enzymes, 4: 454–462 parenchymal disease, 6: 321–322 CYP1A2, 4: 454–455 pharmacodynamics, 6: 323 CYP2A, 4: 455–456 Alcohols, ketone reduction to secondary alcohol, 4: CYP2B6, 4: 456 354–355 CYP2C, 4: 456–458 Aldehyde carbamate, felbamate bioactivation, 4: 77 CYP2D6, 4: 458–459 Aldehyde dehydrogenase (ALDH), genetically CYP2E1, 4: 459–460 modified animal models, 3: 647–649 CYP3A, 4: 460–462 Aldehyde oxidase (AO): activity variation, 1: 338–344 dose calculations and, 6: 612 ADME studies, pharmacokinetics, 3: 78–80 epoxide hydrolase, 4: 466–467 age-dependent drug metabolism, 4: 465 extrahepatic drug-metabolizing enzymes, 2: 344, classification, 1: 308–310 350 genetically modified animal models, 3: 644 flavin-containing monooxygenases, 4: 462–464 genetics, 1: 312–315 future research issues, 4: 472–474 human studies, 1: 335–336 glutathione S-transferase, 4: 467–469 inhibitors, 1: 331–333 physiological factors, 4: 452–454 monoamine oxidase bioactivation, 4: 71–74 physiologically-based pharmacokinetic modeling, ontogenic expression, 1: 343–344 whole body model, 2: 667–670 overview, 1: 305–306 research background, 4: 451–452 phase I metabolism, 2: 267–269 4: sulfotransferase, 469–470 regulators and inducers, 1: 342–344 UDP glucuronosyltransferase, 4: 471–472 species differences, 1: 336–338 Agonists, pharmacodynamics, 2: 693–694 structure and function, 1: 307–312 inverse agonists, 2: 694–695 in vivo studies, clearance processes, 3: 607–608 partial agonists, 2: 694 xenobiotic biotransformation, 1: 315–331 Agranulocytosis: aldehyde oxidation, 1: 320–321 amodiaquine-induced, 4: 581–582 aromatic N-heterocycle oxidation, 1: 315–320 drug-induced, 6: 422–423 heterocycle reduction, 1: 329–331 myeloperoxidase bioactivation, 4: 83–85 N-hydroxy reduction, 1: 328–329 Alanine aminotransferase (ALT): iminium ion oxidation, 1: 321–324 biomarkers, drug-induced liver injury, 4: 187–192 nitrate/nitrite reduction, 1: 326–327 drug-induced liver injury, 6: 421 nitroreduction, 1: 324–326 idiosyncratic drug-induced liver injury, failure to N- and sulfoxide reduction, 1: 327–328 adapt hypothesis, 4: 599–600 reduction, 1: 324 mitochondrial toxicity, 6: 430–431 Aldehyde oxidation, AO/XOR-mediated reactions, ticrynafen-induced hepatotoxicity, 4: 576 1: 320–321 toxicogenomics: Aldehyde substrates, AO/XOR-mediated reactions, carcinogenicity prediction, 4: 260 1: 321, 325 hepatotoxicity prediction, 4: 256–257 Aldo-ketoreductases (AKR): xenobiotic metabolism, hepatocyte assessment, bioactivation, 4: 86–87 hepatotoxicity assays, 3: 430–432 pediatric phase I metabolism, 6: 550 Albumin effect, uridine diphosphate phase I metabolism, 2: 276–278 glucuronosyltransferases, 1: 468–469 Aldose reductase (AR), extrahepatic metabolism, 2: Albuterol, pharmacology and toxicity, 4: 363 342–343 Alcohol dehydrogenase (ADH): Alendronic acid, ADME studies, 3: 49 INDEX 657

Alimentary canal, intestinal absorption, 2: 46–54 drug discovery and development, 5: 665–670 absorption sites and barriers, 2: 52–54 research background, 2: 532–536 protective and absorptive interfaces, 2: 50–52 Alpidem, toxicity studies, structure-toxicity Aliphatic amines: relationships, 6: 383–384 allylamine, bioactivation, 4: 74–75 Alprazolam: flavin-containing monooxygenase metabolism: cytochrome P450 enzymes, active metabolic secondary amines, 1: 297 actions, 4: 18, 20 tertiary amines, 1: 296–297 drug-drug interactions, probe substrates, 6: Aliphatic hydroxylation, cytochrome P450 enzymes: 119–120 bioactive metabolites, 4: 11–15 Alternative splicing, glutathione transferase biotransformation reactions, 6: 56 transcripts, 1: 565 Aliphatic oxidation, cytochrome P450 enzymes, Alvimopan, oral absorption, bioavailability studies, phase I metabolism, 2: 256–259 2: 475–476 Aliskiren, Lipinski’s rule-of-five and, 3: 53–54 Alzheimers, glutathione transferase superfamily, Alkenes, cytochrome P450 bioactivation, covalent omega class polymorphisms, 1: 575 modification, 4: 47–48 Ambient ionization mass spectrometry: Alkylating agents, oral chemotherapy, 6: 508–517 applications, 5: 103, 106–112 Alkynes, cytochrome P450 bioactivation, covalent explosives, 5: 103, 106 modification, 4: 47–48 imaging mass spectrometry, 5: 108–112 Allele specificity, monoclonal antibodies, 3: pharmaceuticals and counterfeit drugs, 5: 452–453 106–108 Allergic reactions, idiosyncratic drug-induced future research issues, 5: 112–113 reactions, 4: 566–570 high throughput applications, 5: 567–570 All-in-One mass spectrometry, metabolite laser-assisted desorption electrospray ionization, fragmentation, 5: 197–201 5: 97–101 All-ion fragmentation (AIF), hybrid instrumentation, liquid extraction surface analysis, 5: 77–78 5: 199–201 remote sampling, 5: 101–102 Allometric scaling: research background, 5: 87–88 hepatic drug metabolism, in vivo human techniques, 5: 89–90 pharmacokinetics, 3: 357–358 Ames genotoxicity assay, 2: 774 predictive pharmacokinetics, 2: 496–509 Amide drugs, carboxylesterases, hydrolytic human clearance prediction, 2: 497–501 metabolism, 1: 424–426 nonlinear mixed effects modeling, 2: 508–509 Amine oxidases: in vitro metabolic clearance and, 2: 501–503 bioactivation, 4: 71–75 volume distribution in humans, 2: 501–508 monoamine oxidase, 4: 71–74 in vivo studies, clearance mechanisms, 3: 603–605 dopamine, 4: 72–74 Allopurinol: tetrahydropyridines, 4: 71–72 drug-drug interactions, 6-mercaptopurine, 6: semicarbazide-sensitive amine oxidase, 4: 91–92 74–75 molybdenum-containing hydroxylases, XOR allylamine, 4: 74–75 inhibitors, 1: 333–335 classification, 1: 366–375 Allosterism: copper-containing amine oxidases, 1: 367–373 drug-drug interactions, 4: 424–425 amine oxidase, 1: 369 non-Michaelis-Menten enzyme kinetics, 1: 81–87 plasma AOs, 1: 371–373 Allylamine, bioactivation, 4: 74–75 retina-specific (RAO), 1: 369–370 Allylic alcohol: semicarbazied-sensitive AOs, 1: 370–371 bioactivation, 4: 75–76 flavin-containing amine oxidases, 1: 373–375 sulfonation, 4: 123–124 future research issues, 1: 384–385 Aloe, herb-drug interactions, ADME studies, 2: overview, 1: 365–366 812–813 Amine reductases, overview, 1: 365–366 α/β-domain (ABD), epoxide hydrolases, 1: 394–395 Amines: α1-Acid glycoprotein (AAG): N-acetylation, 4: 126–129 distribution mechanisms, plasma protein binding, aromatic, bioactivation, 4: 81–82 2: 118–119 cytochrome P450 bioactivation: equilibrium dialysis, 2: 539–540 heteroatom oxidation, 6: 59–60 pediatric drug metabolism, 6: 555–558 N-oxidation, aromatic amines, 4: 27–28 pharmacokinetic modeling, 6: 589 extrahepatic metabolism, toxicity studies, 2: plasma protein binding: 374–376 658 INDEX

Amines (Continued) solubility and dissolution assessment, oral flavin-containing monooxygenase metabolism, 1: absorption, high energy solids, 3: 534–535 292–298 Amphipathic chemicals, biotransformation, 6: 6–7 aliphatic amines, 1: 296–297 Anabolism, drug metabolism and, 1: 4 cyclic amines, 1: 295 Analysis of variance (ANOVA), proteomics, primary amines, 1: 297–298 label-free protein quantification, 4: 331–332 tertiary amine to N-oxide, 4: 357 Anatomical metabolism sites, drug metabolism, 1: α-Aminitin, ADME and toxicity studies, 2: 925–926 21–23 Amino acid adducts, reactive metabolite Androgen, sex-dependent hepatic drug metabolism, bioactivation, 5: 635–637 1: 107 Amino acid conjugation: Anemia, idiosyncratic adverse drug reactions, 6: biotransformation, 6: 11–12 421–422 cytochrome P450 polymorphisms: Anesthesia: CYP1A, species differences, 1: 124 cirrhosis and, 6: 330–331 CYP1A2, 1: 247 idiosyncratic adverse drug reactions, classification CYP1B, 1: 248 criteria, 6: 434 CYP2A, species differences, 1: 129–131 structure-toxicity relationships, 6: 381–382 3: future research issues, 1: 606 Angiogenesis inhibitors, development of, 28 Angiotensin II, soluble epoxide hydrolase, 1: 411 glucuronosyltransferases (UGTs), 1: 141–143 Angiotensin receptor blockers (ARBs), ADME life span aspects, 1: 605–606 studies, 2: 880–882 phase II metabolism, 6: 217–218 Animal-plant warfare hypothesis: xenobiotic carboxylic acid metabolism: drug metabolizing enzymes, cytochrome P450s, 1: mechanisms for, 1: 596–597 127–128 mitochondrial acyl-coA:glycine phytochemical modulators, 4: 487–488 N-acyltransferase, 1: 602–605 Animal studies. See also specific animals, e.g. inhibitors, 1: 605 Mouse studies structure-activity relationships, 1: 603 alimentary canal, 2: 49–51 in vivo conjugation, 1: 603–605 allometric scaling pharmacokinetics, 2: 497–501 xenobiotic substrates, 1: 603 biotransformation pathway predictions, 6: mitochondrial medium chain acyl-CoA 188–194 1: synthetases, 597–602 radiolabeled compounds, 6: 190–194 inhibitors, 1: 602 species selection, 6: 188–189 structure-activity relationships, 1: 600–602 unlabeled compounds, 6: 189–190 substrates, 1: 599–600 carboxylesterases, human interactions, 1: 446–448 overview, 1: 595–596 cytochrome P450 enzymes: Amino acid transporters: dog enzymes, 6: 73–74 light/catalytic chains, 2: 197 drug discovery and development, 6: 61–76 peptide and protein therapeutics: human enzymes, 6: 61–69 extension techniques, 2: 907 monkey enzymes, 6: 74–76 half-life increase, 2: 903–904 mouse enzymes, 6: 69–71 Amiodarone: rat enzymes, 6: 71–73 cardiovascular drug metabolism, 2: 878 transcriptional regulation, species-related cytochrome P450 polymorphisms, CYP2C8, 1: differences, 1: 223–224 253–254 cytosolic glutathione transferases, classification, 1: Amitriptyline: 562–563 CYP1A2 metabolism, 6: 466 distribution mechanisms, in vivo studies, 2: CYP2C9 metabolism, 6: 464–465 135–136 Amodiaquine: early drug development, transition to human cytochrome P450 enzymes, metabolic activation, studies, 3: 93–99 4: 34–37 flavin-containing monooxygenases, 1: 286–287 cytochrome P450 polymorphisms, CYP2C8, 1: gastrointestinal tract, regional dimensions, 2: 253–254 60–64 hepatotoxicity and agranulocytosis, 4: 581–582 genetically modified models, drug metabolism and toxicity studies, reactive metabolite toxicity transport: elimination and minimization, 6: 387–390 chimeric-humanized liver models, 3: 628–630 Amorphous solids: cytochrome P450, 3: 630–640 defined, 3: 510 CYP1A, 3: 631–633 INDEX 659

CYP2D6, 3: 633–635 acetaminophen bioactivation, 3: 196–198 CYP2E1, 3: 635–637 drug-inflammation interaction, 4: 605–612 CYP3A, 3: 637–640 inflammatory stress hypothesis, 4: 607–610 drug-metabolizing enzymes, 3: 620–622 model comparisons, 4: 610–612 epoxide hydrolases, 3: 640–644 sulindac, 4: 606–607 microsomal epoxide hydrolase, 3: 640–642 future research issues, 4: 612–613 soluble epoxide hydrolase, 3: 642–644 inflammatory response, 4: 601–605 esterases, 3: 650–652 hemostatic system and hypoxia, 4: 603–604 flavin monooxygenases, 3: 649 neutrophils, 4: 604–605 future research issues, 3: 677 reactive oxygen species, 4: 605 humanized mice, 3: 628 tumor necrosis factor-α, 4: 602–603 induction studies, 3: 623–624 proposed mechanisms, 4: 597–601 knock-out (null) models, 3: 627–628 danger hypothesis, 4: 599 nomenclature, 3: 619 failure to adapt hypothesis, 4: 599–600 nuclear receptors, 3: 657–666 hapten hypothesis, 4: 598 aryl hydrocarbon receptor, 3: 665–666 inflammatory stress hypothesis, 4: 600–601, constitutive androstane receptor, 3: 659–661 607–608 farnesoic X-activated receptor, 3: 663–664 metabolic polymorphism hypothesis, 4: multiple nuclear receptor studies, 3: 664–665 597–598 peroxisome-proliferator-activated receptors, mitochondrial dysfunction hypothesis, 4: 599 3: 661–663 multiple determinant hypothesis, 4: 600 pregnane X receptor, 3: 658–659 research background, 4: 595–597 oxidases, 3: 644–649 liquid scintillation counting assays, organ alcohol and aldehyde dehydrogenases, 3: dissection and homogenization, 5: 364–366 647–649 liver slices: aldehyde oxidase, 3: 644–645 CYP induction studies, 3: 472–475 monoamine oxidases, 3: 645–647 phase II enzyme induction, 3: 479–480 research background, 3: 617–619 luminal content analysis, 2: 68–71 sulfotransferase, 3: 656–657 mass balance studies: transporters, 3: 625–626 clinical goals and aims, 2: 417 bile salt export pump, 3: 676–677 pharmacokinetic parameters, 2: 431–434 breast cancer resistant protein, 3: 668–669 preclinical studies: multidrug resistance protein, 3: 669–672 case study, 2: 435–438 organic anion transporters, 3: 675–676 experimental design, 2: 418–430 organic anion transporting polypeptides, 3: biliary excretion, 2: 427–428 672–674 blood and plasma matrices, 2: 422 organic cation transporters, 3: 674–675 carcass and carbon dioxide exhalation, 2: P-glycoproteins, 3: 666–668 428–430 UGTs, 3: 652–656 dose, administration route, and formulation, glucuronosyltransferases (UGTs), 1: 141–143 2: 420–421 idiosyncratic adverse drug reactions, 4: 571–582 excreta and cage wash, 2: 422–425 acetaminophen-induced hepatotoxicity, 4: 576 matrix selection, 2: 421–430 amodiaquine-induced hepatotoxicity and species selection, 2: 418–420 agranulocytosis, 4: 581–582 tissues and organs, 2: 425–427 felbamate-induced hepatotoxicity and aplastic research issues and methodology, 2: 438–440 anemia, 4: 582 radiolabeled compounds, use, selection criteria halothane-induced hepatotoxicity, 4: 573–574 and limitations, 2: 430–431 isoniazid-induced hepatotoxicity, 4: 574–575 research backgound, 2: 415–416 mitochondrial superoxide heterozygote mouse microautoradiography, 5: 383–388 model, 4: 577 physiologically-based pharmacokinetic modeling, nevirapine-induced skin rash, 4: 580–581 blood flow and tissue volume, 2: 640–641 D-penicillamine-induced autoimmunity, 4: 578 phytochemicals, 4: 504 procainamide-induced lupus, 4: 579–580 preclinical studies, 1: 50–51 propylthiouracil-induced autoimmunity, 4: regulatory issues, stability guidelines, 5: 487–490 578–579 solubility and dissolution assessment, oral sulfonamide-induced hypersensitivity, 4: 573 absorption, rate-limiting steps, 3: 498–501 ticrynafen-induce hepatotoxicity, 4: 575–576 species differences, 1: 51–52 idiosyncratic drug-induced liver injury: CYP1A, 1: 128–129 660 INDEX

Animal studies. See also specific animals, e.g. fragments, peptide and protein therapeutics, Mouse studies (Continued) attachment mechanisms, 2: 905 CYP2A enzymes, 1: 129–131 immunoassays: CYP2B enzymes, 1: 131–133 research background, 5: 395–397 CYP2C enzymes, 1: 133–135 selection criteria, 5: 398–399 CYP2D enzymes, 1: 135–137 soluble target assays, 5: 406 CYP2E metabolism, 1: 137–138 microarrays, cellular signaling, 3: 318 CYP3A enzyme, 1: 137, 139–141 pharmacokinetics and targeting mechanisms, 2: tissue distribution assays, whole-body assays, 5: 911–912 363–364 structure, 2: 907–908 toxicogenomics, 4: 254–255 as therapeutic proteins, 2: 907–912 carcinogenicity prediction, 4: 257–260 neonatal Fc receptor recycling, 2: 909–911 hepatotoxicity prediction, 4: 257 Anticancer therapy. See Cancer therapy in vivo studies: Anticoagulants: distribution mechanisms, extrapolation to age-dependent metabolism, CYP2C expression, 4: humans, 3: 599 457–458 drug metabolism models, 3: 612–613 CYP2C9 metabolism, 6: 464–465 food-drug interactions, 3: 597–598 dietary supplement-drug interaction, ginseng, 4: oral absorption and bioavailability, 3: 595–596 518 human models based on, 3: 596–597 herb-drug interactions: ANIT compound: garlic, 2: 818, 6: 287 metabonomic identification, 4: 298–299 gingko biloba, 6: 287 α-naphthylisothiocyanate-induced intrahepatic ginseng, 6: 288 cholestasis, 4: 137–138 St. John’s wort, 6: 284–285 “A Notice of Proposed Rule” (ANPR), dietary monoclonal antibody enantiomer specificity, 3: supplements regulation, 2: 806 453–454 Antagonists, pharmacodynamics, 2: 695–697 pharmacogenetics testing, 6: 26 Antiacids, oral chemotherapeutic agents, 6: 506 Anticonvulsants: Anti-anxiety agents: age-dependent metabolism, CYP2C expression, 4: buspirone, hepatotoxicity prevention strategies, 4: 457–458 181–182 bioactivation: cytochrome P450 enzymes, active metabolic felbamate, 4: 76–77 actions, 4: 18 hydantoins, 4: 83 toxicity studies: biotransformation, efflux transporters, 6: 7 reactive metabolite toxicity elimination and blood-brain barrier penetration, in vivo studies, 3: minimization, 6: 386–390 568–570 structure-toxicity relationships, 6: 382–384 CYP2C9 metabolism, 6: 464–465 Antiarrhythmics: cytochrome P450 enzymes, active metabolic ADME studies, 2: 874–879 reactions, 4: 18–32 β-adrenergic blockade, 2: 876–878 hepatotoxicity: calcium channel blockade, 2: 879 felbamate-induced toxicity, 4: 582–583 class I agents, 2: 874–876 risk assessment, 4: 183–185 potassium channel blockade, 2: 878 microsomal epoxide hydrolase, 1: 400–402 drug-drug interactions, therapeutic efficacy, polypharmacy: CYP-mediated effects, 4: 440–441 brivaracetam, 6: 492–493 Antibiotics: carbamazepine, 6: 477–478 food-drug interactions, grapefruit juice, 6: 295 clobazam, 6: 478, 480, 482–483 thrombocytopenia reaction, 6: 422 clonazepam, 6: 483 Antibodies. See also Monoclonal antibodies; enzyme induction, 6: 476–477, 481–482 Polyclonal antibodies enzyme inhibition, 6: 477 anti-cytokine antibodies, drug metabolizing eslicarbazepine acetate, 6: 483 enzymes and drug transporters, 4: 648–649 ethosuximide, 6: 484 anti-drug antibodies (ADAs), immunoassays, 5: felbamate, 6: 484 412 future research issues, 6: 494 antinuclear antibodies (ANAs): gabapentin, 6: 484 D-penicillamine-induced autoimmunity, 4: 578 ganaxolone, 6: 493 procainamide-induced lupus, 4: 579–580 hepatic isoenzymes, 6: 475–476 propylthiouracil autoimmunity, 4: 578–579 lacosamide, 6: 485 INDEX 661

lamotrigine, 6: 485 CYP3A4 metabolism, 6: 467–468 levetiracetam, 6: 485–486 Antithrombotics, ADME studies, 2: 871–874 oral contraceptives and, 6: 480 antiplatelet drugs, 2: 873–874 oxcarbazepine, 6: 486 warfarin, 2: 871–872 pharmacodynamics and pharmacokinetics, 6: Antley-Bixler syndrome, NADPH-oxidoreductase 475 polymorphism, 6: 22 phenobarbital, 6: 486–487 AOC4 gene, plasma amine oxidase, 1: 372–373 phenytoin, 6: 487–488 APAP. See Acetaminophen (APAP) plasma concentrations, 6: 478–479 Apical sodium-dependent bile salt transporter pregabalin, 6: 488 (ASBT): primidone, 6: 488–489 in humans, 2: 198 research background, 6: 473–475 intestinal metabolism, 2: 209 rufinamide, 6: 489 research on, 2: 197 seletracetam, 6: 493 Aplastic anemia: stiripentol, 6: 489–490 drug-induced, 6: 423 talampanel, 6: 493 felbamate hepatotoxicity and, 4: 582 tiagabine, 6: 490 Apoptosis targeted agents, development of, 3: 28 tonabersat, 6: 493 A posteriori modeling: topiramate, 6: 490–491 drug metabolism and interactions, 6: 582–583 valproic acid, 6: 491–492 population modeling of variability, 6: 594–598 valrocemide, 6: 494 Apparent permeability (Papp) calculation, intestinal vigabatrin, 6: 492 metabolism models, passage study protocols, 3: zonisamide, 6: 492 343–345 stereoselective metabolites, enantiotopic oxidation Apparent solubility, defined, 3: 509 to chiral metabolite, 4: 357–358 Apriori modeling: substrate stereoselective metabolism, 4: 352–353 drug metabolism and interactions, 6: 582–583 Antidepressants: physiologically-based pharmacokinetics, 6: CYP1A2 metabolism, 6: 466 583–585 CYP2B6 metabolism, 6: 467 N-Arachidonoyl-4-hydroxyaniline, phase I CYP2C9 metabolism, 6: 464–465 metabolism, 6: 357 CYP2D6 metabolism, 6: 458, 461–463 Area under curve (AUC) ratio: cytochrome P450 enzymes, CYP2C19, 1: 255 absolute bioavailability calculations, 2: 458–460 hepatotoxicity prevention strategies, 4: 182 ADME studies, renal clearance data, 2: 605–607 St. Johns wort, dietary supplement-drug blood-brain barrier penetration, in vivo neuroPK interaction, 4: 529–532 studies, 3: 566–567 stereoselective metabolic activation, 4: 365–366 distribution calculation, 2: 140–142 toxicity studies, structure-toxicity relationships, 6: drug-drug interactions: 382–383 CYP induction, 4: 430–433 Anti-drug antibodies (ADAs), immunoassays, 5: 412 clearance-dependent induction, 4: 434–437 Antiepileptics. See Anticonvulsant agents route-dependent induction, 4: 433–434 Antigen-presenting cells, idiosyncratic adverse drug CYP inhibition, 6: 95–101 reactions, 6: 428 cytochrome P450 inhibition, 6: 157–158 Antigen retrieval, imaging mass spectrometry, drug-metabolizing enzymes, 6: 155–156 sample preparation, 5: 222–226 fraction metabolized by primary enzyme (fmi), Antimetabolites, oral chemotherapeutic agents, 6: 4: 420–421 519–520 intestinal metabolism, 4: 418–420 Antinuclear antibodies (ANAs): predictive studies, 6: 154–155 D-penicillamine-induced autoimmunity, 4: 578 in vitro-in vivo correlation, 4: 414–425 procainamide-induced lupus, 4: 579–580 MIST analysis guidelines, plasma availability and propylthiouracil autoimmunity, 4: 578–579 pooling strategy, 4: 211–212 Antiplatelet drugs, ADME studies, 2: 873 oral bioavailability, 2: 82–83 Antiproliferative agents, hepatic drug metabolism, organ metabolism/transport, 2: 559–564 liver transplant, 6: 337–338 pharmacokinetics/toxicokinetics profiles, 2: Antipsychotics: 584–585 CYP1A2 metabolism, 6: 466–467 physiologically-based pharmacokinetic modeling, CYP2B6 metabolism, 6: 467–468 2: 572–574 CYP2C19 metabolism, 6: 464 intestinal modeling, 2: 653–656 CYP2D6 metabolism, 6: 462–463 liver, 2: 650–652 662 INDEX

Area under curve (AUC) ratio (Continued) Aryl hydrocarbon receptor (AhR): proteomics, multiple reaction monitoring, 4: biotransformation: 334–335 enzyme induction, 6: 16 safety testing, stable metabolites, 3: 222–227 flavin-containing monooxygenases, 6: 12 solubility and dissolution assessment, oral cytochrome P450 genes, transcriptional regulation: absorption: coactivators and corepressors, 1: 210 BDDCS classification, 3: 504–507 human studies, 1: 206–207 excipient effects, 3: 543–544 mechanisms, 1: 209, 213–215 xenobiotic metabolism, hepatocyte assessment, in receptor cross talk, CYP1A1/2, 1: 216 vitro studies, metabolic stability, 3: 397–402 drug conjugation and transport, 6: 225–226 Arenes, epoxidation, 4: 28–34 drug-drug interactions, cytochrome P450 Aripriprazole: induction, 6: 160 CYP2D6 metabolism, 6: 462–463 drug metabolism, 1: 30–31 hepatotoxicity prevention strategies, 4: 181–182 drug-metabolizing enzymes, species differences, Aristolochic acid (AA): 1: 121–123, 125 ADME and toxicity studies, 2: 920–922 genetically modified animal models, 3: 665–666 reductive bioactivation, 4: 88–90 hepatic drug metabolism, CYP enzyme induction, Aromatase inhibitors, oral chemotherapeutic agents, 3: 374–378 6: 524–525 plant secondary metabolites, human studies, 4: Aromatic amines: 491–492 N-acetylation, amine-benzidine, 4: 128–129 sulfotransferases, induction, 1: 544–545 bioactivation: toxicogenomics, hepatic drug metabolism analysis, cytochrome P450, N-oxidation, 4: 27–28 4: 266–270 PGHS levels, 4: 81–82 xenobiotic metabolism, hepatocyte assessment, Aromatic hydrazines, N-acetylation, 4: 127 induction, 3: 410–419 Aromatic hydrocarbon receptor (AhR): Arylhydroxamic acids: cytochrome P450 polymorphisms, CYP1 family, glucuronidation, 4: 118–121 1: 241–248 sulfonation, 4: 124–126 drug-drug interactions: Arylhydroxylamines, sulfonation, 4: 124–126 enzyme induction, 1: 63–65 Aryloxypropanolamines, phase I metabolism, 6: NME-precipitated CYP induction, 6: 109–111 356–357 Aromatic hydroxylation, cytochrome P450 enzymes: Aryl piperazines, bioactivation, 4: 66, 68–69 bioactive metabolites, 4: 11–15 As Low As Reasonably Acceptable (ALARA), mass biotransformation reactions, 6: 56–57 balance human studies, dose calculations, 2: Aromatic N-heterocycles, oxidation, 441–446 AO/XOR-mediated reactions, 1: 315–320 Aromatic oxidation, cytochrome P450 enzymes, Aspartate aminotransferase (AST), xenobiotic phase I metabolism, 2: 260–261 metabolism, hepatocyte assessment, Arsenic, ADME and toxicity studies, 2: 922–923 hepatotoxicity assays, 3: 430–432 Aspirator mobility analyzer, ion mobility mass Arterial concentration (CA), membrane-limited pharmacokinetics model, 2: 647–648 spectrometry, 5: 267 Artesunate: Asymptotic models, pharmacodynamics, disease DESI-MS analysis, 5: 108–109 progression, 2: 726–727 metabolite analysis, 2: 623 Atazanavir, pediatric drug metabolism, drug-drug Artorvastatin, cytochrome P450 bioactive interactions, 6: 566 metabolites, 4: 11–15 Atenolol, ADME studies, 3: 12–13 Arylamines: Atmospheric pressure ionization (API) mass cytochrome P450 bioactivation, N-oxidation, 4: spectrometry: 27–28 analytical standards, 5: 66 N-acetyltransferases (NATs): basic principles, 5: 50 N-acetylation, 4: 126–129 chip-based nano-ESI and, 5: 56–57 drug-disease-drug interactions, 4: 639 image analysis, 5: 109–112 pharmacogenetics, 4: 386–387 matrix suppression, 5: 58–59 Aryl compounds, cytochrome P450 catalytic cycle, metabolite identification, 3: 138–146 1: 193–194 Q-TOF instrumentation, 5: 192–195 Aryl hydrocarbon hydroxylase (ARH), genetically quantitative analysis, 5: 77 modified animal models, CYP1A expression, 3: research background, 5: 546–548 631–633 sensitivity, 5: 58 INDEX 663

Atmospheric pressure solid anlaysis probe (ASAP), CYP2C, 4: 633–634 basic principles, 5: 93–97 CYP2D, 4: 634–635 Atomoxetine, CYP2D6 metabolism, 6: 463 CYP2E1, 4: 635 Atorvastatin: CYP3 subfamily, 4: 636 ADME studies, 3: 49–51 CYP4 subfamily, 4: 637 dose calculations, metabolic pathways and, 6: uridine diphosphate-glucuronosyltransferases, 4: 614–616 638 toxicity studies, reactive metabolite toxicity Bait proteins, protein microarrays, 3: 316–317 elimination and minimization, 6: 389–390 Barbiturates, cirrhosis and, 6: 331 ATP-sensitive potassium ion channel, Barium precipitation assay, sulfotransferases, 1: pharmacodynamics mechanisms, 2: 689 537–538 Atracurium besylate, elimination kinetics, 2: Barriers to metabolism: 628–629 blood-brain barrier: Atropaldehyde, felbamate hepatotoxicity and, 4: 582 distribution barriers, 2: 124–125 Autoactivation, enzyme kinetics, 3: 300–301 permeability/transporters, 2: 24–25 Autoimmunity, drug-induced: distribution mechanisms, 2: 122–125 idiosyncratic adverse drug reactions: blood-brain barrier, 2: 124–125 drug-induced liver injury, 6: 421 mammary gland, 2: 123–124 lupus-like syndrome, 6: 417 maternal:fetal barrier, 2: 123 multiple IDRs, 6: 435 physiological barriers, 2: 122–125 organ specificity, 6: 417 transporter expression, 2: 129 idiosyncratic drug-induced reactions, 4: 568–570 water barriers, 2: 114–116 D-penicillamine, 4: 578 gastrointestinal absorption, 2: 52–54 Autoinduction: gut-blood barrier hypothesis, 1: 541–542 biotransformation pathway predictions, in vitro Base peak chromatograms, metabolite identification, studies, 6: 186 high resolution mass spectrometry, 5: 43–45 metabolic drug interaction, 1: 21 Basic drugs, distribution mechanisms, 2: 109–112 Automation: Batch processing, high throughput quantitative mass high throughput quantitative mass spectrometry, spectrometry, 5: 551–552 sample preparation and batch processing, 5: Bayesian analysis, a posteriori population modeling, 551 6: 597–598 imaging mass spectrometry, 5: 233 B-CLEAR hepatocytes, ADME studies, permeability Autoradiography (ARG). See also and transporters, 2: 25 Microautoradiography (MARG) Becquerel units, mass balance studies, human phosphor imaging vs., 5: 366–367 studies, dosimetry calculations, 2: 442–446 therapeutic peptides and proteins, 5: 378–379 Benoxaprofen, phase-II-enzyme-catalyzed xenobiotic tissue studies, 5: 364 conjugation, 4: 115–117 Average function unbound in tissues, allometric 1,3-Benzdioxole groups, cytochrome P450 enzymes, scaling pharmacokinetics, 2: 507–508 quasi-irreversible inactivation, 4: 45 Azathioprine, hepatic drug metabolism, liver Benzidine, N-acetylation, 4: 128–129 transplant, 6: 338 Benzo[a]pyrenes (BaP): Azoles, biotransformation, 6: 27–29 bioactivation, 4: 83 Azo reductases, 1: 375–380 cytochrome P450 enzymes, epoxidation, 4: 28, classification, 1: 375–377 30–34 cytochrome P450, 1: 377–380 Benzodiazepines: flavoproteins, 1: 376–377 cytochrome P450 enzymes, dealkylation reaction, 4: 16–18 Background subtraction, MIST analysis, hepatic drug metabolism: high-resolution mass spectrometry, 4: 212–214 alcoholism, 6: 323 Bacterial flora: cirrhosis and, 6: 331 intestinal metabolism, 2: 71 herb-drug interactions, St. John’s wort, 6: 284 2: oral absorption, bioavailability studies, phase I metabolism, active metabolites, 6: 357 475–476 Benzyl derivatives, carboxylesterases, 1: 436–438 Bacterial identification, MALDI-MS Benzylic-O-hydroxy metabolites, sulfonation, 4: characterization, 5: 139 122–123 Bacterial infection, drug-disease-drug interactions: Best practices, immunoassays, 5: 408–410 CYP1 subfamily, 4: 630 CYP2B, 4: 633 664 INDEX

Biacore assay, basic principles, 5: 401–402 tissue partition coefficient, 2: 642–645 Bi-bi ping-pong kinetics: Bioactivation: amine oxidases, 1: 367 ADME studies, DME inhibition, 2: 16–17 phase II metabolism: adverse drug reactions, overview, 4: 63–64 acyl coA synthetase, 2: 289–290 alcohol dehydrogenase, 4: 75–79 UGT enzymes, 2: 279–281 abacavir, 4: 77–79 sulfotransferases, 1: 539 allyl alcohol, 4: 75–76 BIBX1382 drug candidate, clinical programs, felbamate, 4: 76–77 1: 348 aldo-ketoreductases, 4: 86–87 Bile: polyaromatic hydrocarbons, 4: 86 drug excretion: amine oxidases, 4: 71–75 mechanisms of, 6: 219–220 monoamine oxidase, 4: 71–74 urinary excretion vs., 6: 218–219 dopamine, 4: 72–74 hepatic drug metabolism: tetrahydropyridines, 4: 71–72 cholestatic disease, 6: 323–324 semicarbazide-sensitive amine oxidase, 4: excretion mechanisms, 6: 317 74–75 intestinal metabolism, 2: 70–71 allylamine, 4: 74–75 mass balance studies, animal studies, 2: 427–428 cytochrome P450s: Bile acid homeostasis: chemically reactive metabolites, 4: 27–50 toxicogenomics, cholestasis and hepatotoxicity, 4: arene and olefin epoxidation, 4: 28–34 263–264 aromatic amines, N-oxidation, 4: 27–28 UGT isoform regulation, UGT2B4, 1: 488 consequences, 4: 48–50 Bile pocket experiments, organ clearance electron rich compounds, two-electron mechanisms, 2: 564 oxidation, 4: 34–42 Bile salt export pump (BSEP): iminium ions, 4: 40–42 genetically modified animal models, 3: 676–677 imino methide, 4: 39–40 nefazodone toxicity, 3: 198–199 quinone imines, 4: 34–37 pediatric drug metabolism, 6: 560–562 quinone methide, 4: 37–39 pregnancy drug metabolism and, 2: 941–945 quinones, 4: 37 reactive metabolite bioactivation, adverse drug mechanism-based inactivators, 4: 42–48 reactions, 5: 629–630 covalent modification, 4: 45–48 safety testing, stable metabolites, 3: 225–227 quasi-irreversible inactivation, 4: 43–45 vectorial transport, 2: 552–558 metabolic reactions, 4: 9–10 in vitro studies, 2: 215–216 pharmacologically active metabolites, 4: 10–27 xenobiotic metabolism, hepatocyte assessment, aromatic/aliphatic hydroxylation, 4: 11–15 hepatobiliary transport, 3: 419–428 consequences, 4: 26–27 Bile salts, intestinal metabolism, 2: 70–71 dealkylation reactions, 4: 15–18 Biliary excretion: inactive compounds (prodrugs), 4: 23–25 ADME studies, pharmacokinetic modeling, 2: miscellaneous reactions, 4: 18–23 603–607 extrahepatic metabolism, 2: 354–356 drug conjugation, transport proteins, 6: 219–220 flavin-containing monooxygenases, 4: 64–71 hepatic drug metabolism, 6: 312, 317 aryl piperazines, 4: 66, 68–69 mass balance studies, animal studies, 2: 427–428 4-fluoro-N-methylanilines, 4: 69–71 metabolite identification, 3: 128–129 thiocarbonyls, 4: 65–67 pharmacokinetic modeling, 6: 593 hepatoxicity prevention and minimization of, 4: species differences in, 2: 593–594 165–172 in vivo studies, 3: 609–610 non-P450 metabolic enzymes: Biliary excretion index (BEI), organ clearance expression and subcellular localization, 4: mechanisms, 2: 564 63–65 Bilirubin metabolism: future research issues, 4: 94–95 constitutive androstane receptor transcription, 1: toxicity studies, 4: 95 213 oxidative stress: homeostasis, constitutive androstane receptor acetaminophen case study, 3: 192–198 model, knockout mouse model, 3: 660–661 cellular consequences, 3: 193–194 pediatric drug metabolism, 6: 551–553 circadian rhythm, 3: 197–198 Binding associated constant (KA), drug-induced liver injury: physiologically-based pharmacokinetic animal studies, inflammatory response, 3: modeling, 2: 641–642 196–197 INDEX 665

inflammation and, 3: 194–196 glucuronidation, 4: 108–121 hepatotoxicity, 3: 192–193 acyl glucuronidation, 4: 109–118 acyl glucuronide case study, 3: 200–204 benoxaprofen, 4: 115–117 reactive metabolites, 3: 201–203 diclofenac, 4: 117–118 toxicity mechanisms, 3: 203–204 arylhydroxamic acids, 4: 118–121 adverse drug reactions, 3: 180–181 2-acetylaminofluorene, 4: 119–121 cellular defense, 3: 182–183 glutathione conjugation, 4: 129–140 glutathione effects, 3: 183 S-acyl-glutathione thioester adducts, reactive oxygen species generation, 3: 182 carboxylic-acid-containing drugs, 4: biomarkers, 3: 188–192 139–140 mercapturate conjugate in vivo indicators, 3: bromobenzene, 4: 133–134 190–192 ethylene dibromide episulfonium ion nevirapine case study, 3: 206 formation, 4: 130–131 in vitro biomarkers and trapping agents, 3: hexachlorobutadiene-induced nephrotoxicity, 189–190 4: 136–137 drug metabolism and, 3: 178–179 3,4-methylenedioxymethamphetamine-induced nefazodone case study, 3: 198–200 neurotoxicity, 4: 131–133 bile salt export pump inhibition, toxicity α-naphthylisothiocyanate-induced intrahepatic studies, 3: 198–199 cholestasis, 4: 137–138 mitochondrial dysfunction, 3: 199–200 sevoflurane-induced nephrotoxicity, 4: reactive metabolite formation and covalent 134–136 binding, 3: 198–199 metabolic activation pathways, 4: 105–108 nevirapine case study, 3: 204–206 overview, 4: 103–104 reactive metabolites: sulfonation, 4: 121–126 acyl glucuronide case study, 3: 201–203 allylic alcohols, 4: 123–124 glutathione and thiol status disruption, 3: 185 arylhydroxylamines and arylhydroxamic irreversible binding to macromolecules, 3: acids, 4: 124–126 186–188 polycyclic aromatic benzylic alcohols, 4: lipid peroxidation, ROS generation, 3: 185 122–123 mechanisms and consequences, 3: 183–188 xenobiotic metabolism classification, 4: mitochondrial dysfunction, 3: 185 104–105 nefazodone case study, 3: 199–200 reactive metabolites: nefazodone case study, 3: 198–199 data processing, 5: 647–650 redox cycling and ROS generation, 3: DNA adducts, 5: 639–642 184–185 toxicity initiation, 3: 179–180 drug-induced adverse reactions, 5: 627–630 research overview, 3: 177–178 peptide and protein adduct detection, 5: peroxidases, 4: 79–85 630–645 clozapine, 4: 85 amino acid-related adducts, 5: 635–637 myeloperoxidase, 4: 83–85 GSH thiol derivatives, 5: 631–635 diclofenac, 4: 84 nonbiological agent trapping, 5: 642–645 ticlopidine, 4: 84–85 semiquantitative determination, 5: 645–647 prostaglandin H synthase, 4: 79–83 in vitro studies protocol, 5: 647 acetaminophen (APAP), 4: 80–81 reductive bioactivation, 4: 86, 88–94 aromatic amines, 4: 81–82 antitumor prodrugs, 4: 91–94 hydantoins, 4: 83 mitomycin C and CB 1954, 4: 92–94 polyaromatic hydrocarbons, 4: 82–83 tirapazamine, 4: 92 phase I metabolism: NADPH cytochrome P450 reductase, 4: 90–91 conjugation mechanisms, 6: 355–356 flutamide, 4: 90–91 drug-metabolite-bioactivation continuum, 6: 355 paraquat, 4: 90 phase II enzyme-catalyzed xenobiotic conjugation: NADPH-quinoneoxidoreductase, 4: 88–90 N-acetylation, 4: 126–129 aristolochic acid, 4: 88–90 aromatic amines-benzidine, 4: 128–129 sulfotransferase sulfation, 1: 542–543 aromatic hydrazines, 4: 127 UGT enzymes, 6: 254–262 acyl-S-CoA formation, 4: 140–144 glucuronidation, toxicity prevention, 6: acyl-adenylates, 4: 144 261–262 S-acyl-coA thioesters, 4: 142–144 pharmacology, 6: 260–261 future research issues, 4: 144–145 toxicity studies, 6: 254–260 666 INDEX

Bioactivation (Continued) recovery, 5: 484–486 in vitro toxicity studies, intestinal metabolism, 4: research background, 5: 469–475 230–233 response calibration, 5: 475–482 Bioanalysis: quality controls, 5: 480–482 basic strategies, 5: 5 standards, 5: 479–480 biofluid analysis systems: sample reanalysis, 5: 494–497 future research issues, 5: 462–463 specificity and selectivity, 5: 490–491 miniaturized solid- phase extraction cartridges, stability, 5: 487–490 5: 451–452 system sustainability and response changes, 5: monolithic chromatography, 5: 455–457 493–494 online solid- phase extraction, 5: 447–451 in vitro studies, 5: 5–10 research background, 5: 445–447 enzyme inhibition, 5: 7–8 restricted access media, 5: 445, 452–455 metabolic stability, 5: 7 turbulent-flow chromatography, 5: 457–462 metabolite identification, 5: 8–10 data quality, research background, 5: 517–518 permeability, 5: 6–7 defined, 5: 3–5 protein binding, 5: 8 drug discovery and development, plasma protein in vivo studies, 5: 10–13 binding: metabolite identification, 5: 12–13 basic techniques, 5: 660–661 pharmacokinetics, 5: 10–12 capillary electrophoresis, 5: 666–667 Bioavailability. See also Hepatic bioavailability (FH) chromatographic techniques, 5: 665–666 absolute bioavailability calculations, 2: 458–459 emerging technologies, 5: 665–666 absorption kinetics, Wagner-Nelson method, 2: equilibrium dialysis, 5: 661, 663–664 610–612 radiometry vs. LC-MS/MS, 5: 664–665 ADME studies, 2: 5 research background, 5: 657–660 pharmacokinetics, 3: 73–80 solid-phase microextraction, 5: 669 basic principles, 2: 456–462 spectroscopic methods, 5: 668 drug-drug interactions, CYP induction, 4: surface plasmon resonance biosensors, 5: 668 430–433 TRANSIL™ membrane and protein beads, 5: drug-protein binding, 2: 535–536 669–670 early drug development, nonclinical studies, 3: ultracentrifugation, 5: 664 94–98 ultrafiltration, 5: 661 estimate variability, 2: 459–462 undeterminable protein binding, 5: 670–671 extrahepatic metabolism, 2: 356–365 in vitro study comparisons, 5: 662 future research issues, 2: 486 electrochemical array, complex matrices, 5: 323 hepatic drug metabolism, cirrhosis, 6: 327 human microdosing: hepatic metabolsim, 2: 484–486 accelerator mass spectrometry, 5: 602–614 intestinal metabolism, 2: 480–484 comparison of techniques, 5: 620–622 oral bioavailability, 2: 82–83 liquid chromatography-mass spectrometry, 5: determinants, 2: 470–480 614–618 estimate variability, 2: 459–460 positron emission tomography, 5: 618–620 Lipinski’s rule-of-five, 2: 85 research background, 5: 599–602 in vivo studies, 3: 594–595 nano-ESI spectrometry, small molecules, 5: 76–77 oral chemotherapeutic agents, 6: 501–508 regulatory guidelines: antiacid medications, 6: 506 assay transfers and changes, 5: 501–502 first-pass metabolism, 6: 501–502 carryover, 5: 486 food effect, 6: 506–507 clinical trials, 5: 503–504 intestinal ABCBA1 efflux, 6: 503–506 contamination, 5: 491–493 surgery, 6: 508 dilutions, 5: 486–487 pharmacokinetic/toxicokinetic profiles, 2: 588 documentation, 5: 502–503 research background, 2: 455–456 dried blood spots, 5: 507–508 solubility and dissolution assessment, oral future issues, 5: 508 absorption, rate-limiting steps, 3: 500–501 instrument qualification, 5: 503 Bioequivalence: large molecules, 5: 504–507 basic principles, 2: 462–470 matrix effects, 5: 482–484 clinical studies, 2: 468 multiple analyte assays, 5: 497–501 future research issues, 2: 486 drug-drug interactions, 5: 500–501 parallel-group design, 2: 465 metabolites, 5: 498–500 partial-block crossover design, 2: 465 INDEX 667

pharmacodynamic studies, 2: 468 early drug development, decision-making studies, pharmacokinetic studies, 2: 467 3: 105–109 randomized crossover design, 2: 464–465 immunoassays, 5: 406–407 research background, 2: 455–456 metabonomic identification, 4: 296–299 solubility and dissolution assessment, oral pharmacodynamics: absorption, BCS classification, 3: 501–504 developmental stages, 2: 701–703 statistics, 2: 465–466 genomic biomarkers, 2: 699–701 study design, 2: 464–465 activity-based biomarkers, 2: 701 in vitro studies, 2: 469–470 imaging-based biomarkers, 2: 701 Biofluid analysis systems: overview, 2: 697–698 future research issues, 5: 462–463 proximal and distal biomarkers, 2: 698 miniaturized solid- phase extraction cartridges, 5: technology-based classification, 2: 698–699 451–452 pharmacogenetics, 4: 379 monolithic chromatography, 5: 455–457 toxicity studies, targeted therapeutics, 3: 29–30 online solid- phase extraction, 5: 447–451 toxicogenomics: research background, 5: 445–447 hepatotoxicity prediction, 4: 256–257 restricted access media, 5: 445, 452–455 summary of studies, 4: 259 turbulent-flow chromatography, 5: 457–462 translational research, 2: 777–781 Bioinformatics: two-dimensional electrophoresis applications, 4: DNA microarrays, toxicogenomics, 3: 327–328 322 high throughput quantitative mass spectrometry: Biomolecular characterization: data processing, 5: 564–565 bioanalysis, large molecules, 5: 504–507 mass analyzer tuning and selection, 5: 553–555 matrix-assisted laser/desorption ionization mass proteomics analysis, 4: 337 spectrometry techniques, 5: 134–137 Biological aspects: in-source decay, 5: 136–137 drug metabolism, 1: 30–31 post-source decay, 5: 136 soluble epoxide hydrolase, 1: 408–410 Biopharmaceutical Classification System (BCS): Biological matrices, metabolite identification, 3: intestinal absorption classifications, 2: 97 139–146 solubility and dissolution assessment, oral Biomarkers: absorption, 3: 501–504 bioactivation: drug discovery and development, 3: 505–507 nevirapine, 3: 206 in vitro bioequivalence studies, 2: 469–470 oxidative stress, 3: 188–192 Biopharmaceutical Drug Disposition Classification mercapturate conjugate in vivo indicators, 3: System (BDDCS): 190–192 ADME studies, 2: 763–764 nevirapine case study, 3: 206 drug-drug interactions, NME disposition and, 6: in vitro biomarkers and trapping agents, 3: 125–126 189–190 solubility and dissolution assessment, oral cardiovascular drugs, 2: 865–866 absorption, 3: 504–507 drug discovery and development, 2: 592–593 drug discovery and development, 3: 505–507 assay validation vs., 5: 593 in vitro bioequivalence studies, 2: 469–470 disease and diagnostic biomarkers, 5: 580–581 Biopharmaceuticals: future research issues, 5: 593–594 anti-cytokine antibodies, 4: 648–649 patient selection and trial stratification, 5: cancer therapies, targeted therapies, 3: 24–25 581–583 drug-disease-drug interactions, research pharmacodynamic biomarkers, 5: 582 background, 4: 623–624 characteristics, 5: 584–585 early drug development, 3: 98 PK/PD models, 5: 582–583 animal-to-human transition, 3: 94 assay and data quality, 5: 589–593 immunoassays, research background, 5: 396–397 fit-for-purpose models, 5: 585–587 peptides and proteins: study design, 5: 588–589 antibody fragment attachment, 2: 905 quantitative/qualitative assays, 5: 587–588 carrier protein attachment, 2: 905 research background, 5: 577–579 catabolism reduction, 2: 901–904 target, mechanism, outcome, and surrogate plasma half-life, 2: 901–904 biomarkers, 5: 579–580 enzymatic clearance, 2: 897–901 translational research, 5: 583, 593 hydrolysis, 2: 898–900 drug-disease-drug interactions, 4: 630 peptidase selectivity, 2: 900–901 drug-induced liver injury, 4: 186–192 half-life extension: 668 INDEX

Biopharmaceuticals (Continued) pharmacogenetics, 6: 40–41 posttranslational modification, 2: 905–907 processes and methods, 6: 36 serum protein fusion, 2: 904–905 drug metabolism: renal clearance, 2: 897 basic principles, 1: 4–5 therapeutic protein antibodies, 2: 907–912 clinical aspects, 6: 35–41 regulatory guidelines, 5: 473–474 enzyme induction, 6: 13–20 larger molecules, 5: 505–507 basic mechanisms, 6: 13–14 research background, 2: 895–897 clinical consequences, 6: 19–20 targeted anticancer drugs, 3: 24–25 cytochrome P450 enzymes, 6: 14–17 Biophase/link models, pharmacodynamics, 2: CYP2D6 noninduction, 6: 17 708–712 CYP2E1 and the proteasome, 6: 16 Bioprecursors, phase I metabolism, 6: 363–367 cytoplasmic receptor mediation, 6: 16 clopidogrel and prasugrel, 6: 365–367 nuclear receptor mediation, 6: 15–16 nabumetone, 6: 364–365 receptor cross talk, 6: 18–19 tirapazamine, 6: 367 sulfonyltransferases, 6: 17–18 Bioreductive activation. See also Reduction transporters, 6: 18 uridine diphospho-glucuronosyltransferases, reactions, reductive bioactivation 6: 17 antitumor prodrugs, 4: 91–94 hepatic drug metabolism, 6: 312 phase I metabolism, Tirapazamine, 6: 367 high resolution mass spectrometry, metabolite Biosensors, plasma protein binding, drug discovery identification, 5: 40–45 and development, 5: 668 inhibition, clinical consequences, 6: 27–32 Biotransformation: anticancer agentse, 6: 31–32 clinical drug usage: clinical relevance, 6: 30–32 coordination of, 6: 13 conjugative inhibitors, 6: 30 cytochrome P450, 6: 8–10 cytochrome P450 inhibitors, 6: 27–29 drug development, 6: 35–41 irreversible inhibitors, 6: 29–30 drug metabolism, 6: 35–36 rhabdomyolysis, 6: 31 efficacy and toxicity, 6: 4–5 sedation, 6: 31 enzyme induction, 6: 19–20 sulfonation inhibitors, 6: 30 6: flavin monooxygenases, 12 torsades des pointes, 6: 30–31 inhibition, consequences of, 6: 27–32 UGT inhibitors, 6: 30 anticancer agents, 6: 31–32 microdose studies, accelerator mass spectrometry, rhabdomyolysis, 6: 31 5: 612–613 sedation, 6: 31 oral chemotherapeutic agents, 6: 501–508 torsades des pointes, 6: 30–31 antiacid medications, 6: 506 miscellaneous pathways, 6: 11–12 first-pass metabolism, 6: 501–502 patient factors, 6: 32–35 food effect, 6: 506–507 “phase 3” transformations, 6: 12 intestinal ABCBA1 efflux, 6: 503–506 research background, 6: 3–4 surgery, 6: 508 sulfonyltransferases, 6: 11 pathway predictions: transporters: future research issues, 6: 198–199 efflux, 6: 7 research background, 6: 177–180 influx, 6: 6–7 in silico tools, 6: 180–182 uridine diphospho-glucuronosyltransferases, 6: in vitro tools, 6: 182–188 10–11 expressed enzyme systems, 6: 187–188 cytochrome P450 enzymes, 6: 56–61 hepatocytes, 6: 185–186 clinical drug usage, 6: 8–10 intestinal homogenates, 6: 188 dehydrogenation reactions, 6: 60–61 liver slices, 6: 186–187 epoxidation, 6: 59 research background, 6: 182 heteroatomic oxidation, 6: 59–60 tissue-specific microsomes, 6: 182–185 hydroxylation, 6: 56–59 in vivo tools: induction, 6: 14–17 animal studies, 6: 188–194 inhibition, clinical consequences, 6: 27–29 radiolabeled compounds, 6: 190–194 drug discovery and development, 6: 35–41 species selection, 6: 188–189 drug interactions, 6: 40 unlabeled compounds, 6: 189–190 drug metabolites, 6: 36–39 human studies, 6: 194–198 hybrid mass spectrometry, 5: 178–180 first-in-human studies, 6: 194–195 INDEX 669

microtracer and accelerator mass aplastic anemia, 6: 423 spectrometry studies, 6: 196–198 thrombocytopenia, 6: 422 radiolabeled studies, 6: 195–196 mass balance studies, animal studies, 2: 422 patient factors, 6: 32–35 Blood-brain barrier (BBB): children and neonates, 6: 33 ADME studies: diet, 6: 35 mechanics, 2: 8–10 disease states, 6: 34–35 permeability/transporters, 2: 24–25 elderly, 6: 32–33 multiparameter optimization, 3: 70–71 gender, 6: 33–34 capillary permeability, 2: 121–122 pregnancy, 6: 34 distribution kinetics: pharmacogenetics: plasma concentration-time data, 2: 620–622 drug development, 6: 21–22, 40–41 protective mechanisms, 2: 124–125 drug efficacy, 6: 20–27 in vitro studies, 2: 134–135 future research issues, 6: 26–27 future research issues, 3: 583–585 polymorphisms, 6: 22–25 microdose studies, positron emission tomography, cytochrome P450, 6: 22–24 5: 619 flavin monooxygenases, 6: 24 organ clearance mechanisms, 2: 561–564 NADPH oxidoreductase, 6: 22 penetration parameters, 3: 564–567 sulfonotransferases, 6: 25 physiology, 3: 563–564 testing protocols, 6: 25–26 retroanalysis, Pfizer clinical candidates, 3: uridine-diphosphate glucuronosyltransferases, 577–583 6: 24–25 central nervous system penetration predictions, “real-world” drug usage, 6: 5–6 3: 579–581 sulfotransferases, tissue distribution, 1: 533–535 physicochemical predictability, in vitro and in in vitro research methodology, 1: 75–76 vivo studies, 3: 581–582 xenobiotic, XOR/AO molybdenum-containing preclinical and clinical data, 3: 578–579 enzymes, 1: 315–331 in silico predictions and simulations, 3: 576–577 aldehyde oxidation, 1: 320–321 computational models, 3: 576 aromatic N-heterocycle oxidation, 1: 315–320 multiparameter optimization, 3: 576 heterocycle reduction, 1: 329–331 PBPK models, 3: 577 N-hydroxy reduction, 1: 328–329 solute carrier transporters in, 2: 201, 212–213 iminium ion oxidation, 1: 321–324 in vitro penetration studies, 3: 572–576 nitrate/nitrite reduction, 1: 326–327 brain tissue binding, 3: 573–574 nitroreduction, 1: 324–326 permeability, 3: 572–573 N- and sulfoxide reduction, 1: 327–328 transporters, 3: 574–576 reduction, 1: 324 in vivo studies: Biphasic enzyme kinetics: distribution mechanisms, 3: 599–600 basic principles, 1: 83–84 penetration studies, 3: 566–572 mechanisms, 3: 299–300 cerebrospinal fluid surrogate, 3: 567–569 translational research, CYP enzyme inhibition, 2: microdialysis, 3: 569–570 754 PET imaging, 3: 570–572 Biphenyl hydrolase-like protein (BPHL), phase I preclinical neuro pharmacokinetics, 3: metabolism, valacyclovir, 6: 362–363 566–567 Bitter orange, herb-drug interactions, 2: 813 whole body autoradiography, drug penetration, 5: Black-box drugs, hepatotoxicity prediction, 4: 371–372 177–179 Blood-cerebrospinal fluid barrier (BCSFB): Black cohosh, drug interaction, 4: 506–507 physiology, 3: 563–564 ADME studies, 2: 813–814 in vivo neuroPK studies, 3: 566–567 Black pepper, dietary supplement-drug interaction, in vivo studies, CSF as surrogate, 3: 567–569 4: 522–524 Blood clearance (CIbl), enzyme kinetics, in vitro/in Blood analysis. See also Red blood cell partitioning vivo correlation, 3: 305–307 ADME studies, noncompartmental analysis, 2: Blood disorders: 602–603 carbamazepine therapy, hepatotoxicity studies, 4: bioanalysis regulations, dried blood spots, 5: 184–185 507–508 myeloperoxidase bioactivation, 4: 83–85 idiosyncratic adverse drug reactions, 6: 421–423 Blood flow: agranulocytosis, 6: 422–423 ADME studies, clearance mechanisms, 2: anemia, 6: 421–422 761–763 670 INDEX

Blood flow (Continued) physiologically-based pharmacokinetic modeling, distribution mechanisms and, 2: 117 enzyme-transporter biochemistry, 2: 646–647 red blood cell partitioning, 2: 119–120 pregnancy drug metabolism and, 2: 941 gastrointestinal absorption, 2: 54–55 small molecule transport, substrate binding hepatic, pediatric drug metabolism, 6: 555–556 specificity, 2: 161–165 physiologically-based pharmacokinetic modeling, xenobiotic metabolism, hepatocyte assessment, 2: 640–641 hepatobiliary transport, 3: 419–428 intestinal modeling, 2: 653–656 Brivaracetam, drug-drug interactions, 6: 492–493 Bromobenzene, glutathione conjugation, 4: 133–134 Blood perfusion rate, distribution mechanisms, 2: Buffered solubility, defined, 3: 509–510 117 Buffer ionic strength, in vitro studies, incubation Blood to plasma concentration (B/P), enzyme conditions, 1: 76–77 kinetics, 3: 305–307 Buffer systems: Body mass index (BMI), dose calculations based on, chromatographic quality control, 5: 527–528 6: 613 in vitro studies, incubation conditions, 1: 76–77 Body surface area conversion factor (BSA-CF), early Bupropion: drug development, clinical pharmacology, 3: CYP2B6 metabolism, 6: 467 101–102 cytochrome P450 enzymes, bioactive metabolites, Boltzmann constant, dissolution, 3: 512 4: 13–15 Boltzmann distribution, nuclear magnetic resonance, cytochrome P450 metabolism, 6: 462 5: 336–337 cytochrome P450 polymorphisms, CYP2B6, 1: Bosentan, transporter effects, 2: 865 251 Boundary-activated dissociation, quadrupole ion trap Buspirone: mass spectrometry, 5: 169–170 drug-drug interactions, probe substrates, 6: Brachymorphic mice, sulfotransferase deficiency, 3: 119–120 657 hepatotoxicity prevention strategies, 4: 181–182 Brain concentration-to-total plasma concentration toxicity studies, structure-toxicity relationships, 6: ratio (B/P), blood-brain barrier studies, 3: 382–383 565–566 Busulfan, oral chemotherapeutic agents, 6: 518 Brain tissue distribution: Buthionine sulfoxide, halothane hepatotoxicity, 4: codeine activation, 2: 355–356 574 in vitro studies, 2: 134–135 Butyrylcholinesterase (BChE), genetically modified Brain tumors, imaging mass spectrometry, 5: animal studies, 3: 651–652 233–234 Brain weight (BRW): C1 carbon, nucleophilic attack, UGT enzymes, 2: allometric scaling pharmacokinetics, animal 279–281 studies, 2: 498–501 Caco-2 cell line: pharmacokinetic predictive studies, 2: 495–496 intestinal metabolism, TC7 comparisons: Branching analysis, kinetic isotope effects, rate cellular model, 3: 338–339 experimental protocols, 3: 341–342 limiting effects, cytochrome P450, 1: 189–190 passage study protocols, 3: 343–345 Breast cancer, imaging mass spectrometry, 5: phase I enzymes, 3: 339 234–236 phase II enzymes, 3: 339–340 Breast cancer resistance protein (BCRP): transporters, 3: 340–341 biotransformation, 6: 7 in vitro studies, bioanalysis, 5: 6–7 blood-brain barrier penetration, in vitro studies, 3: Caffeine: 574–576 age-dependent metabolism, CYP1A2, 4: 454–455 cancer drug resistance, 2: 169 drug-disease-drug interactions, 4: 631 cardiovascular drug metabolism: drug-drug interactions, probe substrates, 6: angiotensin receptor blockers, 2: 881 118–120 drug-drug interaction, 2: 869 food-drug interactions, grapefruit juice, 6: 295 statin therapies, 2: 869–870 hepatic drug metabolism, pregnancy, 6: 319–320 transporter effects, 2: 864–865 Cage wash, mass balance studies, 2: 422–425 genetically modified animal models, 3: 668–669 Cahn-Ingold-Prelog (CIP) convention, oral absorption, 2: 91–92 stereoselectivity, 4: 347–351 bioavailability studies, 2: 480 Calcium channel antagonists, food-drug interactions, organ metabolism/transport, 2: 560–564 grapefruit juice, 6: 292–293 pharmacogenetics, 4: 393 Calcium channel blockers, ADME studies, 2: 879 INDEX 671

Calcium channels, pharmacodynamics mechanisms, immune-modulating agents, 6: 525 2: 690–691 mechanism of action and clinical Cancer therapy. See also Carcinogens and pharmacology, 6: 509–517 carcinogenicity; Oncology, imaging mass mTOR inhibitors, 6: 523 spectrometry plant alkaloids, 6: 520 ABC transporters and drug resistance, 2: 167–170 research background, 6: 499–501 ABCB1, 2: 167 small molecule tyrosine kinase inhibitors, 6: ABCC1, 2: 168 520–523 ABCC2, 2: 168–169 platinum drugs, inductively coupled plasma mass ABCG2, 2: 169 spectrometry, 5: 299–303 ADME studies: proteomics analysis, drug discovery and carboplatin and hyperbaric oxygenation, 2: development, 4: 335–336 848–849 reductive bioactivation, anticancer drugs: future research issues, 2: 849 antitumor prodrugs, 4: 91–94 irinotecan and UGTs, 2: 847–848 flutamide, 4: 90–91 letrozole, CYP2A6 and, 2: 843–844 toxicity studies: 6-mercaptopurine, 2: 848 cardiotoxicity screening, 3: 27–28 research background, 2: 841–842 clinical trials or post marketing studies, 3: tamoxifen, CYP2D6, 2: 844–846 30–31 tegafur, CYP2A6 and, 2: 842–843 cytotoxics, 3: 24 thalidomide and CYP3A4/5, 2: 846–847 drug discovery and development, 3: 25–28 thiopurine-S-methyltransferase, 2: 848 exploratory and phase 0 trials, 3: 38–39 biotransformational inhibition, 6: 31 future research issues, 3: 39–40 cytochrome P450 enzymes, polymorphisms: hepatic toxicity screening, 3: 27 CYP1A, 1: 242 immunomodulatory drugs, 3: 31 CYP1B, 1: 247–248 molecular targets, 3: 28–29 CYP2A, 1: 250 adverse event prediction, 3: 37–38 CYP2B6, 1: 252 multikinase inhibitors, 3: 35–36 CYP2C8, 1: 253–254 nonclinical studies, 3: 25–26 CYP2D6, 1: 258 research background, 3: 23–24 CYP2E, 1: 258–260 signaling pathways, 3: 32–35 drug-disease-drug interactions: epidermal growth factor, 3: 32–35 chronic diseases, 4: 630 vascular endothelial factor, 3: 35 CYP1 subfamily, 4: 632 targeted therapies: CYP2C, 4: 634 adverse event prediction, 3: 37–38 CYP3 subfamily, 4: 636 biomarkers, 3: 29–30 drug-drug interactions: molecular challenges, 3: 32 clinical perspectives, 6: 91–92 research background, 3: 24–25 compartmental analysis, 2: 623–626 in vitro studies, 4: 226–227 glutathione transferase superfamily, mu class toxicogenomics, carcinogenicity prediction, 4: polymorphisms, 1: 570–571 257–260 herb-drug interactions, St. John’s wort, 2: 824, 6: UGT isoforms: 283 UGT1A7, 1: 482 microdose studies, targeting techniques, 5: UGT1A10, 1: 486 619–620 whole-body autoradiography, tumor penetration, microsomal epoxide hydrolase, genetic 5: 376–377, 380 polymorphism, 1: 403–405 Candesartan ciletexil, ADME studies, 3: 51 oral chemotherapeutic agents: Canicular multispecific organic anion transporter antimetabolites, 6: 519–520 (cMOAT), species differences, conjugation and, bioavailability, 6: 501–508 6: 228–230 antiacid medications, 6: 506 Cannabinoid-1 inverse receptor agonist (CB1R), first-pass metabolism, 6: 501–502 taranabant optimization, 4: 173–174 food effect, 6: 506–507 Cannabinoid-1 receptor (CB-1 R) inverse agonist, intestinal ABCBA1 efflux, 6: 503–506 safety testing, reactive metabolites, 3: surgery, 6: 508 229–237 cytotoxic agents, 6: 508, 518–519 Capecitabine: future research issues, 6: 526 oral chemotherapeutic agents, 6: 519 hormonal agents, 6: 523–525 phase I metabolism, 6: 363–364 672 INDEX

Capillary electrophoresis (CE): classification, 1: 428 inductively coupled plasma mass spectrometry expression and regulation, 1: 438–440 integration, 5: 293–297 CES1/2 induction, 1: 439–440 interfaces, 5: 294–295 CES1/2 suppression, 1: 440 quantitative analysis, 5: 295–297 ontogenic expression, 1: 432–433 micellar electrokinetic chromatography and, 5: tissue distribution, 1: 438 421–422 extrahepatic metabolism, 2: 339–340 plasma protein binding, 2: 546 functions, 1: 424–428 drug discovery and development, 5: 666–667 hydrolysis-based drug design, 1: 426 Capillary permeability, distribution mechanisms, 2: hydrolytic ester and amide metabolism, 1: 118, 121–122 424–426 Captopril, ADME studies, 2: 879–880 insecticide detoxification, 1: 427 Carbamazepine (CBZ): lipid mobilization, 1: 426 cytochrome P450 enzymes, active metabolic protein trafficking, 1: 427–428 reactions, 4: 18–21 future research issues, 1: 447 drug-drug interactions, 6: 477–478 human form, 1: 429–432 hepatotoxicity studies, 4: 164, 183–185 animal comparison with, 1: 446–448 microsomal epoxide hydrolase, 1: 400–402 species-specific hydrolysis, 1: 446–447 skin reactions to, 4: 164–165 tissue distribution, 1: 446 Carbazeran: biotransformation pathway predictions, 6: aldehyde oxidase variation, 1: 341–344 179–180 clinical programs, 1: 345, 348 CES1 family, 1: 430–432, 439–440 pharmacokinetics, 3: 78–80 CES2 family, 1: 431–432, 439–440 Carbohydrates: CES3 family, 1: 431 MALDI-MS analysis, 5: 129 CES5 family, 1: 431 nano-electrospray ionization mass spectrometry, 5: CES6 family, 1: 432 74–75 regulated expression, 1: 447–448 13Carbon: substrate specificity, 1: 432–434 metabolite identification, NMR spectroscopy, 3: tissue distribution, 1: 438 157, 159–160 pharmacogenomics, 1: 440–446 nuclear magnetic resonance, passive nuclei, 5: 338 cytochrome P450 enzyme system, 1: 442 Carbon 14 (14C): drug-insecticide interactions, 1: 445–446 ADME study, MIST guidelines, 4: 215 drug transporter interactions, 1: 443–445 microdose studies: polymorphisms, 1: 441–442 accelerator mass spectrometry, 5: 604–606 uridine diphosphate drug discovery and development, 5: 606–610 (UDP)-glucuronosyltransferases, 1: Carbon-carbon bonds: 442–443 cytochrome P450 catalytic cycle, 1: 195–196 phase I metabolism, 2: 271–274 double bonds, chiral reduction, 4: 355–356 capecitabine prodrug, 6: 363 Carbon dioxide: clopidogrel and prasugrel, 6: 366 exhalation, mass balance studies, animal studies, oseltmavir, 6: 362 2: 428–430 secondary and crystal structure, 1: 429 quantitative whole-body radiography, effect of, 5: structure, 1: 428–429 370 Carboxylic acid metabolism: Carbon nanotubes (CNTs): abacavir bioactivation, 4: 78–79 basic principles, 5: 132–133 S-acyl-glutathione thioester adducts, 4: 139–140 micellar electrokinetic chromatography, 5: amino acid conjugation: 428–429 mechanisms for, 1: 596–597 Carbon oxidation, cytochrome P450 reactions, 1: 190 mitochondrial acyl-coA:glycine hydroxylation, 6: 57–59 N-acyltransferase, 1: 602–605 Carbon-oxygen bonds, cytochrome P450 catalytic inhibitors, 1: 605 cycle, 1: 195–196 structure-activity relationships, 1: 603 Carboplatin, ADME studies, 2: 848–849 in vivo conjugation, 1: 603–605 Carboxylesterases (CESs): xenobiotic substrates, 1: 603 activators and inhibitors, 1: 434–438 mitochondrial medium chain acyl-CoA age-dependent drug metabolism, 4: 466 synthetases, 1: 597–602 basic properties, 1: 423–424 inhibitors, 1: 602 catalytic mechanism, 1: 432 structure-activity relationships, 1: 600–602 INDEX 673

substrates, 1: 599–600 Cardiovascular system, drug metabolism in, overview, 1: 595–596 pregnancy and, 2: 934–937 phase-II-enzyme-catalyzed xenobiotic conjugation, Carrier-linked prodrugs, phase I metabolism, 6: 354, 4: 109–121 360–363 UGT enzyme bioactivation, toxicity studies, 6: capecitabine, 6: 363 256–260 fosprofol, 6: 361 Carcass analysis, mass balance studies, animal oseltmavir, 6: 362 studies, 2: 428–430 valacyclovir, 6: 362–363 Carcinogens and carcinogenicity. See also Cancer Carrier proteins, peptide and protein therapeutics, therapy; Oncology, imaging mass spectrometry attachment mechanisms, 2: 905 aromatic amines, bioactivation, 4: 81–82 Carryover, bioanalysis regulations, 5: 486 toxicogenomics, prediction studies, 4: 257–260 Carvedilol, cardiovascular metabolism, 2: 877 UGT polymorphisms, 6: 24–25 Cassette-accelerated rapid rat screen (CARRS), Cardiac allograft vasculopathy (CAV), CYP2C in vivo studies, pharmacokinetics screening, 5: inhibition, 2: 862 10–11 Cardiotoxicity: Cassette dosing: allylamine, 4: 74–75 ADME in vivo studies, 3: 60–61 anticancer drugs, screening for, 3: 27–28 in vivo studies, pharmacokinetics screening, 5: biotransformational inhibition, torsades des 10–11 pointes, 6: 30–31 Catabolic reactions, peptide and protein therapeutics, cytochrome CYP3A4, 4: 4 2: 901–904 early drug development, nonclinical studies Catabolism, drug metabolism and, 1: 4 95–98 Catalytic constant (kcat), enzyme kinetics, Cardiovascular drugs: Michaelis-Menten kinetics, 1: 79–81 ADME studies: Catalytic mechanisms: ACE inhibitors, 2: 879–880 carboxylesterases, 1: 432 angiotensin receptor blockers, 2: 880–881 cytochrome P450 enzymes, 1: 173–175, 182–184 antiarrhythmics, 2: 874–879 drug discovery and development, 6: 54–56 α-adrenergic blockade, 2: 876–878 cytosolic glutathione transferases, 1: 577–579 calcium channel blockade, 2: 879 molybdenum-containing hydroxylases, 1: class I agents, 2: 874–876 310–312 potassium channel blockade, 2: 878 Catecholamines, sulfotransferase sulfation, 1: antithrombotics, 2: 871–874 541–542 antiplatelet drugs, 2: 873–874 Catechol O-methyltransferase (COMT): warfarin, 2: 871–872 biomarkers and metabolomics, 2: 865–866 extrahepatic metabolism, 2: 339–340 cytochrome P450 superfamily, 2: 856–861 phase II metabolism, 6: 214–216 CYP1A2, 2: 860 Cationic surfactants, micellar electrokinetic CYP2C, 2: 859–860 chromatography, pseudophases, 5: 426–427 CYP2D6, 2: 858–859 cDNA, DNA microarrays, 3: 319–320 CYP3A, 2: 857–858 Cefotetan, allometric scaling pharmacokinetics, metabolite effects, 2: 862–863 volume of distribution, 2: 503, 505–508 phase II enzymes, 2: 861 Celecoxib: diuretics, 2: 871 sulfotransferase kinetics, 1: 540 drug-drug interactions, 2: 863–864 UGT enzyme bioactivation, 6: 255–260 drug-metabolizing enzymes, 2: 855–856 Cell-based assays: expression mechanisms, 2: 861–862 ADME studies, permeability/transporters, 2: 24 future research issues, 2: 882 blood-brain barrier penetration, in vitro studies, 3: lipid-lowering agents, 2: 866–871 575–576 gemfibrozil, 2: 870–871 distribution mechanisms, transporter studies, 2: statins, 2: 866–870 134 research background, 2: 855–856 nano-electrospray ionization, live single cells, 5: transporters, 2: 864–865 78–80 cytochrome P450 metabolism, 2: 333 pharmacokinetics predictive studies: food-drug interactions, grapefruit juice, 6: absorption and disposition kinetics prediction, 290–293 2: 515–516, 518–521 herb-drug interactions, St. John’s wort, 6: DNA binding, 2: 515–517 284–285 lysosome drug distribution, 2: 510–513 674 INDEX

Cell-based assays (Continued) Cetirizine, cytochrome P450 enzymes, bioactive mitochondrial sequestration of drug molecules, metabolites, 4: 14–15 2: 513–515 Charcot-Marie-Tooth disease, cytosolic glutathione solute carrier proteins, in vitro studies, 2: 215–217 transferases, 1: 563 Cell cycle targeted agents, development of, 3: 28 Charged residue mechanism (CRM), electrospray Cell kill models, pharmacodynamics, 2: 721–722 ionization, 5: 49 Cell life span models, pharmacodynamics, 2: “Cheese-effect,” monoamine oxidase, 4: 71–72 715–718 Chemical derivatization, metabolite identification, 3: Cell monolayer transport assays, blood-brain barrier 146–150 penetration, in vitro studies, 3: 572–573 Chemical inhibitors: Cellular systems. See also Hepatocytes drug discovery studies, reaction phenotyping, 1: drug-induced oxidative stress: 59–61 acetaminophen, 3: 193–194 microsomal analysis, specificity and potency, 3: defense mechanisms, 3: 182–183 460–462 irreversible reactive metabolite binding, 3: reactive metabolites, toxicity elimination and 186–188 minimization, 6: 386–390 drug metabolism, in vitro models, 1: 47–48 Chemical ionization, gas chromatography-mass intestinal metabolism models: spectrometry, 5: 23–25 Caco-2/TC7 comparisons, 3: 338–339 Chemical liquid technique, MALDI-MS samples, 5: experimental protocols, 3: 341–342 127 passage study protocols, 3: 343–345 Chemically-based pharmacokinetic (CBPK) model, protein microarray analysis, signaling predictive studies, 2: 496 mechanisms, 3: 318 Chemically induced inflammatory bowel disease, Center for Drug Evaluation and Research (CDER), dextran sulfate sodium injection, 4: 632 MIST guidelines, 4: 205–208 Chemically reactive metabolites. See also Reactive carbon 14 (14C) ADME study, 4: 215 metabolites Central dogma (CD) tagging, hepatotoxicity cytochrome P450 bioactivation, 4: 27–50 screening, 3: 27 arene and olefin epoxidation, 4: 28–34 Central nervous system (CNS): aromatic amines, N-oxidation, 4: 27–28 ADME studies, 2: 7–10 consequences, 4: 48–50 blood-brain barrier, in silico studies, electron rich compounds, two-electron multiparameter optimization, 3: 576 oxidation, 4: 34–42 distribution mechanisms in, 2: 110–112 iminium ions, 4: 40–42 drug-disease-drug interactions, 4: 641 imino methide, 4: 39–40 drug metabolism, CYP enzymes, 2: 332–333 early drug development, nonclinical studies, 3: quinone imines, 4: 34–37 95–98 quinone methide, 4: 37–39 food-drug interactions, grapefruit juice, 6: quinones, 4: 37 293–295 mechanism-based inactivators, 4: 42–48 herb-drug interactions, St. John’s wort, 6: 284 covalent modification, 4: 45–48 penetration data, retroanalysis, Pfizer clinical quasi-irreversible inactivation, 4: 43–45 candidates, 3: 579–581 idiosyncratic adverse drug reactions, 6: 434 physiology, 3: 563–564 phase I metabolism, bioprecursors, 6: 363–367 in vivo studies, preclinical species penetration, 3: reduction of, 3: 123 600–602 Chemical shift, nuclear magnetic resonance, 5: whole body autoradiography, drug penetration, 5: 333–335 371–372 Chemical transformation: Cerebrospinal fluid (CSF): drug metabolism, 1: 5–14 blood-brain barrier, in vivo studies, CSF as intestinal metabolism, 3: 336 surrogate, 3: 567–569 Chemiluminescent immunoassay (CLIA), basic central nervous system penetration, retroanalysis, principles, 5: 400–401 Pfizer clinical candidates, 3: 580–581 Chemistry assays, pharmacodynamics, 5: 413 in vivo studies, preclinical species penetration, 3: Chemokine receptors: 600–602 covalent drug-protein adducts, 4: 164–165 whole body autoradiography, drug penetration, 5: drug metabolizing enzymes and drug transporters, 371–372 4: 647–649 Certified reference materials (CRMs), inductively idiosyncratic drug-induced reactions, tumor coupled plasma mass spectrometry, 5: 290 necrosis factor-α, 4: 603 INDEX 675

inflammation and infection, drug-disease-drug Cholestatic disease, hepatic drug metabolism, 6: interactions, 4: 629 323–324 Children. See also Fetal development; Pediatric Cholestyramine, hepatic drug metabolism, 6: 324 populations Cholinesterases, genetically modified animal studies, Child-Turcotte-Pugh (CTP) scoring, 6: 325 3: 650–652 hepatic dose calculations based on, 6: 614 Chromatographic techniques. See also specific Chimeric/humanized mouse models: techniques, e.g. Liquid chromatography aryl hydrocarbon receptor model, 3: 666 column temperature elevation, 5: 533–535 chimeric-humanized liver models, 3: 628–630 hybrid silica particles, 5: 528–529 aldehyde oxidase expression, 3: 644 metabolite identification, 3: 131–133 CYP3A expression, 3: 639–640 metabonomics analysis, 4: 286 epoxide hydrolase expression, 3: 642 plasma protein binding, drug discovery and chimeric/humanized liver models, development, 5: 665–666 Fah/-Rag2-/-Il2rg-/- mouse, 3: 629–630 quality assurance and control: chimeric-humanized liver models: buffer selection, 5: 527–528 UGT expression, 3: 655–656 performance optimization, 5: 526–527 uPA+/+/SCID mice, 3: 628–629 pH levels, 5: 527 soluter carrier transporters, in vivo studies, 2: 220 resolution, 5: 524–526 in vivo drug metabolism studies, 1: 52–56 selectivity, 5: 526–527 Chip-based nano-electrospray ionization, 5: 56–58 resolution quality, 5: 524–526 analytical standards, 5: 66–67 sample introduction, 5: 52–53 lipid characterization, 5: 73–74 sample preparation quality control, orthogonality, noncovalent interactions, 5: 72 5: 520–521 proteomics analysis, 5: 70–71 Chromosome topology, cancer therapy, 3: 24 quantitative analysis, 5: 76–77 Chronic disease, drug-disease-drug interactions, 4: ChipCube hardware, nano-electrospray ionization, 5: 629–630 55–56 C-hydroxylation, cytochrome P450 reactions, 1: Chiral columns, basic principles, 5: 529–530 190–191 Chiral mobile phase additives, chiral columns, 5: Chylomicrons, gastrointestinal absorption, 2: 529–530 56–59 Chiral molecules: Chyme, intestinal metabolism, 2: 49 stereoselectivity, 4: 346–351 Cinnoline, AO/XOR-mediated reactions, 1: carbon-carbon double bond reduction, 4: 317–320 355–356 Circadian rhythms: enantiotopic moiety to chiral metabolite, 4: acetaminophen toxicity and, 3: 197–198 357–358 drug metabolism, 1: 31 inversion, 4: 358–359, 363–364 Cirrhosis: substrate metabolism, 4: 352–353 drug-disease-drug interactions, 4: 632 sulfide oxidation to chiral sulfoxide, 4: 356–357 hepatic drug metabolism, 6: 325–331 Chloral hydrate, hepatic drug metabolism, anesthesia, 6: 330–331 alcoholism, 6: 323 cascular architecture and hepatic blood supply, Chloramphenicol: 6: 326–327 cytochrome P450 bioactivation, 4: 28 clearance reduction, 6: 329 pediatric drug metabolism, 6: 551–553 drug response, 6: 330 p-Chlorobenzoic acid, phase II metabolism, acyl first pass and bioavailability, 6: 327 coA synthetase, 2: 288–290 hepatic enzymes, 6: 328–329 Chloroquine, whole-body autoradiography, melanin protein binding and volume distribution, 6: binding, 5: 375 327–328 Chlorpromazine, in vitro toxicity screening, reactive renal impairment, 6: 329–330 metabolites, 4: 241–243 Cisapride: Chlorzoxazone, age-dependent drug metabolism, age-dependent drug metabolism, 4: 462 CYP2E1 expression, 4: 459–460 pediatric metabolism, 6: 547 Cholestasis: Citalopram, monoamine oxidase bioactivation, 4: ABC transporter mutations, 2: 180 71–74 drug transporters, 4: 643–644 Citrus juices. See also Grapefruit juice toxicogenomics, hepatotoxicity and, 4: 262–264 biotransformation, irreversible inhibition, 6: xenobiotic metabolism, hepatocyte assessment, 29–30 hepatobiliary transport, 3: 421–428 food-drug interactions, 4: 496–499 676 INDEX

Clarithromycin: SGX523, 1: 348–349 dietary supplement-drug interaction, black cohosh, zaleplon, 1: 348 4: 506–507 Clinical studies and trials: dose calculations, 6: 615 bioequivalence studies, 2: 468 Clark’s rule, ADME, permeability properties, 2: biotransformation, enzyme induction, 6: 19–20 8–10 blood-brain barrier penetration, retroanalysis, Clearance-dependent CYP induction, drug-drug Pfizer clinical candidates, 3: 578–579 interactions, 4: 434–437 cancer therapies: Clearance mechanisms: exploratory/phase 0 trials, 3: 38–39 ADME studies, 2: 761–763 toxicity studies, 3: 30–31 pharmacokinetics, 3: 79–80 distribution mechanisms, altered drug disposition, allometric scaling pharmacokinetics: 2: 143–147 animal studies, 2: 498–501 absorption and, 2: 143 in vitro studies, 2: 501–503 renal elimination, 2: 143, 146 biotransformation: transporter-mediated distribution, 2: 146–147 CYP isoforms, 6: 9–10 drug development, 1: 15–16 drug efficacy and toxicity and, 6: 5 drug-drug interactions: drug-drug interactions, CYP inhibition, 6: 98–100 anticonvulsants, 6: 477–492 drug metabolism and, 1: 16–21 drug-metabolizing enzyme involvement, 6: drug-protein binding, 2: 534–536 155–156 glucuronidation, predictive studies, 6: 262–264 incidence of clinically significant DDI, 6: hepatic drug metabolism, 6: 312–317 152–153 allometric scaling, 3: 357–358 new molecular entities pharmacology, 6: bile formation and biliary excretion, 6: 317 115–120 cirrhosis and, 6: 328–329 overview, 6: 90–92 in elderly, 6: 318–319 preclinical assessment, DDI potential, 6: fetal and newborn clearance, 6: 317–318 153–154 liver transplantation, 6: 333–334 prescription guidance, 6: 136–139 liver transplant patients, 6: 333–334 relevance assessments, 6: 134–136 nutritional status, 6: 319 strategies for, 6: 121–122 physiological changes, 6: 317–320 study design, analysis, and results pregnancy, 6: 319–320 interpretation, 6: 129–136 in vivo human studies, 3: 355–358 transporter mechanisms, 6: 222 metabolism of, 1: 5–6 types and mechanisms of DDIs, 6: 154–155 metabolite identification: drug-metabolizing enzyme induction, 3: 469–470 drug discovery, 3: 123 early drug development, 3: 99–115 human clearance pathways, 3: 125–126 decision-making studies, 3: 105–109 metabolite pharmacology, 1: 19 drug-drug interactions, 3: 113–114 organ metabolism/transport, enzyme isoforms, 2: first in human studies, 3: 101–102 559–564 labeling issues, 3: 114–115 pediatric drug clearance and exposure, 6: metabolic disposition studies, 3: 110–111 562–563 premarketing phase, NDA, 3: 114 pharmacokinetic predictive studies, 2: 495–496, radiolabeled studies (ADME), 3: 110 585–587 research methods, 3: 102–104 physiologically-based pharmacokinetic modeling: in vitro drug metabolism/interaction studies, 3: liver, 2: 650–652 111–112 renal metabolism, 2: 656–659 idiosyncratic adverse drug reactions, 6: 405–417 toxicity studies, 2: 585–587 immunoassay applications, pharmacodynamics, 5: in vivo studies, 3: 603–610 413 allometric scaling, 3: 603–605 inhibition studies, biotransformation, 6: 27–32 Clinical drug candidates: pediatric drug metabolism, 6: 563–566 discovery phase of drug development, 1: 15 research design and methodology, 6: 566–570 molybdenum-containing hydroxylases, 1: a posteriori population modeling, 6: 595–598 345–349 pregnancy drug metabolism, 2: 951 BIBX1382, 1: 348 regulatory guidelines, 5: 503–504 BK3453, 1: 349 soluter carrier transporters, 2: 220–221 carbazeran, 1: 345, 348 genetic polymorphism, 2: 228–230 RO1 metabolite, 1: 348 sulfotransferases: INDEX 677

drug-drug interactions, 1: 546–548 reactive metabolites, thiophene ring formation, 6: induction, 1: 544–545 390–391 polymorphisms, 1: 543–544 safety testing, 3: 235–237 reaction phenotyping, 1: 545–546 Clorazepate, phase I metabolism, 6: 357 uridine diphosphate Clozapine: (UDP)-glucuronosyltransferases (UGTs): bioactivation, 4: 85 absorption mechanisms, 6: 252–254 CYP1A2 metabolism, 6: 466–467 bioactivation mechanisms, 6: 254–262 toxicity studies, structure-toxicity relationships, 6: glucuronidation, toxicity prevention, 6: 384–385 261–262 Coactivator recruitment, pregnane X receptor, pharmacology, 6: 260–261 cytochrome P450, transcriptional regulation, 1: toxicity studies, 6: 254–260 208–211 classification, 6: 244–245 Coagonist, pharmacodynamics, 2: 693–694 clearance mechanisms, glucuronidation, 6: Coagulation system, idiosyncratic drug-induced 262–264 reactions, inflammation, 4: 603–604 drug-drug interactions, 6: 269–270 Cocaine, phase I metabolism, carboxylesterases, 2: patient factors, 6: 264–269 272–274 drug-drug interactions, 6: 266–267 Cocrystals, solubility and dissolution assessment, genetic polymorphism, 6: 265–266 oral absorption: glucuronidation inhibition, 6: 267–269 dissolution measurements, 3: 525–526 research background, 6: 243–244 multicomponent formulation, 3: 536 substrate specificity, 6: 245–251 Codeine: 2: tissue distribution, 6: 251–252 brain metabolism, 355–356 drug-drug interactions, therapeutic efficacy, 4: 441 UGT isoforms: pharmacodynamics mechanisms, 2: 688–689 relevance studies, 1: 475–482 phase I metabolism, active metabolites, 6: 358 UGT1A1, 1: 475 UGT biotransformation, 6: 260–261 UGT1A3, 1: 477 UGT isoform regulation, UGT2B7, 1: 491–492 UGT1A4, 1: 478 Coenzymes: UGT1A6, 1: 481 drug metabolism, 2: 252–256 UGT1A7, 1: 482 mitochondrial coenzyme Q, 2: 513–514 UGT1A9, 1: 485 Cohesive Technologies, multiplexing technology, 5: UGT1A10, 1: 486 536 UGT2B4, 1: 488 Collision-activated dissociation (CAD), quadrupole 1: UGT2B7, 491–492 devices, 5: 157 UGT2B10, 1: 493 Collision energy (CE), nano-electrospray ionization, UGT2B15, 1: 495 5: 67–68 UGT2B17, 1: 496 Collision energy spread (CES), QTRAP Clobazam, drug-drug interactions, 6: 478, 480, instrumentation, 5: 191 482–483 Collision-induced dissociation (CID): clog P values: ion trap mass spectrometry, 5: 29–33 ADME studies, pharmacokinetics, 3: 74–80 liquid chromatography mass spectrometry: Lipinski’s rule-of-five, drug design and, 3: 48–54 sample introduction, 5: 53–54 Clomipramine, CYP1A2 metabolism, 6: 466 simultaneous fraction collection, 5: 68–69 Clonazepam, drug-drug interactions, 6: 483 MALDI-MS techniques, instrumentation, 5: Clopidogrel: 124–125 ADME studies, 2: 873–874 metabolite identification, 3: 137–146 carboxylesterases, hydrolytic metabolism, 1: quadrupole ion trap mass spectrometry, 5: 32 425–426 ion activation, 5: 167 cytochrome P450 enzymes: ion-ion reactions, 5: 171–172 active metabolites, 4: 26–27 nonresonance excitation, 5: 169–170 bioactivation, 4: 24–25 operating theory, 5: 157 CYP2C19, 1: 255 reactive metabolite bioactivation, glutathione cytochrome P450 enzymes, biotransformational derivatives, 5: 631–635 polymorphism, 6: 22–23 signal averaging, 5: 64 drug-drug interactions, ADME studies, 2: spray-based ionization, 5: 90–93 863–864 triple quadrupole mass spectrometry, origins, phase I metabolism, 6: 365–366 5: 158 678 INDEX

Column efficiency: Concentration gradient, solubility and dissolution chiral columns, 5: 529–530 assessment, oral absorption, dissolution high throughput quantitative mass spectrometry, measurement, 3: 523–524 staggered parallel dual columns, 5: 560–561 Concentration-normalized rate, drug clearance, 1: hybrid silica particles, 5: 528–529 17–18 monolithic columns, 5: 530 Confidence intervals, bioequivalence studies, 2: 466 resolution quality, chromatographic techniques, 5: Conjugation. See also specific conjugation enzymes, 524–526 e.g., Uridine diphosphate Column temperature elevation, chromatographic (UDP)-glucuronosyltransferases (UGT); specific techniques, 5: 533–535 mechanisms, e.g., Glucuronidation Combinatorial analyses, monoclonal antibodies, aflatoxin production and toxicity, 2: 920 microsomal drug metabolism, 3: 454–455 bioactivation, in vivo NAC conjugators, 3: Comparative molecular similarity indices analysis 190–192 (CoMISA), in silico studies, 3: 253 biotransformational pathways, 6: 11–12 Compartmental analysis: inhibitors, 6: 30 ADME studies, research background, 2: 600 dietary phytochemicals and herbal supplements, 6: distribution calculations: 226–227 one-compartment model, 2: 139–140 drug-disease-drug interactions, 4: 638–639 two-compartment model, 2: 140–142 drug-drug interactions: drug-drug interaction, 2: 623–624 drug-metabolizing enzymes, 6: 156, 161 pharmacokinetics modeling: NME metabolism, 6: 124 dose calculations, 2: 590–592 drug metabolism, 1: 3–14, 2: 252–256 metabolite analysis, 2: 622–623 human studies, phase II enzymes, 6: 207–218 plasma studies, 2: 608–633 amino acids, 6: 217–218 absorption kinetics, 2: 608–618 glutathione-S-transferases, 6: 213–214 distribution kinetics, 2: 618–622 methyltransferases, 6: 214–216 elimination kinetics, 2: 626–633 N-acetyltransferases, 6: 216–217 metabolism kinetics, 2: 622–626 sulfotransferases, 6: 210–213 plasma concentration-time data, 2: 626–629 UGT enzymes, 6: 207–210 Competitive inhibition: phases of, 6: 205–206 drug-drug interactions: enterohepatic recirculation, 6: 224 cytochrome P450 enzymes, 6: 156–158 excretion studies, transport proteins, 6: inhibition mechanisms, 4: 408–409 218–222 enzyme kinetics, 1: 88–89 bile vs. urine routes, 6: 218–219 Competitive molecular field analysis (CoMFA), in biliary excretion, 6: 219–220 silico studies, 3: 253 drug interactions and clinical relevance, 6: 222 Complementary determining regions (CDRs), hepatic drug metabolism, 6: 220 antibody structure, 2: 908 renal excretion, 6: 221–222 Compound descriptor models, in silico studies, 3: future research issues, 6: 231 252 hepatic drug metabolism, CYP enzymes, 3: 355 Compound interactions: human elimination pathways, 6: 222–223 electrospray ionization: hepatic and renal impairment, 6: 224–225 amenable compounds, 5: 51–52 intrinsic and extrinsic factors in, 6: 230–231 automated tuning, 5: 67 microdose studies, accelerator mass spectrometry, sensitivity analysis, 5: 50–51 5: 612–613 in silico studies, 3: 266–268 nuclear receptors, 6: 225–226 Compound-solvent mixing, solubility and dissolution phase-II-mediated bioactivation: assessment, oral absorption, 3: 516 N-acetylation, 4: 126–129 Compound structure models, in silico studies, 3: aromatic amines-benzidine, 4: 128–129 252–253 aromatic hydrazines, 4: 127 Computational modeling: acyl-S-CoA formation, 4: 140–144 blood-brain barrier, in silico studies, 3: 576 acyl-adenylates, 4: 144 drug discovery process, 2: 743–746 S-acyl-coA thioesters, 4: 142–144 toxicity testing, 2: 772–773 future research issues, 4: 144–145 Concentration-effect relationship, glucuronidation, 4: 108–121 pharmacodynamics, 2: 693–694, 704–706 acyl glucuronidation, 4: 109–118 agonist on antagonist, 2: 695–696 benoxaprofen, 4: 115–117 potency studies, 2: 695–696 diclofenac, 4: 117–118 INDEX 679

arylhydroxamic acids, 4: 118–121 plant secondary metabolites, human studies, 4: 2-acetylaminofluorene, 4: 119–121 491–492 glutathione conjugation, 4: 129–140 sulfotransferases, induction, 1: 544–545 S-acyl-glutathione thioester adducts, toxicity studies, cancer therapy, 3: 26–27 carboxylic-acid-containing drugs, 4: toxicogenomics: 139–140 cholestasis and hepatotoxicity, 4: 263–264 bromobenzene, 4: 133–134 hepatic drug metabolism analysis, 4: 266–270 ethylene dibromide episulfonium ion pharmacokinetic parameters, 4: 251–252 formation, 4: 130–131 UGT isoforms, UGT1A1, 1: 472 hexachlorobutadiene-induced nephrotoxicity, xenobiotic metabolism, hepatocyte assessment, 4: 136–137 induction, 3: 410–419 3,4-methylenedioxymethamphetamine-induced Constitutive liver enhancer module of CYP3A4 neurotoxicity, 4: 131–133 (CLEM4), cytochrome P450 genes, α-naphthylisothiocyanate-induced intrahepatic transcriptional regulation, receptor cross talk, 1: cholestasis, 4: 137–138 220 sevoflurane-induced nephrotoxicity, 4: Contaminants: 134–136 bioanalysis guidelines, 5: 491–493 metabolic activation pathways, 4: 105–108 herb-drug interactions, 2: 808 overview, 4: 103–104 phytochemicals, 4: 505–506 sulfonation, 4: 121–126 Contribution ratio (CR), drug-drug interactions, in allylic alcohols, 4: 123–124 vitro-in vivo correlation, 4: 417–425 arylhydroxylamines and arylhydroxamic Coomassie brilliant blue (CBB) dye, acids, 4: 124–126 two-dimensional electrophoresis, protein polycyclic aromatic benzylic alcohols, 4: detection, 4: 316–317 122–123 Cooperativity, cytochrome P450 catalytic cycle, xenobiotic metabolism classification, 4: substrate binding, 1: 184–186 104–105 Copper-containing amine oxidases (CAOs), 1: species-specific differences in, 6: 227–230 365–366 sulfotransferases, 1: 536–543 classification, 1: 367–373 reaction phenotyping, 1: 545–546 diamine oxidase, 1: 369 transcriptional regulation, 6: 225–226 plasma AO, 1: 371–373 Consortium on Metabonomic Toxicology (COMET), retina-specific amine oxidase (RAO), 1: 4: 284, 294–296 369–370 Constant neutral loss scan, metabolite identification, semicarbazide-sensitive AO, 1: 370–371 3: 62, 136–146 Coprophagy, intestinal metabolism, 2: 71 Constitutive androstane receptor (CAR): Copy number variations (CNVs): ABC transporter transcriptional regulation, 2: 174 pharmacogenetics, 4: 378 biotransformation, enzyme induction, 6: 15–16 species differences in drug metabolism, CYP2D cytochrome P450 enzymes: enzymes, 1: 135–137 CYP2B6, 1: 251 Corepressor recruitment, pregnane X receptor, transcriptional gene regulation: cytochrome P450, transcriptional regulation, 1: coactivators and corepressors, 1: 210 208–211 human studies, 1: 206–207 Correction voltage (CV), ion mobility spectrometry, mechanisms, 1: 209, 211–213 5: 35 receptor cross talk: Correlation analysis: CYP2B6, 1: 216–217 drug discovery studies, reaction phenotyping, 1: CYP2C8, 1: 218 60–61 CYP2C9, 1: 219 sulfotransferases, reaction phenotyping, 1: species-related differences, 1: 222–224 545–546 drug conjugation and transport, 6: 225–226 Correlation spectroscopy (COSY), basic principles, drug-drug interactions: 5: 340–341 cytochrome P450 induction, 6: 160 Corticotrophin-releasing factor-1 (CRF1) receptor enzyme induction, 1: 63–65 antagonists, drug discovery and development, 3: NME-precipitated CYP induction, 6: 109–111 16–17 drug metabolism, 1: 30–31 Cosolvents, solubility and dissolution assessment, drug-metabolizing enzymes, species differences, oral absorption, 3: 538 1: 121–123, 125 Coulometric flow cell, electrochemical liquid genetically modified animal models, 3: 659–661 chromatography mass spectrometry, 5: 314 680 INDEX

Coumadin, pediatric metabolism, 6: 547 reactive metabolites, 4: 241–243 Counterfeit drugs, ambient ionization applications, 5: whole-body autoradiography, 5: 377 106–108 Covariates, a posteriori population modeling, 6: Counterregulatory model, pharmacodynamics, 2: 596–598 728–729 CP-85,958 development, leukotriene receptor Coupling reactions, cytochrome P450 catalytic cycle, antagonist optimization, 4: 174–175 1: 195–196 Cranberry, drug interactions, 2: 814 Covalent binding: C-reactive protein (CRP), drug-disease-drug cytochrome P450 enzymes, 4: 45–48 interactions, 4: 630 drug-protein adducts: Crigler-Najar syndrome: biomarkers, drug-induced liver injury, 4: hepatic drug metabolism, 6: 324–325 186–192 phase II metabolism, 6: 209–210 future research issues, 4: 192 UGT isoforms, UGT1A1, 1: 475 hepatotoxicity prevention strategies, 4: 165–186 Critical micelle concentration (CMC): covalent binding evaluation, hepatotoxicity micellar electrokinetic chromatography, 5: 425 prediction, 4: 176–179 solubility and dissolution assessment, oral limitations of covalent binding studies, 4: absorption, compound-solvent mixing, 3: 516 185–186 Critical path initiative (CPI), new drug development, reactive intermediate formation, minimization 3: 91 of, 4: 165–176 Cross-species comparisons: dual A2A/A1 receptor antagonist bioanalysis guidelines, 5: 499–500 optimization, 4: 174–176 lipopolysaccharides, drug-inflammation leukotriene receptor agonist optimization, interaction, 4: 610–612 4: 174 metabolite identification, 3: 125 SERM optimization, 4: 173–174 Cruciferous vegetables, food-drug interactions, 4: taranabant optimization, 4: 172–173 494–496 risk assessment, covalent binding data, 4: Crushed crystal sample preparation, MALDI-MS 179–185 analysis, 5: 126 anticonvulsants, 4: 183–185 Cryocytes, biotransformation pathway predictions, in buspirone, 4: 181–182 vitro studies, 6: 185–186 paroxetine, 4: 182 Cryopreserved suspensions: propranolol, 4: 179–181 microautoradiography, 5: 385–388 raloxifene, 4: 182–183 precision cut tissue slices, 3: 481–485 sudoxicam, 4: 183 xenobiotic metabolism, hepatocyte assessment: reactive metabolites, 3: 186–188 toxicity studies: hepatobiliary transport, 3: 423–428 hypersensitivity reactions, 4: 161–164 in vitro studies, metabolic stability, 3: 397–402 overview, 4: 159–165 Cryptic peptides, hapten hypothesis, 6: 424–425 skin reactions, 4: 164–165 Crypts of Lieberkuhn, intestinal metabolism, 3: 336 idiosyncratic drug-induced reactions, 4: 570–571 Crystal structure: metabolite identification, 3: 64–65 carboxylesterases, 1: 429 phase I metabolism, monoamine oxidase, 2: cytosolic glutathione transferases, 1: 575–577 270–271 mitochondrial medium chain acyl-CoA phase II enzyme-catalyzed xenobiotic conjugation: synthetases, 1: 602 acyl glucuronidation, 4: 113–118 Cultured primary human hepatocytes, xenobiotic benoxaprofen, 4: 116–117 metabolism, hepatocyte assessment: S-acyl-coA thioesters, 4: 143–144 hepatobiliary transport, 3: 423–429 reactive metabolite formation, nefazodone case in vitro studies, metabolic stability, 3: 399–402 study, 3: 198–199 Cumulative absorption values, plasma safety testing, reactive metabolites, 3: 229–237 concentration-time data, Wagner-Nelson toxicity studies: method, 2: 610–612 reactive metabolite trapping, 6: 391–393 Cumulative excretion values, mass balance studies, structure-toxicity relationships, 6: 382 human studies, 2: 445–446, 449–450 UGT enzyme bioactivation, toxicity studies, 6: Curcumin, drug interactions, 2: 814–815 255–260 Cyanide ions, reactive metabolite bioactivation, in vitro toxicity screening: adduct detection, 5: 643–644 determination techniques, 4: 243–244 α-Cyano-4-hydroxycinnamic acid (CHCA), imaging hepatotoxicity, 4: 237–239 mass spectrometry, 5: 224 INDEX 681

Cyclic adenosine monophosphate (cAMP), ADME studies: pharmacodynamics mechanisms, 2: 690 cancer therapy: Cyclic amines, flavin-containing monooxygenase carboplatin and hyperbaric oxygenation, 2: metabolism, 1: 295 848–849 Cyclic-nucleotide-dependent signaling, aryl future research issues, 2: 849 hydrocarbon receptor transcription, 1: 215 6-mercaptopurine, 2: 848 Cyclodextrins: research background, 2: 841–842 micellar electrokinetic chromatography, 5: thiopurine-S-methyltransferase, 2: 848 430–431 drug-drug interactions, 3: 57–58 solubility and dissolution assessment, oral identification/mapping techniques, 2: 28–29 absorption: induction, 2: 17–18, 30–31 excipient effects, 3: 544 inhibition, 2: 16–17, 29–30 multicomponent formulation, 3: 536–537 in silico studies, 2: 23–24 solution formulations, 3: 538–539 age-dependent drug metabolism, 4: 454–462 Cyclooxygenase (COX) compounds. See also antiarrhythmics, ADME studies, 2: 874–879 Prostaglandin H synthase (PGHS) azo reductases, 1: 377–378 bioactivation, 4: 79–83 bioactivation: phase I metabolism, nabumetone, 6: 365 adverse drug reactions, 4: 63–64 Cyclophosphamide: chemically reactive metabolites, 4: 27–50 cytochrome P450 bioactivation, 4: 24–25 arene and olefin epoxidation, 4: 28–34 cytochrome P450 polymorphisms, CYP2B6, 1: aromatic amines, N-oxidation, 4: 27–28 251, 252, 6: 31 consequences, 4: 48–50 drug-drug interactions, compartmental analysis, 2: electron rich compounds, two-electron 624–626 oxidation, 4: 34–42 metabonomics analysis, 4: 290 iminium ions, 4: 40–42 oral chemotherapeutic agents, 6: 508–518 imino methide, 4: 39–40 pulmonary metabolism, 2: 354–356 quinone imines, 4: 34–37 Cyclosporin A, ABC transport modulation, 2: quinone methide, 4: 37–39 172–173 quinones, 4: 37 Cyclosporine: mechanism-based inactivators, 4: 42–48 dose calculations, 6: 615–616 covalent modification, 4: 45–48 food-drug interactions, grapefruit juice, 6: 295 quasi-irreversible inactivation, 4: 43–45 hepatic metabolism, liver transplantation, 6: 334, drug metabolism and, 3: 178–179 336–337 metabolic reactions, 4: 9–10 herb-drug interactions, 4: 504–505 pharmacologically active metabolites, 4: 10–27 St. John’s wort, 6: 282–283 aromatic/aliphatic hydroxylation, 4: 11–15 in vitro toxicity studies, 4: 226–230 consequences, 4: 26–27 Cysteine-S-conjugates, sevoflurane-induced dealkylation reactions, 4: 15–18 nephrotoxicity, 4: 134–136 inactive compounds (prodrugs), 4: 23–25 Cystic fibrosis transmembrane regulator (CFTR), miscellaneous reactions, 4: 18–23 ABC transporter mutations, 2: 180–181 biotransformation, 6: 8–10 Cytidine deaminase, phase I metabolism, children and neonates, 6: 33 capecitabine prodrug, 6: 363 dehydrogenation reactions, 6: 60–61 Cytochrome b5: diet and, 6: 35 electron donors, 1: 172–173 disease states, 6: 34–35 rate limiting effects, 1: 188–190 drug discovery and development, 6: 56–61 reductive bioactivation, 4: 91 elderly patients, 6: 32–33 mitomycin C/CB, 4: 94 epoxidation, 6: 59 Cytochrome P450 reductase (CPR): heteroatomic oxidation, 6: 59–60 drug-disease-drug interactions, intestinal hydroxylation, 6: 56–59 metabolism, 4: 639–640 induction, 6: 14–17 electron donors, 1: 172–173 inhibitors, 6: 27–32 NADPH-CPR, bioactivation, 4: 90–91 pathway predictions: phase I metabolism, tirapazamine, 6: 367 research background, 6: 179–180 Cytochrome P450 (CYP) superfamily: in silico techniques, 6: 180–182 abundance, polymorphisms, and variability, 1: tissue-specific microsomes, 6: 183–185 166–168 in vitro studies, 6: 186 acyl glucuronide inhibition, 6: 259–260 pharmacogenetics and, 6: 40–41 682 INDEX

Cytochrome P450 (CYP) superfamily (Continued) skin absorption, 2: 333–334 pregnancy and, 6: 34 urinary metabolism, 2: 331 reaction phenotyping, pathway predictions, 6: in vitro-in vivo correlation studies, 6: 79 184–185 xenobiotic metabolism, hepatocyte sex differences in, 6: 33–34 assessment, 3: 406–409, 413–419 carboxylesterases pharmacogenomics, 1: 442 CYP1A2: cardiovascular drug metabolism, 2: 333 aflatoxin production and toxicity, 2: 919–920 ADME studies, 2: 856–861 age-dependent drug metabolism, 4: 454–455 metabolite effects, 2: 862–863 aristolochic acid ADME and toxicity, 2: phase II enzymes, 2: 861 920–922 antiplatelet drugs, 2: 873 biotransformation and induction, 6: 16 antithrombotics, 2: 871–874 cardiovascular drug metabolism, 2: 333, drug-drug interactions, 2: 863–864 860–861, 872–877 gemfibrozil, 2: 870–871 cruciferous vegetable inhibition, 4: 494–496 statin therapies, 2: 866–869 dietary supplement-drug interaction: catalytic cycle, 1: 173–175, 182–184 black cohosh, 4: 506–507 drug discovery and development, 6: 54–56 Echinacea spp., 4: 509–510 central nervous system metabolism, 2: 332 garlic, 4: 512–513 chemical properties, 1: 162–165 kava kava, 4: 521–522 covalent binding studies, limitations of, 4: drug-drug interactions: 185–186 dose-dependent induction, 4: 437–439 CYP1 subfamily: inhibition mechanisms, 4: 407–413 CYP1A: NME clinical pharmacology, 6: 117–120 cancer, 4: 632 probe substrates, 6: 118–120 dietary supplement-drug interaction, 4: toxicity induction, 4: 443–444 509–510 early drug development, 3: 104 drug-disease-drug interaction, 4: 631 hepatic drug metabolism, 6: 319–320, drug-drug interactions, toxicity induction, 4: 322–324 442–444 induction, 3: 374–380 genetically modified animal models, 3: herb-drug interactions, St. John’s wort, 6: 286 631–633 human expression and activity, 6: 65 human expression and activity, 6: 65 metabonomics analysis, 4: 288–291 liver slices, induction studies, 3: 473–475 mitochondrial superoxide drug reactions, 4: monkey studies, 6: 74–76 577 mouse studies, 6: 69–71 pediatric drug metabolism, 6: 540–541 polymorphisms, 1: 242–243, 247 pharmacogenetics, 4: 385–386 rat studies, 6: 71 pregnancy drug metabolism, 2: 946–951 receptor cross talk, transcriptional gene psychotropic drug metabolism, 6: 458, regulation, 1: 216 461–463, 465–467 species differences in drug metabolism, 1: pulmonary system metabolism, 2: 330–331 128–129 in silico studies, drug-drug interactions, 3: CYP1A1: 260–261 biotransformation and induction, 6: 16 skin absorption, 2: 333–334 cardiovascular drug metabolism, 2: 333, viral infection, 4: 631 861–862 in vitro-in vivo correlation studies, 6: 79 central nervous system metabolism, 2: 332 in vitro toxicity screening, 4: 242 dietary supplement-drug interaction, ginseng, xenobiotic metabolism, hepatocyte 4: 517–518 assessment, 3: 406–409, 412–419 drug-drug interactions, dose-dependent CYP1B: induction, 4: 437–439 human expression and activity, 6: 65–66 hepatic drug metabolism, in children, 6: 318 polymorphisms, 1: 247–248 hepatic drug metabolism induction, 3: species differences in drug metabolism, 1: 374–380 129 human expression and activity, 6: 65 CYP1B1: intestinal metabolism, 2: 328–329 biotransformation and induction, 6: 16 metabonomics analysis, 4: 288–290 cardiovascular drug metabolism, 2: 861 pharmacogenetics, 4: 385–386 human expression and activity, 6: 65–66 pulmonary system metabolism, 2: 330–331 intestinal metabolism, 2: 328–329 INDEX 683

pharmacogenetics, 4: 385–386 cardiovascular drug metabolism, 2: 861, pulmonary system metabolism, 2: 330–331 873–874 rat studies, 6: 71 central nervous system metabolism, 2: 332 CYP19A1, letrozole, ADME studies, 2: dietary supplement-drug interaction, 4: 843–844 506–507 CYP19A2, cardiovascular drugs, 2: 860–861 drug-drug interactions, inhibition dog studies, 6: 73 mechanisms, 4: 407–413 drug-disease-drug interactions, 4: 630–632 enzyme induction, 6: 15–16 pediatric drug metabolism, 6: 540–541 human expression and activity, 6: 66 pharmacogenetics, 4: 385–386 polymorphisms, 6: 23–24 CYP2 subfamily: psychotropic drug metabolism, 6: 461–462, CYP2A: 467–468 age-dependent metabolism, 4: 455–456 pulmonary system metabolism, 2: 330–331 dog studies, 6: 73 substrate stereoselective metabolism, 4: 353 drug-disease-drug interactions, 4: 632–633 transcriptional gene regulation, receptor cross human expression and activity, 6: 66 talk, 1: 216–218 mouse studies, 6: 69–71 xenobiotic metabolism, hepatocyte pediatric drug metabolism, 6: 541–542 assessment, 3: 406–409, 412–419 pharmacogenetics, 4: 383–384 CYP2B7, human expression and activity, 6: 66 polymorphisms, 1: 249–250 CYP2C: rat studies, 6: 71–72 age-dependent metabolism, 4: 456–458 species differences in drug metabolism, 1: biotransformation, 6: 9–10 129–131 cardiovascular drugs, 2: 859–862 cirrhosis and drug metabolism, 6: 328–329 CYP2A5, drug-disease-drug interactions, 4: dog studies, 6: 74 632–633 drug-disease-drug interactions, 4: 633–634 CYP2A6: human expression and activity, 6: 66–67 drug-disease-drug interactions, 4: 632–633 liver slices, induction studies, 3: 474–475 human expression and activity, 6: 66 monkey studies, 6: 74–76 letrozole, ADME studies, 2: 843–844 mouse studies, 6: 70–71 pediatric populations, 6: 541 pharmacogenetics, 4: 383–384 pulmonary system metabolism, 2: 330–331 polymorphisms, 1: 253–256 tegafur, ADME studies, 2: 842–843 rat studies, 6: 72 tertiary amine oxidation to N-oxide species differences in drug metabolism, 1: metabolite, 4: 357 133–135 CYP2A7: CYP2C8: human expression and activity, 6: 66 age-dependent metabolism, 4: 456–458 pulmonary system metabolism, 2: 330–331 anticancer agents, 6: 31 skin absorption, 2: 334 biotransformation, 6: 9–10 CYP2A13, human expression and activity, 6: 66 cardiovascular metabolism, 2: 333, 864 CYP2B: central nervous system metabolism, 2: 332 dog studies, 6: 73–74 diuretics, 2: 871 drug-disease-drug interactions, 4: 633 drug-drug interactions, 6: 100–101 human expression and activity, 6: 66 carbamazepine, 6: 477–478 liver slices, induction studies, 3: 474 clearance-dependent induction, 4: 435–437 monkey studies, 6: 74–76 inhibition mechanisms, 4: 407–413 mouse studies, 6: 69–71 extrahepatic metabolism, 2: 376–377 pharmacogenetics, 4: 383–384 human expression and activity, 6: 66–67 polymorphisms, 1: 251–253 irreversible inhibitors, 6: 29–30 rat studies, 6: 72 molecular genetics and pharmacology, 1: species differences in drug metabolism, 1: 253–259 131–133 organ metabolism/transport, 2: 560–564 CYP2B1/2: pediatric populations, 6: 541 cardiovascular drug metabolism, 2: 861–862 polymorphisms, 6: 23–24 intestinal metabolism, 2: 329 pulmonary system metabolism, 2: 330–331 CYP2B6: receptor cross talk, transcriptional gene age-dependent metabolism, 4: 456 regulation, 1: 218 anticancer agents, 6: 31 statin therapies, 2: 866–869 684 INDEX

Cytochrome P450 (CYP) superfamily (Continued) CYP2C18: xenobiotic metabolism, hepatocyte age-dependent metabolism, 4: 456–458 assessment, 3: 406–409 human expression and activity, 6: 66–67 CYP2C9: pediatric populations, 6: 541 age-dependent metabolism, 4: 456–458 pulmonary system metabolism, 2: 330–331 biotransformation, 6: 9–10 CYP2C19: biphasic enzyme kinetics, 3: 299–300 active metabolites, 4: 26–27 cardiovascular metabolism, 2: 333, 869, age-dependent metabolism, 4: 456–458 872–874 biotransformation, 6: 9–10 dietary supplement-drug interaction: cardiovascular drugs, 2: 860, 863–864, black cohosh, 4: 506–507 873–874 Echinacea spp., 4: 509–510 dietary supplement-drug interaction: garlic, 4: 511–513 black cohosh, 4: 506–507 ginseng, 4: 517–518 garlic, 4: 511–513 milk thistle, 4: 527–528 kava kava, 4: 521–522 diuretics, 2: 871 drug-drug interactions: drug-drug interactions: genotyping, 4: 421–422 allosterism, 4: 424–425 inhibition mechanisms, 4: 407–413 clearance-dependent induction, 4: time- and dose-dependent CYP induction, 435–437 4: 438–439 genotyping, 4: 421–422 toxicity induction, 4: 443–444 inhibition mechanisms, 4: 407–413 in vitro-in vivo correlation, 4: 417–425 intestinal metabolism, 4: 418–420 early drug development, 3: 104 therapeutic efficacy, 4: 440–441 ethnic differences in expression, 6: 76–77 in vitro-in vivo correlation, 4: 415–425 hepatic drug metabolism, 6: 319–320 early drug development, 3: 104, 113–114 herb-drug interactions, 2: 824–825 enzyme induction, 6: 16 St. John’s wort, 6: 286 ethnic differences in expression, 6: 76–77 human expression and activity, 6: 66–67 extrahepatic metabolism, 2: 376–377 mitochondrial superoxide drug reactions, 4: hepatic drug metabolism, 3: 368–370 577 herb-drug interactions, 2: 824–825 pediatric populations, 6: 541–542, 565–566 St. John’s wort, 6: 284–285 polymorphisms, 6: 22–23 human expression and activity, 6: 66–67 pregnancy drug metabolism, 2: 946–951 intestinal metabolism, 2: 329 psychotropic drug metabolism, 6: 461–464 molecular genetics and pharmacology, 1: reversible inhibitors, 6: 28–29 254–255, 255–256 substrate stereoselective metabolism, 4: 353 oral absorption and intestinal metabolism, 2: tamoxifen, ADME studies, 2: 845–846 93–94 thalidomide, ADME studies, 2: 846–847 pediatric populations, 6: 541–542 xenobiotic metabolism, hepatocyte pharmacogenetics testing, 6: 26 assessment, 3: 406–409 polymorphisms, 6: 22 CYP2D: pregnancy drug metabolism, 2: 946–951 biotransformation, 6: 9–10 pulmonary system metabolism, 2: 330–331 dog studies, 6: 74 receptor cross talk, transcriptional gene drug-disease-drug interactions, 4: 634–635 regulation, 1: 218–219 hepatotoxicity prevention strategies, 4: reversible inhibitors, 6: 28–29 180–181 in silico studies, drug-drug interactions, 3: human expression and activity, 6: 67 260–261 monkey studies, 6: 74–76 statin therapies, 2: 866–869 mouse studies, 6: 70–71 substrate inhibition, 3: 304 pharmacogenetics, 4: 383–384 ticrynafen-induced hepatotoxicity, 4: polymorphisms, 1: 256–258 575–576 rat studies, 6: 72 xenobiotic metabolism, hepatocyte species differences in drug metabolism, 1: assessment, 3: 406–409, 413–419 135–137 CYP2C11: CYP2D6: ticrynafen-induced hepatotoxicity, 4: active metabolites, 4: 26–27 575–576 age-dependent metabolism, 4: 458–459 transcriptional regulation, 4: 649–650 biotransformation, 6: 10 INDEX 685 cardiovascular drug metabolism, 2: 858–859, tamoxifen, 6: 524 874–877 tamoxifen, ADME studies, 2: 844–846 central nervous system metabolism, 2: 332 in vitro-in vivo correlation studies, 6: 79 dealkylation reactions, 4: 15–18 in vitro toxicity screening, 4: 242 dietary plant secondary metabolites, 4: xenobiotic metabolism, hepatocyte 492–494 assessment, 3: 406–409 goldenseal, 4: 519–520 CYP2E: dietary supplement-drug interaction: polymorphisms, 1: 258–259 black cohosh, 4: 506–507 species differences in drug metabolism, 1: Echinacea spp., 4: 509–510 137–138 garlic, 4: 512–513 CYP2E1: kava kava, 4: 521–522 age-dependent drug metabolism, 4: 459–460 piperine/black pepper, 4: 523–524 cardiovascular drug metabolism, 2: 862 drug-drug interactions: central nervous system metabolism, 2: 332 allosterism, 4: 424–425 cruciferous vegetable inhibition, 4: 494–496 competitive/noncompetitive inhibition, 6: dietary supplement-drug interaction: 156–158 black cohosh, 4: 506–507 fraction metabolized by primary enzyme Echinacea spp., 4: 509–510 (fmi), 4: 420–421 garlic, 4: 512–513 genotyping, 4: 421–422 kava kava, 4: 521–522 inhibition mechanisms, 4: 407–413 disease-base biotransformation, 6: 34–35 non-P450 metabolism, 4: 422–423 drug-disease-drug interactions, 4: 635 therapeutic efficacy, CYP-mediated effects, drug-drug interactions: 4: 440–441 inhibition mechanisms, 4: 407–413 in vitro-in vivo correlation, 4: 415–425 toxicity induction, 4: 442–444 early drug development, 3: 104, 113 enzyme induction, 6: 16 enantiotopic oxidation to chiral metabolite, 4: genetically modified animal models, 3: 358 635–637 enzyme noninduction, 6: 17 halothane hepatotoxicity, 4: 574 ethnic differences in expression, 6: 76–77 hepatic drug metabolism, 6: 322–323 genetically modified animal models, 3: herb-drug interactions, 2: 817–818 633–635 human expression and activity, 6: 68 hepatic drug metabolism, 3: 353, 366–368, idiosyncratic adverse drug reactions, 6: 320 metabolic idiosyncrasy, 6: 429 hepatic extraction and uptake, 2: 485–486 monkey studies, 6: 74–76 hepatotoxicity prevention strategies, 4: mouse studies, 6: 69–71 180–181 pregnancy drug metabolism, 2: 946–951 herb-drug interactions, 2: 817–818, 823 rat studies, 6: 72 human expression and activity, 6: 67 transcriptional regulation, 4: 649–650 identification of, 4: 378 urinary metabolism, 2: 331 intestinal metabolism, 2: 329 in vitro-in vivo correlation studies, 6: 78–79 irreversible inhibitors, 6: 29–30 CYP2J: mechanism-based inhibition, 6: 103–105 cardiovascular drug metabolism, 2: 862 metabonomic analysis, 4: 292–293 intestinal metabolism, 2: 329 pediatric drug metabolism, 6: 543–545 pulmonary system metabolism, 2: 331 pharmacogenetics testing, 6: 26 urinary metabolism, 2: 331 phase I metabolism, active metabolites, 6: CYP2J2, cardiovascular metabolism, 2: 333, 358–359 861–862 polymorphisms, 1: 256–258, 6: 23 CYP2S1: sulfotransferase, 1: 543–544 central nervous system metabolism, 2: 332 pregnancy drug metabolism, 2: 946–951 pulmonary metabolism, 2: 331 psychotropic drug metabolism, 6: 458, urinary metabolism, 2: 331 461–463 CYP2U1, central nervous system metabolism, pulmonary system metabolism, 2: 331 2: 332 species differences in metabolism, 2: dog studies, 6: 73–74 593–594 pediatric drug metabolism, 6: stereoselective inhibition, 4: 359–361 541–544 substrate inhibition, 3: 304 pharmacogenetics, 4: 381–384 686 INDEX

Cytochrome P450 (CYP) superfamily (Continued) drug-disease-drug interactions, 4: 636 CYP3 subfamily: transcriptional regulation, 4: 649–650 CYP3A: CYP3A4: aflatoxin production and toxicity, 2: 919–920 age-dependent drug metabolism, 4: 460–462 age-dependent drug metabolism, 4: 460–462 biotransformation, 6: 9–10 biotransformation pathway predictions, 6: polymorphism, 6: 22 188 cardiac toxicity, 4: 4 cardiovascular drug metabolism, 2: 857–858, cardiovascular drug metabolism, 2: 863–864, 866–869 872, 874–876 central nervous system metabolism, 2: central nervous system metabolism, 2: 332–333 332–333 chiral reduction, carbon-carbon double bond, dealkylation reaction, 4: 16–18 4: 355–356 dietary supplement-drug interaction: dietary supplement-drug interaction, 4: black cohosh, 4: 506–510 509–510 garlic, 4: 511–513 goldenseal, 4: 519–520 ginseng, 4: 517–518 St. Johns wort, 4: 532 goldenseal, 4: 519–520 Schisandra spp., 4: 525–526 kava kava, 4: 521–522 drug-disease-drug interactions, 4: 640 milk thistle, 4: 528 drug-drug interactions, 6: 90–92 piperine/black pepper, 4: 523–524 clinical evaluation strategies, 6: 121–122 Schisandra spp., 4: 525–526 inducer-based risk assessment, 6: 126–127 drug-drug interactions: induction, 6: 114–115 allosterism, 4: 424–425 inhibition, 6: 101 carbamazepine, 6: 477–478 NME clinical pharmacology, 6: 117–120 clearance-dependent induction, 4: 435–437 NME pharmacokinetics and risk clonazepam, 6: 483 assessment, 6: 125 induction, 6: 114–115 probe substrates, 6: 119–120 intestinal metabolism, 4: 418–420 protease inhibitors, 6: 368 noncompetitive inhibition, 4: 409–411 toxicity induction, 4: 444 protease inhibitors, 6: 368 ethnic differences in expression, 6: 76–77 therapeutic efficacy, 4: 440–441 genetically modified animal models, 3: time- and dose-dependent CYP induction, 637–640 4: 438–439 hepatic drug metabolism, 3: 369–378, 6: toxicity induction, 4: 443–444 318–319 uncompetitive inhibition, 4: 411–413 herb-drug interactions, 2: 810–811 in vitro-in vivo correlation, 4: 417–425 human expression and activity, 6: 68 early drug development, 3: 104, 112–114 intestinal metabolism, 2: 329 enzyme kinetics, 3: 302 liver slices, induction studies, 3: 474 extrahepatic metabolism, 2: 376–377 monkey studies, 6: 74–76 food-drug interactions: mouse studies, 6: 70–71 citrus juices, 4: 496–499 oral absorption and intestinal metabolism, 2: cruciferous vegetables, 4: 494–496 93–94 germander ADME and toxicity, 2: 927 pediatric drug metabolism, 6: 544–547, 565, hepatic drug metabolism, 2: 484–486, 6: 567–570 319–320, 322–323 pharmacogenetics, 4: 384–385 induction, 3: 372–380 polymorphisms, 1: 259–261 inhibition, 3: 362–370 pulmonary metabolism, 2: 331 liver transplant, 6: 336–337 rat studies, 6: 73 hepatotoxicity: species differences in drug metabolism, 1: metabolic polymorphism hypothesis, 4: 137, 139–141 597–598 species differences in metabolism, 2: prevention strategies, 4: 181–182 593–594 herb-drug interactions, 2: 817–818, 823, statin therapies, 2: 866–869 824–825, 4: 500–501 xenobiotic metabolism, hepatocyte St. John’s wort, 6: 284–285 assessment, 3: 412–419 in vivo human studies, 4: 504–505 CYP3A1, drug-disease-drug interactions, 4: 636 heterocycle reduction, 1: 330–331 CYP3A2: human expression and activity, 6: 67–68 INDEX 687

induction studies, 6: 15–16 hepatic drug metabolism, in children, 6: 318 irreversible inhibitors, 6: 29–30 human expression and activity, 6: 67–68 letrozole, ADME studies, 2: 844 pediatric drug metabolism, 6: 544–547 Lipitor metabolism, 6: 615–616 pharmacogenetics, 4: 384–385 mitochondrial superoxide drug reactions, 4: polymorphisms, 1: 261 577 pregnancy drug metabolism, 2: 947–951 mitochondrial toxicity, 6: 430–431 in vitro-in vivo correlation studies, 6: 79 nefazodone metabolite formation and CYP3A8, monkey studies, 6: 75 covalent binding, 3: 198–199 CYP3A43: NME-precipitated induction, 6: 111–115 central nervous system metabolism, 2: OATP transporters, drug-drug interactions, 2: 332–333 223–224 pediatric drug metabolism, 6: 544–547 oral absorption and intestinal metabolism, 2: pharmacogenetics, 4: 384–385 93–94 polymorphisms, 1: 259–260 oral chemotherapeutic agents, 6: 501–503 dog studies, 6: 74 organ metabolism/transport, 2: 560–564 drug-disease-drug interactions, 4: 636 pediatric drug metabolism, 6: 544–547 cancer, 4: 630 pharmacogenetics, 4: 384–385 intestinal extraction, 2: 480–484 polymorphisms, 1: 259–261 pediatric drug metabolism, 6: 544–547 pregnancy drug metabolism, 2: 947–951 pharmacogenetics, 4: 384–385 psychotropic drug metabolism, 6: 464–465, rat studies, 6: 73 467–468 CYP4 subfamily: pyrrolizidine alkaloid ADME and toxicity, 2: cardiovascular drug metabolisms, 2: 863 926–927 CYP4A, peroxisome-proliferator-activated raloxifene hepatotoxicity risk, 4: 182–183 receptor, mouse model, 3: 662–663 receptor cross talk, transcriptional gene drug-disease-drug interactions, 4: 637 regulation, 1: 220–221 human expression and activity, 6: 68–69 reversible inhibitors, 6: 28–29 monkey studies, 6: 76 in silico studies, 3: 68–69, 249–250 rat studies, 6: 73 skin absorption, 2: 334 cytokines, 4: 646–649 substrate inhibition, 3: 304 drug discovery and development, 3: 14–17 substrate stereoselective metabolism, 4: 353 biotransformation, 6: 56–61 urinary metabolism, 2: 331 catalytic cycle, 6: 54–56 in vitro-in vivo correlation studies, 6: 79 ethnic variablity in, 6: 76–77 in vitro toxicity studies, intestinal mucosa, 4: future research issues, 6: 79–80 226–233 metabolic stability, in vitro studies, 3: 55–56 xenobiotic metabolism, hepatocyte nomenclature and classification, 6: 54–55 assessment: reaction phenotyping, 1: 59–61 hepatobiliary transport, 3: 420–428 research background, 6: 53–54 induction, 3: 412–419 species differences in drug metabolism, 6: inhibition studies, 3: 405–409 61–76 CYP3A4/5: in vitro-in vivo extrapolation, 6: 77–79 drug-drug interactions, in vitro-in vivo drug-disease-drug interactions: correlation, 4: 415–425 central nervous system, 4: 641 early drug development, 3: 104 intestinal metabolism, 4: 639–640 thalidomide, ADME studies, 2: 846–847 kidneys, 4: 640–641 CYP3A5: lungs, 4: 640 age-dependent drug metabolism, 4: 461–462 drug-drug interactions: biotransformational polymorphism, 6: 22 anticonvulsants, 6: 476 central nervous system metabolism, 2: 333 bioanalysis guidelines, 5: 500–501 hepatic drug metabolism, inhibition, 3: 367 competitive and noncompetitive inhibition, 6: human expression and activity, 6: 67–68 156–158 pediatric drug metabolism, 6: 544–547 genetic polymorphisms and pharmacogenetics, pharmacogenetics, 4: 384–385 6: 169–170 polymorphisms, 1: 261 high-throughput screening assays, 6: 166–167 urinary metabolism, 2: 331 induction, 1: 63–65, 2: 17–18, 6: 158–160 CYP3A7: future research issues, 4: 444–445 age-dependent drug metabolism, 4: 460–462 pharmacodynamics, 4: 439–444 688 INDEX

Cytochrome P450 (CYP) superfamily (Continued) pathophysiology and inborn errors of therapeutic efficacy, 4: 439–441 metabolism, 2: 350–354 toxicity effects, 4: 441–444 food-drug interactions, grapefruit juice, 6: pharmacokinetics, 4: 430–439 290–296 clearance-dependent induction, 4: 434–437 future research issues, 1: 175–176, 6: 79–80 route-dependent induction, 4: 433–434 genetically modified animal models, 3: 630–640 theoretical issues, 4: 430–433 genomic structure, 1: 162–165 time- and dose-dependent induction, 4: hepatic drug metabolism, 6: 312 437–439 alcoholism, 6: 322–323 research background, 4: 429 in children, 6: 317–318 inhibition, 1: 61–63, 3: 57–58 cholestatic disease, 6: 323–324 ADME studies, 2: 16–17 cirrhosis, 6: 328–329 reversible inhibition, 3: 57–58 clearance mechanisms, 6: 313–317 multiple enzyme studies, 6: 164–165 in elderly, 6: 318–319 NME precipitants: future research issues, 3: 380 clinical pharmacology, 6: 115–120 herb-drug interactions, 6: 338–339 induction, 6: 108–115 liver disease, 6: 321–322 inhibition, 6: 93–101 liver transplant, 6: 334 quantitative magnitude predictions, 6: predictive studies, metabolism and drug-drug 98–101 interactions: surrogate selection, 6: 97–98 induction, 3: 371–379 in vitro studies, 6: 93–97 FαN-4 cells, 3: 377–378 mechanism-based inactivation, 6: 101–108 HepaRG cells, 3: 376–377 oral drug induction, 3: 10 human hepatocytes, 3: 375–376 predictive studies, 6: 155–156 reporter gene assay, 3: 372, 374–375 in vitro-in vivo correlation, 4: 413–425, in vivo studies, 3: 378–379 417–425 inhibition, 3: 359–371 drug metabolism, 1: 29 reversible inhibition, 3: 359–365 in vitro models, 1: 45 time-dependent inhibition, 3: 365–367 early drug development: in vivo inhibition, 3: 367–371 clinical pharmacology, 3: 104 metabolic stability, 3: 353–355 drug-drug interactions, 3: 111–115 research background, 3: 351–352 metabolic disposition studies, 3: 110–111 total metabolism, 3: 355 nonclinical studies, 3: 96–98 in vivo pharmacokinetics, 3: 355–358 electrochemical liquid chromatography mass pregnancy, 6: 319–320 spectrometry, “mimicry” of metabolism, 5: herb-drug interactions: 321 bitter orange, 2: 813 electron-donor partners, 1: 172–173 black cohosh, 2: 813–814 enzyme-catalyzed reduction reactions, 1: 381–384 curcumin, 2: 814–815 cytochrome P450, 1: 384 danshen, 2: 815 dechlorination, 1: 383 dong quai, 2: 815–816 hydroperoxides, 1: 383–384 echinacea, 2: 816, 6: 286 quinones, 1: 381–383 garlic, 2: 816–818, 6: 286–287 α,β-unsaturated aldehydes, 1: 384 ginseng, 2: 813 enzyme kinetics: green tea, 2: 820 atypical reactions, 3: 298–304 kava kava, 2: 820–821, 6: 288 non-Michaelis-Menten enzyme kinetics, 1: licorice, 2: 821 81–87 liver disease, 6: 338–339 solvent effects, 3: 298 milk thistle, 2: 821–822 substrate inhibition, 3: 302–304 regulatory issues, 2: 794 in vitro studies, 3: 289–292 St. John’s wort, 2: 823–825, 6: 281–286 epoxide hydrolases, 1: 394 saw palmetto, 2: 822 ethnic variability in, 6: 76–77 Siberian ginseng, 2: 823 extrahepatic metabolism, 2: 328–334, 371 human enzymes: age and gender factors, 2: 344, 350 classification, 6: 54 drug-drug interactions, 2: 376–380 structures, 1: 169–172 food-drug interactions, 2: 354 hydroperoxide reduction, 1: 383–384 genetic polymorphisms, 2: 344–349 idiosyncratic adverse drug reactions, 6: 418–419 INDEX 689

drug-induced liver injury, metabolic catalytic cycle, 2: 256–258 polymorphism hypothesis, 4: 597–598 clopidogrel and prasugrel, 6: 365–367 induction studies: olefin oxidation, 2: 259–260 precision cut tissue slices, 3: 469–470 pediatric populations, 6: 540–547 in vitro ADME studies, 3: 59 protease inhibitors, drug-drug interactions, 6: inflammation, regulation mechanisms, 4: 649–651 368 inhibition studies: phytochemical modulators: drug-drug interactions, 6: 93–101 dietary supplement-drug interaction, 4: competitive and noncompetitive inhibition, 6: 515–516 156–158 kava kava, 4: 521–522 quantitative magnitude predictions, 6: methylenedioxyphenyl compounds, 4: 98–101 518–526 surrogate selection, 6: 97–98 St. Johns wort, 4: 532 in vitro studies, 6: 93–97 food-drug interactions: hepatic drug metabolism, 6: 313–317 citrus juices, 4: 496–499 predictive studies, 3: 359–371 cruciferous vegetables, 4: 494–496 inhibition, 3: 359–371 plant secondary metabolites, 4: 488–494 reversible inhibition, 3: 359–365 human studies, 4: 490–492 time-dependent inhibition, 3: 365–367 polymorphisms: in vivo inhibition, 3: 367–371 clinical significance, 1: 239–241 metabolic stability, 3: 353–355 CYP3 subfamily, human drug-metabolizing research background, 3: 351–352 enzymes, 1: 259–261 reversible inhibition, 3: 359–365 dietary plant secondary metabolites, 4: 492–494 time-dependent inhibition, 3: 365–367 dose calculations and, 6: 617–618 total metabolism, 3: 355 drug-drug interactions, 6: 169–170 in vivo inhibition, 3: 367–371 future research issues, 1: 261–262 in vivo pharmacokinetics, 3: 355–358 human drug-metabolizing enzymes, 1: 241–261 herb-drug interactions, 2: 812 idiosyncratic drug-induced liver injury, translational research, 2: 754–756, 755–756 metabolic polymorphism hypothesis, 4: in vitro studies, 5: 7–8 597–598 intestinal metabolism, 2: 317, 328–329 pharmacogenetics, 1: 240–241 Caco-2/TC7 cell line comparisons, 3: 339 precision-cut tissue slices, induction studies, 3: isoforms, summary table, 6: 61–63 471–478 mechanism-based inhibition, 2: 756–757 cryopreservation, 3: 481–485 metabolite identification, lability reduction, 3: pregnancy drug metabolism, 2: 945–951 122–123 psychotropic drug metabolism (See also specific monoclonal antibody analyses: CYP compounds under this heading) allele specificity, 3: 452–453 pulmonary system metabolism, 2: 329–331 enantiomer specificity, 3: 453–454 reaction mechanisms: epitope specificity, 3: 452 active oxygenation, 1: 186–188 human liver microsomes, 3: 448–451 complex drug transformations, 1: 195–196 multifunctional compounds, 3: 462–463 future research issues, 1: 196 research background, 3: 447–448 oxidation, 1: 190–194 single CYP450 metabolism, 3: 454–459 carbon, 1: 190 nomenclature, 1: 165–166, 6: 54 heteroatoms, 1: 190–193 pharmacogenetics, 4: 380–386 π-bond substrates, 1: 193–194 CYP1 subfamily, 4: 385–386 rate-limiting procedures, 1: 188–190 CYP2 subfamily, 4: 381–384 research overview, 1: 181–184 CYP2A, 4: 383–384 substrate binding, 1: 184–186 CYP2B, 4: 384 in vitro toxicity studies, 4: 240 CYP2C, 4: 382–383 renal disease, 4: 644 CYP2D, 4: 381–382 research background, 1: 161–165 CYP3 subfamily, 4: 384–385 safety testing: drug-drug interactions, 6: 169–170 reactive metabolites, 3: 228–237 pharmacokinetic modeling, 6: 590–591 stable metabolites, 3: 223–227 phase I metabolism, 2: 256–265 sex differences in drug metabolism: aliphatic oxidation, 2: 258–259 hepatic drug-metabolizing enzymes, 1: 104–107 aromatic oxidation, 2: 260–261 hormonal determinants, 1: 107–110 690 INDEX

Cytochrome P450 (CYP) superfamily (Continued) hepatic drug metabolism, 4: 236–239 molecular determinants, 1: 110–112 inhibition and drug-drug interactions, 4: 238, human studies, 1: 106–107 240 rat studies, 1: 105–106 overview, 4: 223–225 research overview, 1: 101–102 polymorphisms, 4: 231–233 sigmoidal autoactivation, 2: 754 in vivo studies, clearance processes, 3: 606–607 in silico studies: xenobiotic metabolism, hepatocyte assessment: drug discovery and development, 3: 270–274 FDA draft guidance concerning, 3: 433–435 mechanisms, 3: 248–251 hepatobiliary transport, 3: 420–428 physiologically-based pharmacokinetic induction, 3: 409–419 modeling, 3: 267–268 inhibition studies, 3: 405–409 skin absorption, 2: 333–334 Cytokines: solute carrier transporters and, 2: 221–223 drug-metabolizing enzymes and drug transporters, species differences in drug metabolism, 1: 52, 4: 645–649 127–141 idiosyncratic drug-induced reactions: dog enzymes, 6: 73–74 drug-inflammation model comparisons, 4: drug discovery and development, 2: 593–594, 611–612 6: 61–76 sulindac, 4: 607–610 α human enzymes, 6: 61–69 tumor necrosis factor- , 4: 603 monkey enzymes, 6: 74–76 inflammation: mouse enzymes, 6: 69–71 drug-disease-drug interactions: regulatory mechanisms, 4: 629 overview, 1: 127–128 research background, 4: 623–625 rat enzymes, 6: 71–73 drug-drug interactions, 4: 623 spectroscopic properties, 1: 168–169 transcriptional regulation, 4: 649–650 stereoselectivity: liver surgery and regeneration, drug metabolism detoxification pathways, 4: 365 and, 6: 331–332 enantiomer-second drug interactions, 4: 361 molybdenum-containing hydrolases, 1: 342–344 inhibition, 4: 359–361 mouse studies, 4: 648–649 substrate metabolism, 4: 352–353 regulation mechanisms, 4: 649–651 sulfonation, allylic alcohols, 4: 123–124 Cytoplasmic receptors, biotransformation, enzyme toxicity studies: induction and, 6: 16 aflatoxin production and toxicity, 2: 919–920 Cytosol, drug metabolism, in vitro models, 1: 46–47 6: reactive metabolite formation, 394–395 Cytosolic glutathione transferases: toxicogenomics, carcinogenicity prediction, 4: 260 genetics, 1: 561 transcriptional gene regulation: human functional genomics: aryl hydrocarbon receptor, 1: 213–215 alpha class, 1: 565–570 constitutive androstane receptor, 1: 211–213 GSTA1, 1: 565, 569 future research issues, 1: 227 GSTA2, 1: 569 genetic polymorphisms, 1: 226 GSTA3, 1: 569 methodology, 1: 222 GSTA4, 1: 570 pregnane X receptor, 1: 206–211 GSTA5, 1: 570 receptor cross talk, 1: 215–221 classification, 1: 562–563 research background, 1: 205–206 function and nomenclature, 1: 563 species specificity, 1: 222–224 genes, 1: 563–565 splice variants, 1: 224–226 alternative splicing, 1: 565 translational research, 2: 752–757 pseudogenes, 1: 563–564 concurrent induction/inhibition, 2: 757 genetic polymorphism, 1: 565–575 drug discovery, ADME studies, 2: 745–746 historical perspective, 1: 561–562 induction, 2: 755–756 mu class, 1: 570–571 inhibition, 2: 754–755 GSTM1, 1: 570 urinary metabolism, 2: 331 GSTM2, 1: 570 in vitro-in vivo extrapolation, 6: 77–79 GSTM3, 1: 571 in vitro studies: GSTM4, 1: 571 inhibition studies, 5: 7–8 GSTM5, 1: 571 organic solvent effects, 1: 77–78 omega class, 1: 574–575 toxicity screening, early drug discovery: GST01, 1: 574–575 gastrointestinal tract, 4: 225–233 GST02, 1: 575 INDEX 691

pi class, 1: 571–572 N-Dealkylation: GSTP1, 1: 571–572 cytochrome P450 oxidation, phase I metabolism, sigma class, 1: 573 2: 261–264 structure and function, 1: 575–579 cytochrome P450 oxidations, 1: 190–193 active site and catalysis, 1: 577–579 hydroxylation, 6: 57–59 crystal structures, 1: 575–577 O-Dealkylation, cytochrome P450 oxidation: theta class, 1: 572–573 hydroxylation, 6: 57–59 GSTT1, 1: 572–573 phase I metabolism, 2: 264–265 GSTT2, 1: 573 P -Dealkylation, cytochrome P450 catalytic cycle, zeta class, 1: 573–574 heteroatom oxidations, 1: 192–194 Cytosolic sulfotransferases, classification and S-Dealkylation, cytochrome P450 catalytic cycle, nomenclature, 1: 530–532 heteroatom oxidations, 1: 192–194 Cytotoxicity assays: Debrisoquine: cancer therapies, 3: 24 cytochrome P450 enzymes and, 6: 67 exploratory toxicology, 2: 776 enantiotopic oxidation to chiral metabolite, 4: 358 pharmacogenetics, 4: 378 “Daily dose of covalent binding” equivalents, Dechlorination, enzyme-catalyzed reduction hepatotoxicity prediction, 4: 176–179 reactions, 1: 383 Daily dose studies, reactive metabolite exposure, 6: Decision-making studies: 393–395 early drug development, clinical pharmacology, 3: Damage-associated molecular patterns (DAMPs), 105 drug-disease-drug interactions, inflammation, 4: solubility and dissolution assessment, oral 626–628 absorption, drug development, decision trees D-amino acid oxidases (DAAO), classification, 1: for, 3: 531–532 374–375 Degree of interaction, organic anion transporter Danger hypothesis: polypeptides, 2: 220–221 drug-induced liver injury, 4: 599 Dehydroepiandrosterone (DHEA), age-dependent hepatotoxicity studies, 4: 163–165 drug metabolism: idiosyncratic adverse drug reactions, 6: 425–426 CYP3A expression, 4: 461–462 Danshen, drug interactions, 2: 815 sulfotransferases, 4: 470 Dapsone, phase II metabolism, N-acetyltransferase, Dehydrogenation reactions, cytochrome P450 2: 286–288 enzymes, 6: 60–61 Data processing: Delayed effect models, pharmacodynamics, 2: biomarkers, PK/PD data quality, 5: 589–593 707–721 high throughput quantitative mass spectrometry, biophase/link models, 2: 708–712 bioinformatics, 5: 564–565 cell life span models, 2: 715–718 imaging mass spectrometry, 5: 230–232 indirect response models, 2: 712–715 ion mobility mass spectrometry-mass spectrometry time-dependent transduction, 2: 718–721 integration, 5: 271–274 Delayed extraction (DE), MALDI-MS techniques, 5: metabonomics analysis, 4: 286–288 124 microdose studies, accelerator mass spectrometry, Derivatization reactions, metabolite identification, 5: 609–610 mass spectrometry, 5: 36–38 proteomics, multiple reaction monitoring, 4: Dermal absorption: 334–335 CYP enzymes, 2: 333–334 quality controls: pharmacokinetic modeling, 6: 586–588 chiral columns, 5: 529–530 Desalkylflurazepam, phase I metabolism, 6: 357 hybrid silica particles, 5: 528–529 Desaturation, cytochrome P450 reactions, carbon hydrophilic interaction chromatography, 5: oxidation, 1: 190–191 530–531 Desensitization response, pharmacodynamics monolithic columns, 5: 530 mechanisms, 2: 692 pelicular (fused-core) silica, 5: 533 Desflurane, structure-toxicity relationships, 6: research background, 5: 516–518 381–382 sub-2-μm chromatography, 5: 531–532 Design of experiments (DOE) standards, reactive metabolite bioactivation, 5: 647–650 immunoassays, 5: 407 Dead-end complexes, sulfotransferase kinetics, 1: Desloratidine, cytochrome P450 enzymes, 539 dealkylation reaction, 4: 15–16 Dealkylation, cytochrome P450 enzymes, bioactive Desmethyldiazepam, phase I metabolism, metabolites, 4: 15–18 6: 357 692 INDEX

O-Desmethyltramadol, phase I metabolism, 6: Dichloroacetate (DCA), age-dependent drug 358–359 metabolism, glutathione S-transferases, 4: Desorption atmospheric pressure chemical ionization 468–469 (DAPCI): Dichloroacetic acid (DCA), GSTZ1 polymorphisms, ambient ionization and, 5: 568–570 1: 573–574 basic principles, 5: 93–97 Dichlorofluorescin (DCF), in vitro toxicity screening, explosives applications, 5: 103, 106 oxidative stress, 4: 244–245 Desorption atmospheric pressure ionization (DAPPI), 2,6-Dichloro-4-nitrophenol (DCNP), sulfotransferase basic principles, 5: 90–93 inhibition, 1: 546 Desorption electrospray ionization (DESI): Dichotomous response, pharmacodynamics, basic principles, 5: 90–93 mathematical modeling, 2: 703–704 explosives applications, 5: 103, 106 Diclofenac (DCF): high throughput mass spectrometry, 5: 565 bioactivation, 4: 84 ambient ionization and, 5: 568–570 acyl glucuronides, 3: 201–204 image analysis, 5: 109–112 hepatotoxicity, 3: 185 pharmaceuticals and counterfeit drugs, 5: 106–108 phase-II-enzyme-catalyzed xenobiotic conjugation, Desorption/ionization on silicon (DIOS), basic glucuronidation, 4: 117–118 principles, 5: 131–132 Dielectric barrier discharge ionization (DBDI): Desorption properties, MALDI-MS techniques, 5: basic principles, 5: 93–97 125 explosives applications, 5: 103, 106 Desorption sonic spray ionization (DeSSI), basic Diet: principles, 5: 90–93 biotransformation mechanisms and, 6: 35 Desvenlafaxine, cytochrome P450 enzymes, drug metabolism, 1: 31 dealkylation reactions, 4: 15–18 xenobiotics, 1: 126 Detection enhancement, micellar electrokinetic Dietary Supplement Health and Education Act chromatography, 5: 432–434 (DSHEA): Detoxification, insecticides, carboxylesterases, 1: 427 dietary supplements regulation, 2: 793–807 Detoxification pathways, stereoselectivity in, 4: 365 herb-drug interactions, 4: 499–500 Deuteration effects, cytochrome P450, 1: 189–190 Dietary supplements. See also Food-drug Deuterium isotope effects, cytochrome P450 catalytic interactions; Herb-drug interactions cycle, heteroatom oxidations, 1: 191–193 ADME studies: Developmental defects, cytochrome P450 aloe, 2: 812–813 polymorphisms, CYP1B subfamily, 1: 247–248 bitter orange, 2: 813 Developmental switch, age-dependent drug black cohosh, 2: 813–814 metabolism, future research issues, 4: 473–474 cranberry, 2: 814 Dextran sulfate sodium (DSS), chemically induced curcumin, 2: 814–815 inflammatory bowel disease, 4: 632 danshen, 2: 815 Dextromethorphan, N-andO-demethylation, 1: 6–7 dong quai, 2: 815–816 Dextromethorphan O-demethylase: echinacea, 2: 816 age-dependent drug metabolism, CYP2D6 evening primrose oil, 2: 816 expression, 4: 458–459 future research issues, 2: 825–826 drug-disease-drug interactions, CYP2D, 4: garlic, 2: 816–818 634–635 ginger, 2: 8181 pediatric drug metabolism, 6: 543 Gingko biloba, 2: 818–820 Dextrorotatory compounds, stereoselectivity, 4: ginseng, 2: 813 346–351 green tea, 2: 820 DHEA, sulfotransferase: herb-drug interactions: endogenous substrate sulfation, 1: 542 assessment, 2: 807–809 enzyme kinetics, 1: 539–540 CYP induction and metabolism, 2: 812 Diabetes, peroxisome-proliferator-activated receptor, CYP inhibition and metabolism, 2: 811–812 mouse model, 3: 662–663 transporter-associated absorption, 2: 809–811 Diagnostic biomarkers, drug discovery and underlying mechanisms, 2: 809–812 development, 5: 580–581 kava kava, 2: 820–821 Diamine oxidase (DAOs), classification, 1: 369 licorice, 2: 821 Diazepam, age-dependent metabolism, CYP2C milk thistle, 2: 821–822 expression, 4: 457–458 regulatory issues, 2: 796–807 Dibenzodiazepine, toxicity studies, structure-toxicity research background, 2: 793–796 relationships, 6: 384–385 St. John’s wort, 2: 823–825 INDEX 693

saw palmetto, 2: 822 flavin-containing monooxygenase metabolism, 1: Siberian ginseng, 2: 823 292 US herb use, 2: 812–826 solubility and dissolution assessment, oral valerian, 2: 825 absorption, 3: 514–515 drug conjugation and transport, 6: 226–227 Dipeptidyl peptidase IV, diclofenac glucuronidation, drug interaction, 4: 506–532 4: 117–118 black cohosh, 4: 506–507 Direct analysis in real time (DART) ambient Echinacea spp., 4: 507–510 ionization: garlic, 4: 510–513 basic principles, 5: 93–97 ginkgo biloba, 4: 513–516 explosives applications, 5: 103, 106 ginseng, 4: 516–518 high throughput mass spectrometry, 5: 565 goldenseal, 4: 518–520 ambient ionization and, 5: 568–570 kava kava, 4: 521–522 image analysis, 5: 109–112 methylenedioxyphenyl compounds, 4: 518–526 pharmaceuticals and counterfeit drugs, 5: 107–108 milk thistle, 4: 526–528 Direct effect models, pharmacodynamics, 2: piperine/black pepper, 4: 522–525 706–707 Schisandra spp., 4: 524–526 Direct immunoassays, basic principles, 5: 405–406 St. John’s wort, 4: 529–532 Direct injection high efficiency nebulizers herb-drug interactions, 4: 499–500 (DIHENs), inductively coupled plasma mass Differential high/low field ion mobility spectrometry, spectrometry-liquid chromatography integration, basic principles, 5: 265–266 5: 293 Differential mass analyzers (DMAs), ion mobility Direct plasma analysis, monolithic chromatography, 5: mass spectrometry, 5: 266–267 457 Discontinuous absorption model, plasma Differential mobility spectrometry, basic principles, concentration-time data, 2: 615–617 5: 265–266 Disease states: Diffusion, distribution mechanisms, 2: 120–121 ABC transporter mutations, 2: 179–180 Diffusion-controlled dissolution, solubility and biomarkers: dissolution assessment, oral absorption, 3: drug discovery and development, 5: 522–525 580–581 Digoxin: early drug development, decision-making distribution mechanisms and delivery systems, 2: studies, 3: 106–109 112–113 biotransformation and, 6: 34–35 dose calculations, 6: 616 blood-brain barrier penetration, in vitro studies, food-drug interactions, grapefruit juice, 6: 3: 576 292–293 drug metabolism, 1: 31 herb-drug interactions, St. John’s wort, 6: 285 drug therapy and, 4: 622–624 physiologically-based pharmacokinetic modeling, drug transporters, 4: 643–644 hepatic metabolism, 2: 651–652 liver disease, hepatic drug metabolism: Dihydroartemisinin (DHA), metabolite analysis, 2: alcoholism, 6: 322–323 623 cholestatic disease, 6: 323–324 Dihydropyrimidine dehydrogenase (DPD), drug-drug future research issues, 6: 339 interactions, clinical perspectives, 6: 91–92 Gilbert’s syndrome, 6: 324–325 3,4-Dihydroxyphenylacetaldehyde (DOPAL), MAO herb-drug interactions, 6: 338–339 formation and bioactivation, 4: 72–74 parenchymal disease, 6: 321–322 Dilute and shoot paradigm: pathology, 6: 320–321 monolithic columns, 5: 530 research background, 6: 307–308 sample/chromatography quality control, 5: physiologically-based pharmacokinetic modeling, 520–521 2: 667–670 Dilution, bioanalysis guidelines, 5: 485–487 progression models, pharmacodynamics, 2: 4-Dimethylaminobenzene (DAB), sulfonation, 4: 724–727 124–126 Disintegration per minutes (DPM), mass balance 7,12-Dimethylbenz[a]anthracene (DMBA) studies, animal studies, 2: 423–425 carcinogenesis, microsomal epoxide hydrolase Disk intrinsic dissolution rate (DIDR): expression, knockout mice, 3: 641–642 defined, 3: 512 Dimethylsulfoxide (DMSO): solubility and dissolution assessment, oral cryopreserved precision cut tissue slices, 3: absorption, dissolution measurement, 3: 482–485 522–523 694 INDEX

Disposition kinetics: rate of, 2: 84–85 cell-based studies, 2: 515–516 research background, 3: 493–495 distribution mechanisms, 2: 143–147 schematic, 3: 508 early drug development, metabolic disposition solubility assays, 3: 518–522 studies, 3: 110–111 equilibrium solubility protocols, 3: 521–522 solubility and dissolution assessment, oral intrinsic solubility protocols, 3: 522 absorption, BDDCS classification, 3: kinetic solubility protocols, 3: 518–521 504–507 Distal biomarkers, pharmacodynamics studies, 2: Dissociation constant (pKa): 698–699 distribution mechanisms, 2: 109–112 Distribution mechanisms: drug-protein binding, 2: 532–536 clinical disposition alterations, 2: 143–147 Dissolution: absorption and, 2: 143 ADME mechanics, 2: 7 renal elimination, 2: 143, 146 oral absorption: transporter-mediated distribution, 2: 146–147 bioavailability determinants, 2: 472 defined, 2: 5 Biopharmaceutical Classification System, 3: distribution calculation, 2: 138–143 501–504 hepatic drug clearance, 2: 142 drug discovery and development, 3: 505–507 one-compartment model, 2: 139–140 Biopharmaceutical Drug Disposition PBPK tissue distribution models, 2: 142–145 Classification System, 3: 504–505 two-compartment model, 2: 140–142 drug discovery and development, 3: 505–507 drug discovery and development, 2: 34–35 definitions, 3: 508–512 early drug development, labeling issues, 3: 114 dissolution, 3: 511–512 future research issues, 2: 147 solids, 3: 510 imaging mass spectrometry, 5: 246–248 solubility, 3: 508–510 pharmacokinetic modeling, 6: 588–590 dissolution measurement, 3: 522–530 plasma concentration-time data, 2: 618–622 intrinsic dissolution, 3: 528–530 physicochemical factors, 2: 108–113 powder dissolution, 3: 526–528 drug delivery systems, 2: 112–113 excipient effects on drug disposition, 3: lipophilicity, pH, dissociation, and ionization, 2: 543–544 109–112 formulation strategy, impact on, 3: 540–541 molecular size, 2: 112 decision trees, 3: 531–532 physiological factors, 2: 113–125 high energy solids, 3: 534–535 blood flow, 2: 117 multicomponent solids, 3: 535–537 capillary permeability, 2: 121–122 cocrystals, 3: 536 drug distribution barriers, 2: 122–125 cyclodextrins, 3: 536–537 blood-brain barrier, 2: 124–125 hydrates, 3: 536 mammary gland, 2: 123–124 salts, 3: 535–536 maternal:fetal barrier, 2: 123 solid solutions and dispersions, 3: 537 drug distribution patterns, 2: 116–117 precipitation formulation, 3: 540–541 perfusion and diffusion, 2: 120–121 solution formulations, 3: 537–540 plasma protein binding, 2: 118–119 cosolvents, 3: 538 red blood cell partitioning, 2: 119–120 cyclodextrins, 3: 538–539 tissue storage, 2: 122 lipids, 3: 539–540 water barriers, 2: 114–116 micelles, 3: 539 regulatory issues, 2: 758–760 pH adjustment, 3: 538 research background, 2: 107–108 surface area modification, 3: 532–534 solubility and dissolution assessment, oral future research issues, 3: 544–545 absorption, 3: 514–515 measurement techniques, 3: 513–518 solute carrier transporters, 2: 202–208 assay components, 3: 513–514 transporters, 2: 125–129 compound distribution, 3: 514–515 ABC transporters, 2: 126–128 compound/solvent mixing, 3: 516 barrier membrane expression, 2: 129 solid-liquid separation, 3: 516–517 clinical distribution alterations, 2: 146–147 solute-solid analysis, 3: 517 SLC transporters, 2: 126, 129–131 solvent distribution and selection, 3: 515 in vitro studies, 2: 129–135 preclinical formulations, candidate profiling, 3: brain tissue distribution, 2: 134–135 541–542 plasma protein binding, 2: 129, 132–133 rate-limiting-steps, 3: 495–501 transporter studies, 2: 133–134 INDEX 695

in vivo studies, 2: 135–138, 3: 598–603 Dopamine: animal studies, extrapolation to humans, 3: 599 age-dependent drug metabolism, sulfotransferases, CNS penetration, preclinical species, 3: 4: 470 600–602 monoamine oxidase bioactivation, 4: 72–74 free drug hypothesis, 3: 599 phase I metabolism, monoamine oxidase, 2: human studies, 2: 137–138 269–271 passive drug movement barriers, 3: 599–600 transporters, pregnancy drug metabolism, 2: 943 preclinical animals and ex vivo organs, 2: Dose calculations: 135–136 administration formulation and methods, 6: 612 preclinical studies, 3: 602–603 age factors, 6: 612 Diuretics, ADME studies, 2: 871 daily dose studies, 6: 393–395 Divalent cations, sulfotransferase kinetics, 1: dose recommendations, 6: 611–612 540–541 ethnic differences, 6: 618 Dixon plots: future research issues, 6: 619 drug-drug interactions: genetic polymorphism, 6: 617–618 competitive inhibition, 4: 408–409 hepatic impairment, 6: 614 inhibition mechanisms, 4: 407–413 human studies, mass balance studies, 2: 441–446 noncompetitive inhibition, 4: 410–411 effective dose, 2: 445–446 uncompetitive inhibition, 4: 411–413 gastrointestinal tracts, 2: 444–445 enzyme kinetics, mechanism-based inhibition, 1: organs and tissues, 2: 445 94–96 individualized drug therapy, 6: 618 DNA adducts: mass balance studies, animal studies, 2: 420–421 microdose studies, accelerator mass spectrometry, metabolic pathways, 6: 614–616 5: 614 pediatric drug clearance and exposure, 6: 562–563 reactive metabolite bioactivation, 5: 639–642 pharmacokinetics/toxicokinetics prediction DNA-binding domain (DBD): modeling, 2: 588–592 ABC transporter transcriptional regulation, 2: 174 radiation dosimetry, whole-body autoradiation aflatoxin production and toxicity, 2: 920 studies, 5: 381–383 aristolochic acid ADME and toxicity, 2: 922 recommended doses, 6: 611–612 pharmacokinetic predictive studies, 2: 515 renal impairment, 6: 613 platinum compounds, inductively coupled plasma research background, 6: 609–610 mass spectrometry, 5: 298 size and weight factors, 6: 613 DNA fragmentation, xenobiotic metabolism, Dose-dependent induction, drug-drug interactions, hepatocyte assessment, hepatotoxicity assays, 3: CYP enzymes, 4: 437–439 431–432 Dose number, ADME studies, pharmacokinetics, 3: DNA methylation, idiosyncratic adverse drug 74–80 reactions, epigenetic inhibition, 6: 428 Dose range finding, drug discovery and development, DNA microarrays, in vitro assays, 3: 318–328 exploratory toxicology, 2: 770–777 ADME studies, 3: 320–324 Dose-response relationship: Bioinformatics, 3: 327–328 active metabolites, cytochrome P450, 4: 26–27 toxicogenomics, 3: 324–327 pediatric drug clearance and exposure, 6: 562–563 Docetaxel: Double knock-out mouse models: biotransformational polymorphism, 6: 23–24 monoamine oxidase A/B, 3: 647 in vitro toxicity studies, 4: 226–228 organic cation transporters, 3: 675 Docking mechanisms, in silico studies, 3: 254 Doxepin, CYP2D6 metabolism, 6: 458, 461–463 drug-drug interactions, 3: 259–261 DPP4 inhibitor, C-demethylation of, 1: 10 drug-metabolizing enzymes and transport proteins, Dried-droplet method: 3: 263–264 bioanalysis regulations, blood spots, 5: 507–508 Documentation guidelines, bioanalysis, 5: MALDI-MS sample preparation, 5: 126 502–503 Drift tube ion mobility mass spectrometry: Dog-human proportionality method, allometric basic principles, 5: 262–264 scaling pharmacokinetics, 2: 506–508 kinetic parameters, 5: 259 Dog studies: Drive voltage, quadrupole ion trap mass cytochrome P450 enzymes, 6: 73–74 spectrometry, 5: 154 MDR1 model, 3: 668 Droplet pick-up mechanism, spray-based ionization, in vivo studies, oral absorption and bioavailability, 5: 90–93 3: 596–597 Drug candidate selection, flavin-containing Dong quai, drug interactions, 2: 815–816 monooxygenases, 1: 285–287 696 INDEX

Drug delivery systems: future research issues, 5: 593–594 distribution mechanisms, 2: 112–113 patient selection and trial stratification, MALDI-MS characterization, 5: 140–141 5: 581–583 platinum compounds, inductively coupled plasma pharmacodynamic biomarkers, 5: 582 mass spectrometry, 5: 302–303 characteristics, 5: 584–585 Drug discovery and development: PK/PD models, 5: 582–583 ADME studies, 2: 33–36 assay and data quality, 5: 589–593 assays, table of, 2: 21–22 fit-for-purpose models, 5: 585–587 CYP 450 inhibition, 3: 15 study design, 5: 588–589 drug candidate selection: quantitative/qualitative assays, 5: 587–588 extrinsic attenuating factors, 3: 52–53 research background, 5: 577–579 intrinsic attenuating factors, 3: 52 target, mechanism, outcome, and surrogate Lipinski’s “rule of five” and, 3: 47–54 biomarkers, 5: 579–580 natural products, 3: 54 translational research, 5: 583, 593 Pajouhseh’s “rules,” central nervous system biotransformation, 6: 35–41 compounds, 3: 48–49 drug interactions, 6: 40 physicochemical properties, 3: 47–54 drug metabolites, 6: 36–39 research background, 3: 43–47 pathway predictions, research background, future research issues, 2: 36, 3: 21 6: 178–180 human metabolism studies, 3: 20–21 pharmacogenetics, 6: 40–41 induction screening, 3: 14–15 processes and methods, 6: 36 metabolite identification, 3: 62–65 cytochrome P450 (CYP) superfamily: multiparameter optimization, 3: 70–71 biotransformation, 6: 56–61 oral drug requirements, 3: 6–10 catalytic cycle, 6: 54–56 pharmacokinetics improvements, 3: 71–80 ethnic variablity in, 6: 76–77 plasma protein binding, 3: 16–17 future research issues, 6: 79–80 prodrug use and abuse, 3: 18–20 nomenclature and classification, 6: 54–55 research background, 3: 3–6 research background, 6: 53–54 in silico modeling, 3: 65–70 species differences in drug metabolism, 6: solubility, permeability, and metabolic stability, 61–76 3: 15–16 in vitro-in vivo extrapolation, 6: 77–79 stages of, 3: 4–6 drug-drug interactions, risk assessment target space properties, 3: 6–8 framework, 6: 92–93 tissue distribution, 3: 61–62 flavin-containing monooxygenases, overview, 1: in vitro-in vivo correlation, 3: 17–18 279–281 data integration, 3: 17–18 hybrid mass spectrometry: DDI prediction, 2: 11–12 development stage studies, 5: 180–181 in vitro studies, 2: 24–32, 3: 11–14 discovery stage studies, 5: 178–180 compound progression, 3: 11–13 Lipinski’s rule-of-five and, 3: 47–54 CYP induction, 3: 59 metabolic activation reduction and, 4: 168–172 drug candidate selection, 3: 54–60 metabolism studies, 1: 58–65 drug-drug interactions, 3: 57–58 drug-drug interactions, 1: 61–65 linear/nonlinear processes, 3: 13–14 human hepatic clearance predictions, 1: 58–59 metabolic stability, 3: 55–57 reaction phenotyping, 1: 59–61 permeability, 3: 55 metabolite identification, 3: 121–126 phenotyping, 3: 57 active metabolites, 3: 124 plasma protein and tissue binding, 3: 59 chemically reactive metabolites, 3: 123 transport assays, 3: 59–60 clearance routes, 3: 123 in vivo studies, 3: 60–61 cross-species comparisons, 3: 125 ambient ionization applications, 5: 106–108 human clearance pathways, 3: 125–126 anticonvulsants, 6: 492–494 lability reduction, 3: 122–123 attrition rates in, 3: 44–47 microautoradiography, 5: 386–388 bioanalysis: microdose studies, accelerator mass spectrometry, in vitro studies, 5: 4–10 5: 606–610 in vivo studies, 5: 10–13 nuclear magnetic resonance applications, 5: biomarkers: 346–353 assay validation vs., 5: 593 pediatric patients, research limitations and design disease and diagnostic biomarkers, 5: 580–581 parameters, 6: 566–570 INDEX 697 pharmacodynamics, biomarkers, 2: 701–703 two-dimensional-based protein expression pharmacogenetics and, 6: 21–22 analysis, 4: 313–322 pharmacokinetics: electrospray ionization mass spectrometry, 4: area under the curve values, 2: 584–585 319–320 bioavailability, 2: 588 first-dimension isoelectric focusing, 4: 315 clearance mechanisms, 2: 585–587 image analysis, 4: 317 clinical dose predictions, 2: 588–592 immunoblotting, 4: 318 compartmental analysis, 2: 590–592 mass spectrometric peptide mass noncompartmental analysis, 2: 589–590 fingerprinting, 4: 318–319 future research issues, 2: 596–597 protein detection and quantification, 4: half-life, 2: 588 316–317 maximum plasma concentration/time of protein identification, 4: 317–318 maximum concentration, 2: 585 sample preparation, 4: 315 MIST guidelines, 2: 594–596 second-dimension SDS-PAGE, 4: 315–316 research background, 2: 582–583 toxicity studies, 4: 322 species differences in disposition, 2: 593–594 two-dimensional difference gel steady state, 2: 587 electrophoresis, 4: 320–321 toxicogenomics and biomarkers, 2: 592–593 two-dimensional electrophoresis, 4: 313–314 volume of distribution, 2: 587 quantitative whole-body autoradiography: phase I metabolism, 6: 354–355 ADME studies, 5: 380–381 plasma protein binding: melanin binding, 5: 373–375 basic techniques, 5: 660–661 peptide and protein therapeutics, 5: 378–380 capillary electrophoresis, 5: 666–667 postapproval studies, 5: 383 chromatographic techniques, 5: 665–666 radiation dosimetry predictions, 5: 381–383 emerging technologies, 5: 665–666 therapeutic peptides and proteins, 5: 378–380 equilibrium dialysis, 5: 661, 663–664 in silico studies, 3: 268–274 radiometry vs. LC-MS/MS, 5: 664–665 solubility and dissolution assessment, oral research background, 5: 657–660 absorption: solid-phase microextraction, 5: 669 BCS/BDDCS classifications, 3: 505–507 spectroscopic methods, 5: 668 formulation strategy, impact on, 3: 540–541 surface plasmon resonance biosensors, 5: 668 decision trees, 3: 531–532 TRANSIL™ membrane and protein beads, 5: high energy solids, 3: 534–535 669–670 multicomponent solids, 3: 535–537 ultracentrifugation, 5: 664 cocrystals, 3: 536 ultrafiltration, 5: 661 cyclodextrins, 3: 536–537 undeterminable protein binding, 5: 670–671 hydrates, 3: 536 in vitro study comparisons, 5: 662 salts, 3: 535–536 procedures, 1: 14–16 solid solutions and dispersions, 3: 537 clinical development, 1: 15–16 precipitation formulation, 3: 540–541 discovery phase, 1: 14–15 solution formulations, 3: 537–540 preclinical development, 1: 15 cosolvents, 3: 538 proteomics: cyclodextrins, 3: 538–539 bioinformatics, 4: 337 lipids, 3: 539–540 future research issues, 4: 337 micelles, 3: 539 liquid chromatography mass spectrometry-based pH adjustment, 3: 538 analysis, 4: 322–336 surface area modification, 3: 532–534 data interpretation, 4: 335 stereoselective research, 4: 366 label-free protein quantification, 4: 325–332 toxicity studies: MRM transition determination, 4: 332–334 area under the curve values, 2: 584–585 peptide selection, 4: 332 bioavailability, 2: 588 quantification and data analysis, 4: 334–335 clearance mechanisms, 2: 585–587 quantitative applications, 4: 335–336 clinical dose predictions, 2: 588–592 stable-isotope-labeled protein quantification, compartmental analysis, 2: 590–592 4: 323–325 noncompartmental analysis, 2: 589–590 targeted analysis techniques, 4: 332–335 future research issues, 2: 596–597 platforms, 4: 312 half-life, 2: 588 protein microarray, 4: 336–337 maximum plasma concentration/time of research background, 4: 311–312 maximum concentration, 2: 585 698 INDEX

Drug discovery and development (Continued) drug transporters, 4: 641–645 MIST guidelines, 2: 594–596 extrahepatic tissues, 4: 644 research background, 2: 583–584 LPS model, 4: 643 species differences in disposition, 2: 593–594 sterile inflammation, 4: 643 steady state, 2: 587 viral infection, 4: 643 toxicogenomics and biomarkers, 2: 592–593 extrahepatic metabolism, 4: 639–641 toxicophore restriction, 6: 390–391 flavin monooxygenases, 4: 637–638 volume of distribution, 2: 587 intestinal metabolism, 4: 639–640 toxicogenomics, 4: 253–254 kidney metabolism, 4: 640–641 translational drug discovery: lung metabolism, 4: 640 biomarkers, 2: 777–781 research background, 4: 623–624 computational modeling, 2: 743–746 Drug-drug interactions (DDIs). See also Food-drug procedures, 2: 737–741 interactions in vitro toxicity screening: ABC transporters, 2: 171 covalent binding, 4: 243–244 ADME studies, 2: 15–19 CYP inhibition and potential drug-drug DME induction, 2: 17–18 interactions, 4: 238–240 DME inhibition, 2: 16–17 gastrointestinal tract: DME-transporter interaction, 2: 18 metabolic mechanisms, 4: 232–233 guidelines and sources, 2: 22 phase I/II metabolism, 4: 225–232 plasma protein binding, 2: 18–19 in vitro-in vivo precision cut tissue slices, 4: 233 prediction, correlation failures, 2: 11–12 subcellular fractions, 4: 233 transgenic mice studies, 2: 31 hepatic metabolism and toxicity, 4: 235–238 in vitro-in vivo correlation failures, 2: 11–12 future research models, 4: 246–247 in vitro studies: mitochondrial membrane permeability, 4: 245 drug discovery and development, 3: 57–58 overview, 4: 223–225 plasma protein binding, 2: 31–32 oxidative stress, 4: 244–245 transgenic mice, DDI prediction, 2: 31 primary hepatocytes, sandwich culture, 4: 246 anticonvulsants: reactive metabolite formation, 4: 240–243 brivaracetam, 6: 492–493 in vivo studies: carbamazepine, 6: 477–478 MIST guidelines, 3: 611 clobazam, 6: 478, 480, 482–483 preclinical animal studies, 1: 50–51 clonazepam, 6: 483 5: whole-body autoradiography, 370–383 enzyme induction, 6: 476–477, 481–482 ADME studies, 5: 380–381 enzyme inhibition, 6: 477 brain and cerebrospinal fluid penetration, 5: eslicarbazepine acetate, 6: 483 371–372 ethosuximide, 6: 484 enzyme induction/inhibition, 5: 375–376 felbamate, 6: 484 fetal penetration, 5: 377 future research issues, 6: 494 formulation selection, 5: 377 gabapentin, 6: 484 melanin binding, 5: 373–375 ganaxolone, 6: 493 metabolism/covalent binding, 5: 377 hepatic isoenzymes, 6: 475–476 tissue retention, 5: 378 lacosamide, 6: 485 tumor penetration, 5: 376–378 lamotrigine, 6: 485 xenobiotic metabolism, hepatocyte assessment: levetiracetam, 6: 485–486 metabolic stability, 3: 396–402 oral contraceptives and, 6: 480 metabolite identification, 3: 404–405 oxcarbazepine, 6: 486 Drug-disease-drug interactions (DDDIs), pharmacodynamics and pharmacokinetics, 6: inflammation and infection: 475 biomarkers, 4: 630 phenobarbital, 6: 486–487 central nervous system, 4: 641 phenytoin, 6: 487–488 chronic diseases, 4: 629–630 plasma concentrations, 6: 478–479 conjugation enzymes, 4: 638–639 pregabalin, 6: 488 CYP1 subfamily regulation, 4: 631–632 primidone, 6: 488–489 CYP2 subfamily regulation, 4: 632–635 research background, 6: 473–475 CYP3 subfamily regulation, 4: 636 rufinamide, 6: 489 CYP4 subfamily regulation, 4: 637 seletracetam, 6: 493 cytokines and other mediators, 4: 629 stiripentol, 6: 489–490 INDEX 699

talampanel, 6: 493 in vivo inhibition, 3: 367–371 tiagabine, 6: 490 metabolic stability, 3: 353–355 tonabersat, 6: 493 research background, 3: 351–352 topiramate, 6: 490–491 total metabolism, 3: 355 valproic acid, 6: 491–492 in vivo pharmacokinetics, 3: 355–358 valrocemide, 6: 494 distribution alterations, 2: 146–147 vigabatrin, 6: 492 dose calculations and, 6: 615–616 zonisamide, 6: 492 early drug development: bioanalysis guidelines, 5: 500–501 NDA procedures, 3: 113–114 bioequivalence studies: in vitro studies, 3: 111 basic principles, 2: 462–470 in vivo studies, 3: 111–112 clinical studies, 2: 468 enzyme kinetics, 1: 88–96 future research issues, 2: 486 competitive inhibition, 1: 88–89 parallel-group design, 2: 465 IC50 and Ki parameters, 1: 94–96 partial-block crossover design, 2: 465 irreversible inhibition, 1: 91–94 pharmacodynamic studies, 2: 468 mechanism-based inhibition, 1: 91–94 pharmacokinetic studies, 2: 467 mixed inhibition, 1: 90–91 randomized crossover design, 2: 464–465 noncompetitive inhibition, 1: 89 research background, 2: 455–456 reversible inhibition, 1: 88–91 statistics, 2: 465–466 uncompetitive inhibition, 1: 90 study design, 2: 464–465 extrahepatic metabolism, 2: 376–377 in vitro studies, 2: 469–470 future research issues, 6: 139–140 biotransformation and, 6: 6 induction studies, 1: 63–65 biotransformation and, drug development, 6: 40 inductively coupled plasma mass spectrometry, cardiovascular drugs: ruthenium compounds, 5: 305–306 ADME studies, 2: 863–864 inflammation and, 4: 623 transporters, 2: 869 inhibition studies, 1: 61–63 clinical perspectives, 6: 90–92 basic mechanisms, 4: 406–413 study design, analysis, and results circulating metabolites, 4: 424 interpretation, 6: 129–136 competitive inhibition, 4: 408–409 clinical relevance assessment, 6: 134–136 fraction metabolized, 4: 420–421 statistical issues, 6: 133–134 future research issues, 4: 425 compartmental analysis, 2: 623–626 genotypes, 4: 421–422 cytochrome P450 enzymes: intestinal metabolism, 4: 418–420 CYP2D6, 1: 256–258 mixed inhibition, 4: 413 induction-mediated effects: multiple binding sites, 4: 424–425 future research issues, 4: 444–445 noncompetitive inhibition, 4: 409–411 pharmacodynamics, 4: 439–444 non-P450 metabolism, 4: 422–423 therapeutic efficacy, 4: 439–441 pharmacokinetics, 4: 423–424 toxicity effects, 4: 441–444 protein binding, 4: 422 pharmacokinetics, 4: 430–439 research background, 4: 405–406 clearance-dependent induction, 4: 434–437 stereoselective inhibition, 4: 359–361 route-dependent induction, 4: 433–434 uncompetitive inhibition, 4: 411–413 theoretical issues, 4: 430–433 in vitro-in vivo correlations, 4: 413–425 time- and dose-dependent induction, 4: mechanism-based inhibition, 2: 756–757 437–439 metabolic processes, 1: 20–21 research background, 4: 429 molybdenum-containing hydroxylases, AO inhibition mechanisms, 4: 405–406 drug-drug interactions, 1: 333 predictive studies: new molecular entities: induction, 3: 371–379 clinical evaluation strategies, 6: 121–122 FαN-4 cells, 3: 377–378 clinical pharmacologic evaluation, 6: 115–120 HepaRG cells, 3: 376–377 probe substrate drug selection, 6: 118–120 human hepatocytes, 3: 375–376 CYP induction, 6: 108–115 reporter gene assay, 3: 372, 374–375 endpoints in studies, 6: 111–112 in vivo studies, 3: 378–379 molecular mechanisms and in vitro assay inhibition, 3: 359–371 platforms, 6: 109–111 reversible inhibition, 3: 359–365 quantitative magnitude predictions, 6: time-dependent inhibition, 3: 365–367 113–115 700 INDEX

Drug-drug interactions (DDIs). See also Food-drug prescription guidelines using, 6: 136–139 interactions (Continued) psychotropic drugs, CYP2D6 metabolism, 6: risk assessment from, 6: 112–113 461–463 CYP inhibition studies, 6: 93–101 quinidine, 2: 874–875 inducers, risk assessment with, 6: 126–127 regulatory issues, translational research, 2: mechanism-based CYP inactivation, 6: 757–761 101–108 research background, 6: 89–90 CYP turnover half-life, 6: 107–108 risk assessment and evaluation: in vitro-in vivo extrapolation studies, 6: CYP induction, 6: 112–113 105–107 CYP inhibition, 6: 93–101 in vitro studies, 6: 102–105 quantitative magnitude predictions, 6: object drug determinants, 6: 121 98–101 pharmacokinetic properties, risk assessment surrogate selection, 6: 97–98 and, 6: 124–125 in vitro studies, 6: 93–97 quantitative reaction metabolism phenotyping, drug development framework, 6: 92–93 6: 123–124 early clinical development strategies for, 6: risk assessment in early clinical development, 122–123 inducers as tool for, 6: 126–127 6: 122–123 NME pharmacokinetics, 6: 124–125 transporter contributions, 6: 125–126 in silico studies, enzyme isoforms, 3: 257–261 oral drug development, 3: 9–10 solubility and dissolution assessment, oral pediatric populations, 6: 563–566 absorption, BDDCS classification, 3: pharmacokinetic modeling, 6: 593–594 504–507 phase I metabolism: solute carrier proteins: anti-HIV protease inhibitors, 6: 368 inhibition, 2: 223–225 clopidogrel and prasugrel, 6: 365–366 overview, 2: 195–196 physiologically-based pharmacokinetic modeling, regulatory guidelines, 2: 230 6: 582–583 stereoselective inhibition, 4: 359–361 whole body model, 2: 670–672 sulfotransferases, 1: 546–547 physiologically-based pharmacokinetic modeling toxicity studies, 4: 3–4 and simulation, 6: 127–128 translational research, 2: 752–757 predictive studies: concurrent CYP induction/inhibition, 2: 757 clinically significant interactions, 6: 152–153 cytochrome P450 induction, 2: 755–756 clinical mechanisms for, 6: 153–155 cytochrome P450 inhibition, 2: 754–755 drug-metabolizing enzyme involvement, 6: drug-metabolizing enzymes, 2: 752–754 155–156 mechanism-based inhibition, 2: 756–757 genetic polymorphism and pharmacogenetics, 6: transporter action, clinical relevance, 6: 222 169–170 UGT enzymes: high-throughput screening, 6: 165–168 clinical significance, 6: 266–267, 269–270 CYP450, 6: 166–167 isoforms, UGT2B7, 1: 492 limitations, 6: 168 in vitro studies: in silico assessment, 6: 168 CYP inhibition, 4: 238, 240 UGTs, 6: 167 drug discovery and development, 3: 57–58 pharmacokinetics-based reactions, 6: 156–165 intestinal metabolism, 4: 228–233 combined analysis, 6: 163–165 whole-body autoradiography, 5: 372 conjugative drug-metabolizing enzymes, 6: xenobiotic metabolism, hepatocyte assessment, 161 hepatobiliary transport, 3: 420–428 cytochrome P450s: Drug efficacy. See Therapeutic efficacy competitive/noncompetitive inhibition, 6: Drug-induced liver injury (DILI). See also Hepatic 156–158 drug metabolism; Hepatotoxicity induction, 6: 158–160 acetaminophen bioactivation, inflammation and, 3: OATP transporters, 6: 163–164 194–198 P-glycoprotein inhibition and induction, 6: biomarkers, 4: 186–192 162–163 covalent drug-protein adducts: transporters, orally administered drugs, 6: hypersensitivity reactions, 4: 161–164 161–162 overview, 4: 159–161 preclinical assessment, 6: 153 skin reactions, 4: 164–165 research background, 6: 151–152 dominant drugs, table of, 6: 435–441 INDEX 701

drug-disease-drug interactions, acute-phase drug metabolites, 6: 36–39 response, 4: 628 pharmacogenetics, 6: 40–41 hepatic drug metabolism: processes and methods, 6: 36 idiosyncratic drug reactions, 6: 420–421 chemical characterization, 1: 32–35 parenchymal disease, 6: 321–322 ADME studies, 1: 32–33 idiosyncratic: elimination of drug-related materials, 1: 35 animal studies: metabolite structure elucidation, 1: 33–34 drug-inflammation interaction, 4: 605–612 quantitative analysis, 1: 34–35 inflammatory stress hypothesis, 4: chemical transformation, 1: 5–14 607–610 clearance, 1: 16–18 model comparisons, 4: 610–612 drug discovery and development, 1: 14–16 sulindac, 4: 606–607 clinical development, 1: 15–16 future research issues, 4: 612–613 discovery phase, 1: 14–15 inflammatory response, 4: 601–605 preclinical development, 1: 15 hemostatic system and hypoxia, 4: enzymes, 1: 23–29 603–604 high-throughput screening assays, 6: 165–166 neutrophils, 4: 604–605 metabolic-drug interactions, 1: 20–21 reactive oxygen species, 4: 605 metabolites: tumor necrosis factor-α, 4: 602–603 pharmacology, 1: 19 proposed mechanisms, 4: 597–601 toxicity, 1: 19–20 danger hypothesis, 4: 599 metabonomics analysis, 4: 288–293 failure to adapt hypothesis, 4: 599–600 human polymorphism identification, 4: hapten hypothesis, 4: 598 292–293 inflammatory stress hypothesis, 4: metabolic pathway elucidation, 4: 291–292 600–601, 607–608 metabolite identification, 4: 288–290 metabolic polymorphism hypothesis, 4: pediatric patients: 597–598 future research issues, 6: 571 mitochondrial dysfunction hypothesis, 4: research background, 6: 537–538 599 research limitations and design parameters, 6: multiple determinant hypothesis, 4: 600 566–570 research background, 4: 595–597 pharmacodynamics mechanisms, 2: 686–692 drug-induced reactions, 4: 568–570 pharmacokinetics: halothane hepatotoxicity, 4: 574 basic principles, 2: 247–256 mitochondrial toxicity, 6: 429–431 modeling, 6: 590–592 Drug-inflammation interaction, idiosyncratic phase I reactions, 2: 256–278 drug-induced liver injury, 4: 605–612 aldehyde oxidase, 2: 267–269 inflammatory stress hypothesis, 4: 607–610 carboxylesterase, 2: 271–274 model comparisons, 4: 610–612 cytochrome P450, 2: 256–265 sulindac, 4: 606–610 epoxide hydrolase, 2: 274–276 Drug-insecticide interactions, carboxylesterase flavin monooxygenase, 2: 265–267 transport, 1: 445–446 ketoreductase, 2: 276–278 Drug-ligand binding, microdose studies, accelerator monoamine oxidase, 2: 269–271 mass spectrometry, 5: 614 phase II reactions, 2: 278–293 Drug metabolism. See also Hepatic drug acyl-CoA synthetase, 2: 288–290 metabolism; Intestinal drug metabolism; Phase glucuronosyltransferase, 2: 278–281 I, II, and III metabolism glutathione transferase, 2: 281–283 anatomical sites, 1: 21–23 methyltransferase, 2: 290–293 basic principles, 1: 3–5 N-acetyltransferase, 2: 286–288 bioactivation and, 3: 178–180 sulfotransferase, 2: 283–286 biochemical process, 1: 21–31 physiologically-based pharmacokinetic modeling, anatomical metabolism sites, 1: 21–23 6: 582–583 biological factors in, 1: 30–31 physiology of, 1: 43–44 enzymes, 1: 23–29 phytochemical modulators: subcellular localization, 1: 23 adulterants and contamination, 4: 505–506 transporters, 1: 30 dietary supplements, drug interaction, 4: biological aspects of, 1: 30–31 506–532 biotransformation, 6: 35–41 black cohosh, 4: 506–507 drug interactions, 6: 40 Echinacea spp., 4: 507–510 702 INDEX

Drug metabolism. See also Hepatic drug chiral inversion, 4: 358–359 metabolism; Intestinal drug metabolism; drug-metabolizing enzyme inhibition, 4: Phase I, II, and III metabolism (Continued) 359–361 garlic, 4: 510–513 enantiomer-second drug interactions, 4: 361 ginkgo biloba, 4: 513–516 enantioselective pharmacokinetics, 4: 361–362 ginseng, 4: 516–518 metabolites, 4: 353–358 goldenseal, 4: 518–520 chiral reduction, carbon-carbon double bond, kava kava, 4: 521–522 4: 355–356 methylenedioxyphenyl compounds, 4: enantiotopic moiety to chiral metabolite 518–526 oxidation, 4: 357–358 milk thistle, 4: 526–528 ketone reduction, secondary alcohol piperine/black pepper, 4: 522–525 formation, 4: 354–355 Schisandra spp., 4: 524–526 sulfide to chiral sulfoxide oxidation, 4: St. John’s wort, 4: 529–532 356–357 food-drug interactions, 4: 494–499 tertiary amine to N-oxide oxidation, 4: 357 citrus juices, 4: 496–499 substrates, 4: 352–353 cruciferous vegetables, 4: 494–496 subcellular localization, 1: 23 future research issues, 4: 533 toxicogenomics studies, 4: 270–272 herb-drug interactions: translational research, 2: 752–757 content variability, 4: 502–503 concurrent CYP induction/inhibition, 2: 757 DSHEA guidelines and dietary supplements, cytochrome P450 induction, 2: 755–756 4: 499–500 cytochrome P450 inhibition, 2: 754–755 enteric CYP3A/ABC content/activity, 4: drug-metabolizing enzymes, 2: 752–754 500–501 mechanism-based inhibition, 2: 756–757 pharmacogenetics, 4: 501 transporter function in, 1: 30 prediction and interpretation uncertainty, 4: in vitro models, 1: 44–50 500–503 cellular systems, 1: 47–48 synergistic mechanisms, 4: 501–502 enzymes, 1: 44–45 plant-animal “warfare,” metabolic defense organ perfusion, 1: 49–50 mechanisms, 4: 487–488 organ slices, 1: 48–49 plant secondary metabolites: subcellular fractions, 1: 46–47 CYP polymorphisms, 4: 492–494 in vivo models, 1: 50–58 dietary modulation, 4: 490–492 animal studies, 3: 611–613 synthesis vs. human metabolism, 4: 488–494 clearance processes, 3: 605–610 research background, 4: 485–487 current research trends, 3: 591–593 in vitro studies, advantages and limitations, 4: human studies, 1: 56–58 503–504 preclinical animal studies, 1: 50–51 in vivo animal methods, advantages and species differences, 1: 51–52 limitations, 4: 504 transgenic/chimeric mice, 1: 52–56 in vivo human studies, advantages and Drug-metabolizing enzymes (DMEs). See also limitations, 4: 504–505 specific enzymes regulatory issues, translational research, 2: ADME studies, 2: 15–19 757–761 induction, 2: 17–18 sex differences in: inhibition, 2: 16–17 hepatic drug metabolism, 1: 102–112 polymorphism, 2: 19 future research issues, 1: 112 transporter interaction, 2: 18 gonadal hormones, 1: 107–108 age-dependent expression: growth hormone, 1: 108–110 alcohol dehydrogenase, 4: 464–465 HNFα, 1: 112 aldehyde oxidase, 4: 465 hormonal determinants, cytochrome P450s, carboxylesterases, 4: 466 1: 107–110 cytochrome P450 enzymes, 4: 454–462 human cytochrome P450s, 1: 106–107 CYP1A2, 4: 454–455 molecular determinants, 1: 110–112 CYP2A, 4: 455–456 rat cytochrome P450s, 1: 105–106 CYP2B6, 4: 456 STAT5b tyrosine phosphorylation, 1: CYP2C, 4: 456–458 110–111 CYP2D6, 4: 458–459 research overview, 1: 101–102 CYP2E1, 4: 459–460 stereoselectivity, 4: 351–362 CYP3A, 4: 460–462 INDEX 703

epoxide hydrolase, 4: 466–467 clinical and toxicological perspectives, 3: flavin-containing monooxygenases, 4: 462–464 469–470 future research issues, 4: 472–474 cryopreservation, 3: 481–485 glutathione S-transferase, 4: 467–469 extrahepatic slices, 3: 476–478, 481 physiological factors, 4: 452–454 future research issues, 3: 485–486 research background, 4: 451–452 human studies, 3: 475–476, 480–481 sulfotransferase, 4: 469–470 phase I systems, 3: 471–478 UDP glucuronosyltransferase, 4: 471–472 phase II systems, 3: 478–481 bioactivation, overview, 4: 63–64 preparation and culture protocols, 3: 470–471 bioavailability studies: research background, 3: 467–469 enzyme-transporter interplay, 2: 483–484 inflammation, 4: 628–630 intestinal metabolism, 2: 481–484 biomarkers, 4: 630 cardiovascular drugs, ADME studies, 2: 855–856 central nervous system, 4: 641 expression mechanisms, 2: 861–862 chronic diseases, 4: 629–630 cytochrome P450 polymorphisms, 1: 241–261 conjugation enzymes, 4: 638–639 CYP1 family, 1: 241–248 CYP1 subfamily regulation, 4: 631–632 CYP1A subfamily (CYP1A1/CYP1A2), 1: CYP2 subfamily regulation, 4: 632–635 242–243, 247 CYP3 subfamily regulation, 4: 636 CYP1B subfamily, 1: 247–248 CYP4 subfamily regulation, 4: 637 CYP2 family, 1: 248–259 cytokines and other mediators, 4: 629 CYP2A subfamily, 1: 249–250, 251–250 drug-disease-drug interactions, 4: 627–628 CYP2B subfamily, 1: 251–253 drug transporters, 4: 641–645 4: CYP2C subfamily, 1: 253–256 extrahepatic tissues, 644 LPS model, 4: 643 CYP2D subfamily, 1: 256–258 sterile inflammation, 4: 631, 643 CYP2E subfamily, 1: 258–259 viral infection, 4: 643 CYP3 family, 1: 259–261 extrahepatic metabolism, 4: 639–641 cytokines, 4: 645–649 flavin monooxygenases, 4: 637–638 disease states, 4: 622–624 intestinal metabolism, 4: 639–640 drug-drug interactions: kidney metabolism, 4: 640–641 conjugative inhibition, 6: 161 lung metabolism, 4: 640 predictive studies, 6: 155–156 posttranscriptional regulation, 4: 650–651 drug metabolism, pharmacokinetics, 2: 256 research background, 4: 623–624 extrahepatic metabolism: transcriptional regulation, 4: 649–650 age and gender factors, 2: 344, 350 intestinal metabolism, 3: 336 bioavailability, 2: 356–365 isoforms, drug-drug interactions, 3: 257–261 clinical significance, 2: 356–377 organ metabolism/transport, isoforms, 2: 559–564 cytochrome P450 enzymes, 2: 317, 328–334 pediatric populations: drug-drug interactions, 2: 376–380 clearance and exposure mechanisms, 6: future research issues, 2: 377, 381 562–563 genetic polymorphism, 2: 344–349 phase I metabolism, 6: 538–551 inborn errors of metabolism, 2: 350–354 alcohol dehydrogenases, 6: 549–550 non-CYP enzymes, 2: 334–343 cytochrome P450 enzymes, 6: 540–547 epoxide hydrolases, 2: 340–341 CYP1 subfamily, 6: 540–541 flavin-containing monooxygenases, 2: CYP2 subfamily, 6: 541–545 340–341 CYP3 subfamily, 6: 544–547 monoamine oxidases, 2: 341–342 flavin-containing monooxygenases, 6: transferases, 2: 334–340 548–549 physiological conditions, 2: 350–354 hydrolytic enzymes, 6: 550–551 research background, 2: 315–316 monoamine oxidases, 6: 549 tissue distribution and expression, 2: 316–343 oxidative drug-metabolizing enzymes, 6: toxicity, 2: 356, 366–375 539–540 xenobiotic bioactivation and deactivation, 2: reductive enzymes, 6: 550 354–356 research design and methodology, 6: 566–570 genetically modified animal models, 3: 618–622 pharmacogenetics, 4: 378–379 hepatic drug metabolism, 6: 312–317 phase I metabolism, pediatric patients, 6: 538–551 induction studies, precision cut tissue slices: pregnancy drug metabolism, 2: 945–951 animal studies, 3: 472–475, 478–480 cytochrome P450s, 2: 945–951 704 INDEX

Drug-metabolizing enzymes (DMEs). See also Dutasteride, bioequivalence studies, partial-block specific enzymes (Continued) crossover design, 2: 465–466 in fetus, 2: 948, 951 Dynamic range, nano-electrospray ionization, 5: GST, 2: 947–951 61–63 in mother, 2: 945–947 in placenta, 2: 947–949 Eadie-Hofstee plot: sulfotransferases, 2: 947–951 drug-drug interactions: UGTs, 2: 947–951 competitive inhibition, 4: 408–409 sex differences, hepatic enzymes, 1: 104–112 inhibition mechanisms, 4: 407–413 in silico studies, 3: 263–264 noncompetitive inhibition, 4: 410–411 solute carrier transporters and, 2: 221–223 uncompetitive inhibition, 4: 411–413 species differences: enzyme kinetics: cytochrome P450s, 1: 127–141 basic principles, 1: 87–88 CYP1A, 1: 128–129 Ki parameters, 1: 94–96 CYP1B, 1: 129 sigmoidal kinetics, 1: 81–83 CYP2A, 1: 129–131 in vitro studies, 3: 296 CYP2B, 1: 131–133 physiologically-based pharmacokinetic modeling, CYP2C, 1: 133–135 enzyme-transporter biochemistry, 2: 646–647 CYP2D, 1: 135–137 Early drug development: CYP2E, 1: 137–138 animals-to-humans process, 3: 93–99 CYP3A, 1: 137, 139–141 bioanalytical considerations, 3: 93 overview, 1: 127–128 biopharmaceutical considerations, 3: 98 flavin-containing monooxygenases, 1: 146–147 go/no-go decisions, 3: 98–99 future research issues, 1: 148 nonclinical pharmacology and toxicology, 3: glucuronosyltransferases, 1: 141–143 93–98 induction mechanisms, 1: 123, 125–126, clinical pharmacology, 3: 99–115 129–130 decision-making studies, 3: 105–109 overview, 1: 121–124 drug-drug interactions, 3: 113–114 sulfotransferases, 1: 143–146 first in human studies, 3: 101–102 stereoselective inhibition, 4: 359–361 labeling issues, 3: 114–115 sulfotransferases, induction, 1: 544–545 metabolic disposition studies, 3: 110–111 translational research, 2: 752–757 premarketing phase, NDA, 3: 114 in vivo model, subcellular localization, 1: 52–56 radiolabeled studies (ADME), 3: 110 xenobiotic metabolism, hepatocyte assessment, research methods, 3: 102–104 FDA draft guidance concerning, 3: 433–435 in vitro drug metabolism/interaction studies, 3: Drug optimization, flavin-containing 111–112 monooxygenases, 1: 298–299 drug-drug interactions, risk assessment strategies, Drug reaction with eosinophilia and systemic 6: 122–123 symptoms (DRESS), idiosyncratic adverse drug IND-enabling development, 3: 92–93 reactions, 6: 419 overview of process, 3: 89–91 Drug-receptor interactions, pharmacodynamics, 2: regulatory issues, 3: 91 693–695 research background, 3: 87–89 concentration-effect relationship, 2: 704–706 in vitro toxicity screening, cytochrome P450 Drug-related biomarkers, early drug development, superfamily in: decision-making studies, 3: 106–109 gastrointestinal tract, 4: 225–233 Drug resistance: hepatic drug metabolism, 4: 236–239 ABC transporters, 2: 167–170 inhibition and drug-drug interactions, 4: 238, glutathione transferase superfamily, pi class GSTs, 240 1: 571–572 overview, 4: 223–225 Drug-target interactions, pharmacodynamics, 2: polymorphisms, 4: 231–233 768–770 Easson-Stedman hypothesis, stereoselectivity, 4: Drug transporters. See Transporters 349–351 DT-diaphorase (DTD), reductive bioactivation, 4: Easy ambient sonic spray ionization (EASI), basic 88–90 principles, 5: 92–93 Dual A2A/A1 receptor antagonist, hepatotoxicity EC50: prevention, optimization, 4: 174–176 drug-drug interactions, CYP induction, 6: Duloxetine, CYP1A2 metabolism, 6: 466 114–115 INDEX 705

hepatic drug metabolism, CYP enzyme induction, metabolomics, 5: 323–326 3: 377–378 quantitative bioanalysis, complex matrices, 5: 323 xenobiotic metabolism, hepatocyte assessment, Electrochemical detectors, metabolite identification, induction studies, 3: 417–419 3: 133–134 Echinacea, herb-drug interactions, 2: 816, 6: 286 Electrochemical liquid chromatography mass Echinacea spp., dietary supplement-drug interaction, spectrometry (EC-LC-MS): 4: 507–510 array techniques, 5: 321–326 Economic issues: electrochemistry principles, 5: 315 microdose studies, LC-MS/MS, 5: 617 flow cells, 5: 314 nuclear magnetic resonance characterization, 5: flow injection analysis, 5: 316, 322–323 337 metabolism mimicry, 5: 320–321 quantitative whole-body radiography, 5: 369–370 pre- and postcolumn electrochemistry, 5: 316 Ecstasy (MDMA), cytochrome P450 polymorphisms, reactive intermediates, EC generation and CYP2B6, 1: 251 analysis, 5: 318–320 Efavirenz: research background, 5: 313–314 cytochrome P450 polymorphisms: semipreparative EC synthesis, 5: 316–317 CYP2A6, 1: 250 Electrochemiluminescence, basic principles, 5: 401 CYP2B6, 1: 251, 252 Electron capture dissociation (ECD): pediatric drug metabolism, drug-drug interactions, linear trap quadrupole-Fourier transform mass 6: 566 spectrometry, 5: 32, 34 Effective dose, mass balance studies, human studies, quadrupole ion trap mass spectrometry, ion-ion 2: 445–446 reactions, 5: 171–172 Efficacy mechanisms, pharmacodynamics, 2: 695 spray-based ionization, 5: 90–93 Efficiency mechanisms, triple quadrupole/tandem Electron donors, cytochrome P450 enzymes, 1: mass spectrometry, 5: 159 172–173 Efflux transporters: Electron ionization, gas chromatography-mass biotransformation, 6: 6–7 spectrometry, 5: 23 enzyme induction, 6: 18 Electron rich compounds, two-electron oxidation, cardiovascular drug metabolism, 2: 864–865 cytochrome P450 enzyme bioactivation, distribution mechanisms, 2: 146–147 chemically reactive metabolites, 4: 34–42 drug metabolism, 1: 30 iminium ions, 4: 40–42 intestinal absorption, in vitro studies, 2: 96 imino methide, 4: 39–40 oral absorption mechanisms, 2: 89–92 quinone imines, 4: 34–37 bioavailability studies, 2: 477–480 quinone methide, 4: 37–39 oral chemotherapeutic agents, 6: 503–506 quinones, 4: 37 organ clearance, rate-limiting step, 2: 565–568 Electron transfer dissociation (ETD): pediatric drug metabolism, 6: 559–562 linear trap quadrupole-Fourier transform mass xenobiotic metabolism, hepatocyte assessment, spectrometry, 5: 32, 34 hepatobiliary transport, 3: 419–428 quadrupole ion trap mass spectrometry, ion-ion Elderly: reactions, 5: 171–172 age-dependent drug metabolism: spray-based ionization, 5: 90–93 alcohol dehydrogenase, 4: 464–465 Electroosmotic flow: CYP2C expression, 4: 457–458 micellar electrokinetic chromatography, CYP2D6 expression, 4: 458–459 pseudophases, 5: 426–427 CYP2E1 expression, 4: 459–460 uncharged solutes, micellar electrokinetic CYP3A4 expression, 4: 462 chromatography, 5: 422–424 physiological factors, 4: 453–454 Electrospray-assisted laser desorption ionization research background, 4: 452 (ELDI), basic principles, 5: 97–101 UDP glucuronosyltransferase, 4: 472 Electrospray ionization mass spectrometry (ESI-MS): biotransformation in, 6: 6, 32–33 basic principles, 5: 48–52 dose calculations for, 6: 612 bioanalysis guidelines, 5: 483–484 drug-drug interactions in, incidence of, 6: compound properties, 5: 51–52 152–153 electrospray mechanisms, 5: 48–50 hepatic drug metabolism, 6: 318–319 high vs. low liquid flow rates, 5: 52 Electrical discharge ionization techniques, overview, liquid introduction: 5: 93–97 chromatographic processes, 5: 52–54 Electrochemical array (EC-Array): infusion sample introduction, 5: 54 flow injection analysis, 5: 322–323 matrix suppression, ionization, 5: 51 706 INDEX

Electrospray ionization mass spectrometry (ESI-MS) Endogenous metabolism: (Continued) bioanalysis guidelines, 5: 480–481 multicolumn parallel chromatography: biofluid analysis, on-line SPE, 5: 450–451 multiple ion sources, 5: 562–563 imaging mass spectrometry, 5: 248–249 single ionization source, 5: 560, 562 soluble epoxide hydrolase, 1: 411–412 multiplexing technology, 5: 535–536 sulfotransferase sulfates, 1: 541–542 proteomics, two-dimensional electrophoresis, 4: Endoxifen, phase I metabolism, tamoxifen, 6: 360 319 Endpoint measurement: research background, 5: 87–89, 546–548 bioequivalence studies, 2: 468 sensitivity, 5: 50–51 drug-drug interactions, NME-precipitated CYP Elimination kinetics. See also Excretion mechanisms induction, 6: 111–115 antipsychotic metabolism, 6: 467–468 early drug development, in vivo studies, 3: 112 defined, 2: 6 xenobiotic metabolism, hepatocyte assessment, drug discovery and development, 2: 35–36 induction studies, 3: 413–419 drug metabolism, 2: 247–256, 249–256 Energy homeostasis, constitutive androstane receptor drug-related materials, 1: 35 transcription, 1: 213 hepatic drug metabolism, alcoholism, 6: 323 Enhanced mass spectometry, QTRAP human studies: instrumentation, 5: 190 feces, urine, and other routes, 6: 222–223 Enhanced multiply scan (EMS), QTRAP hepatic and renal impairment, 6: 224–225 instrumentation, 5: 191 plasma concentration-time data, 2: 626–633 Enhanced permeability and retention (EPR), compartmental analysis, 2: 626–629 platinum compounds, inductively coupled nonlinear elimination, 2: 629–633 plasma mass spectrometry, 5: 302–303 species differences, conjugation and, 6: 227–230 Enhanced product ion (EPI), QTRAP in vivo studies, 3: 603–611 instrumentation, 5: 190 active transporters, 3: 609 Enhanced-resolution scan (ERS), QTRAP aldehyde oxidase, 3: 607–608 instrumentation, 5: 190 allometric scaling of clearance, 3: 603–605 Enterohepatic recirculation: biliary elimination, 3: 609–610 distribution analysis, plasma concentration-time clearance processes, 3: 605–610 data, 2: 619–620 CYP metabolism, 3: 606–607 drug metabolism, 1: 14 drug metabolism, 3: 605 elimination pathways, 6: 224–225 human clearance, 3: 610 hepatic drug metabolism, cholestatic disease, 6: passive clearance, 3: 608–609 324 renal elimination, 3: 608 intestinal metabolism, 2: 72–73 UGTs, 3: 607 phase II metabolism, 6: 210 Enalapril, physiologically-based pharmacokinetic vectorial transport, 2: 552–558 modeling, renal metabolism, 2: 657–659 Environmental contaminates, microsomal epoxide Enalaprilat, enalapril conversion to, 1: 13 hydrolase, 1: 397–398 Enantiomers: genetic polymorphism, 1: 404–405 chiral columns, 5: 529–530 Enzymatic hydrolysis, metabolite identification, 3: specificity, monoclonal antibodies, 3: 453–454 151–152 stereoselectivity: Enzyme-catalyzed reduction reactions, 1: 381–384 biological activity, 4: 346–351 cytochrome P450, 1: 384 chiral inversion, 4: 358–359 dechlorination, 1: 383 drug metabolism, substrate metabolism, 4: drug metabolism, 2: 249–256 352–353 hydroperoxides, 1: 383–384 metabolic interactions, second drug, 4: 361 quinones, 1: 381–383 pharmacokinetics, 4: 361–362 α,β-unsaturated aldehydes, 1: 384 toxicity studies, 4: 362–366 Enzyme-inhibition (EI) complex, drug-drug antipode toxicity, 4: 363–364 interactions: single enantiomer pharmacology, 4: 363 competitive inhibition, 4: 409 Enantiotopic compounds, oxidation to chiral noncompetitive inhibition, 4: 409–411 metabolite, 4: 357–358 Enzyme kinetics. See also Pharmacokinetics (PK) Encainide, cytochrome P450 bioactivation, 4: 23–25 atypical reactions, 3: 297–304 Endobiotics, monoclonal antibody analyses, 3: autoactivation (sigmoidal) kinetics, 3: 300–301 459–460 biphasic kinetics, 3: 299–300 Endocytosis, oral absorption and, 2: 88 heteroactivation, 3: 301–302 INDEX 707

partial inhibition, 3: 303 inhibition, 1: 61–63 substrate inhibition, 3: 302–304 drug metabolism: current and future research issues, 1: 96 chemical transformation, 1: 6–14 drug-drug interactions, 1: 88–96 superfamilies, 1: 23–29 competitive inhibition, 1: 88–89 sex-dependent drug metabolism, hepatic IC50 and Ki parameters, 1: 94–96 drug-metabolizing enzymes, 1: 104–107 inhibition mechanisms, 4: 407–413 in vitro drug metabolism models, 1: 44–45 irreversible inhibition, 1: 91–94 in vivo drug metabolism models, 1: 51–52 mechanism-based inhibition, 1: 91–94 Enzyme-substrate (E-S) complex: mixed inhibition, 1: 90–91 drug-drug interactions: noncompetitive inhibition, 1: 89 inhibition mechanisms, 4: 406–413 non-P450 metabolism, 4: 422–423 noncompetitive inhibition, 4: 409–411 reversible inhibition, 1: 88–91 uncompetitive inhibition, 4: 411–413 uncompetitive inhibition, 1: 90 mixed inhibition, 1: 90–91 in vitro-in vivo correlation, 4: 413–425 sulfotransferase kinetics, 1: 539–540 Eadie-Hofstee plot, 1: 87–88, 3: 296 uncompetitive inhibition, 1: 90 graphic data presentation, 1: 87–88 Enzyme-substrate-inhibitor (E-S-I) complex: Hane-Woolf plot, 3: 296–297 drug-drug interactions: limitations, 3: 297 noncompetitive inhibition, 4: 409–411 Lineweaver-Burk double reciprocal plot, 3: 296 uncompetitive inhibition, 4: 411–413 Michaelis-Menten kinetics, 1: 78–81, 3: 294–296 uncompetitive inhibition, 1: 90 non-Michaelis-Menten kinetics, 1: 81–87 Epidermal growth factor receptor (EGFR), cancer biphasic kinetics, 1: 83–84 therapies, signaling pathways, 3: 32–35 heteroactivation, 1: 86–87 Epigenetic modulators, development of, 3: 28 sigmoidal kinetics, 1: 81–83 Epigenetics, idiosyncratic adverse drug reactions, 6: substrate inhibition, 1: 84–86 428 organ metabolism/transport, 2: 559–564 Epitope specificity, monoclonal antibodies, 3: 452 peptide and protein therapeutics, 2: 897–901 Epitope spreading, hapten hypothesis, 6: 424–425 pharmacodynamics, inactivation models, 2: Epoxidation, cytochrome P450 enzymes, 6: 59 723–724 arenes and olefins, 4: 28–34 physiologically-based pharmacokinetic modeling: water-proton exchange, 1: 194 enzyme-transporter biochemistry, 2: 646–647 Epoxide hydrolases (EPHX): renal metabolism, 2: 656–659 age-dependent drug metabolism, 4: 466–467 whole body model, 2: 660–664 basic properties, 1: 393–394 research background, 3: 287–288 biotransformational polymorphisms, 6: 25 substrate depletion methods, 3: 297–298 catalytic cycle, 2: 274–276 sulfotransferase, 1: 538–543 drug-drug interactions, anticonvulsants, 6: 476 in vitro-in vivo correlations, 3: 304–307 extrahepatic metabolism, 2: 340 in vitro studies, 3: 288–294 genetically modified animal models, 3: 640–644 expressed enzymes, 3: 290–292 microsomal epoxide hydrolase, 3: 640–642 HepaRG cells, 3: 294 soluble epoxide hydrolase, 3: 642–644 hepatocytes, 3: 292–293 microsomal (EPHX1), 1: 395–407 human liver microsomes, 3: 288–290 biological function, 1: 396–397 liver slices, 3: 293 expression regulation, 1: 405–407 S9 fraction, 3: 293 alternative promoters, 1: 405–406 Enzyme limited clearance, drug-drug interactions, transcription, 1: 405 CYP induction, 4: 430–433 transposable elements, 1: 406–407 Enzyme-linked immunoassay (ELISA): genetically modified animal models, 3: basic principles, 5: 399–401 640–642 bioanalysis regulations, 5: 505–507 genetic polymorphisms, 1: 402–404 biomarkers, data quality, 5: 590–593 substrates and inhibitions, 1: 397–402 Enzyme-multiple substrate (ESS), sulfotransferase environmental/xenoiotic, 1: 397–399 kinetics, 1: 539–540 inhibitors, 1: 402 Enzymes. See also Drug-metabolizing enzymes pharmacological properties, 1: 399–402 (DMEs) summary/pharmacological implications, 1: 407 drug clearance, 1: 17–21 phase I metabolism, 2: 274–276 drug-drug interactions: soluble epoxide hydrolase (EPHX2), 1: 407–412 induction, 1: 21, 63–65 biological functions, 1: 408–410 708 INDEX

Epoxide hydrolases (EPHX) (Continued) in vitro toxicity studies, 4: 231–232 expression regulation, 1: 411 covalent binding, 4: 244 genetically modified animal models, 3: Ethionamide, toxicity studies, 4: 66 642–644 Ethnic differences: genetic polymorphisms, 1: 410 biotransformational polymorphism, 6: 22–25 summary/pharmacological implications, 1: cytochrome P450 enzyme expression and activity, 411–412 6: 76–77 types and general reactions, 1: 394–395 dose calculations and, 6: 618 Epoxides of arachidonic acids (EETs), biological glutathione transferase superfamily: aspects, 1: 408–410 mu class GSTs, 1: 570–571 Epoxyeicosatrienoic acids (EETs), cardiovascular omega class polymorphisms, 1: 574–575 drug metabolism, drug-metabolizing enzymes, molybdenum-containing hydrolases, 1: 344 2: 861–863 Ethosuximide, drug-drug interactions, 6: 484 Equilibrium dialysis, plasma protein binding: 7-Ethoxycoumarin O-deethylase (ECOD) activity, ADME studies, 2: 31 cytochrome P450s, 1: 128 drug discovery and development, 5: 661, Ethoxyresorufin O-deethylase (EROD), CYP1A 663–664 monitoring, 1: 128–129 estimation techniques, 2: 537–540 Ethylene bridged hybrid (BEH) particles, emergence Equilibrium solubility: of, 5: 528–529 defined, 3: 508–509 Ethylene dibromide episulfonium ions, glutathione solubility and dissolution assessment, oral conjugation, phase-II-enzyme-catalyzed absorption: xenobiotics, 4: 130–131 kinetic solubility assays, 3: 518–521 Etoposides, oral chemotherapeutic agents, 6: 520 protocols, 3: 519–522 Etoricoxib, sulfotransferase kinetics, drug-drug Erlotinib: interactions, 1: 547–548 cytochrome P450 epoxidation, 6: 59–60 Eudismic index, stereoselectivity, 4: 349–351 oral chemotherapeutic agents, 6: 522 Eudismic ratio, stereoselectivity, 4: 349–351 Erythromycin, food-drug interactions, grapefruit European Medicines Agency (EMA): juice, 6: 295 dietary supplements regulation, 2: 794 Erythropoietin treatment, drug-induced anemia, 6: safety testing, reactive metabolites, 3: 235–237 422 solute carrier transporter guidelines, 2: 230–231 ESI Chip™: Eutomers, stereoselectivity, 4: 349–351 chip-based nano-electrospray ionization, 5: 56 chiral inversion, 4: 358–359 ion current stability, 5: 59–60 Evening primrose oil, drug interactions, 2: 816 Eslicarbazepine acetate, drug-drug interactions, 6: Everolimus, drug-drug interactions, prescription 483 guidance, 6: 137–138 Esmolol, phase I metabolism, 6: 356–357 Evolutionary molecular modeling, plant-animal Ester/amide cleavage, cytochrome P450 enzymes, 6: “warfare,” 4: 487–488 59 Excipients: Ester drugs: sample preparation quality control, ion carboxylesterases, hydrolytic metabolism, 1: suppression/enhancement, 5: 520 424–426 solubility and dissolution assessment, oral phase I metabolism, clopidogrel and prasugrel, 6: absorption: 365–366 dissolution measurements, 3: 525–526 Estradiol: drug formulation and disposition, 3: 543–544 phase II metabolism: Excitation sculpting, solvent suppression, nuclear sulfotransferases, 2: 283–286 magnetic resonance, 5: 339 UGT enzymes, 2: 278–281 Excreta analysis. See also Fecal analysis vectorial transport, 2: 554–558 ADME studies, radioactive dose recovery, 2: Estrogen, sex-dependent hepatic drug metabolism, 1: 600–602 107–108 mass balance studies, animal studies, 2: 422–425 Estrogen receptors, oral chemotherapeutic agents, 6: biliary excretion, 2: 427–428 523–525 Excretion mechanisms. See also Elimination process Ethinyl estradiol (EE): drug conjugation, transport proteins, 6: 218–222 age-dependent drug metabolism, sulfotransferases, bile vs. urine routes, 6: 218–219 4: 470 biliary excretion, 6: 219–220 sulfotransferase kinetics, 1: 540 drug interactions and clinical relevance, 6: 222 drug-drug interactions, 1: 547–548 hepatic drug metabolism, 6: 220 INDEX 709

renal excretion, 6: 221–222 ADME studies, in silico studies, 3: 65–69 drug discovery and development, 2: 35–36 bioavailability studies: drug metabolism, 2: 248–256 hepatic extraction and uptake, 2: 484–486 early drug development, labeling issues, 3: 114 intestinal extraction, 2: 480–484 pharmacokinetic modeling, 6: 592–593 hepatic drug metabolism, 6: 316–317 pharmacokinetics: physiologically-based pharmacokinetic modeling, future research issues, 2: 575 renal metabolism, 2: 656–659 intrinsic clearance: Extrahepatic metabolism. See also specific sites, e.g., organ clearance and, 2: 569–570 Intestinal drug metabolism rate-limiting step, 2: 564–568 drug-metabolizing enzymes: isoform effect, 2: 559–564 age and gender factors, 2: 344, 350 organ clearance mechanisms, 2: 558–570 bioavailability, 2: 356–365 physiologically-based pharmacokinetic clinical significance, 2: 356–377 modeling, 2: 570–574 cytochrome P450 enzymes, 2: 317, 328–334 vectorial transport: drug-drug interactions, 2: 376–380 hepatic transport, 2: 553–554 future research issues, 2: 377, 381 renal transport, 2: 554–558 genetic polymorphism, 2: 344–349 xenobiotics, 2: 550–558 inborn errors of metabolism, 2: 350–354 in vivo studies, 3: 603–611 non-CYP enzymes, 2: 334–343 active transporters, 3: 609 epoxide hydrolases, 2: 340–341 aldehyde oxidase, 3: 607–608 flavin-containing monooxygenases, 2: allometric scaling of clearance, 3: 603–605 340–341 biliary elimination, 3: 609–610 monoamine oxidases, 2: 341–342 clearance processes, 3: 605–610 transferases, 2: 334–340 CYP metabolism, 3: 606–607 physiological conditions, 2: 350–354 drug metabolism, 3: 605 research background, 2: 315–316 human clearance, 3: 610 tissue distribution and expression, 2: 316–343 passive clearance, 3: 608–609 xenobiotic bioactivation and deactivation, 2: renal elimination, 3: 608 354–356 UGTs, 3: 607 precision cut tissue slices: Exploratory trials, cancer therapies, 3: 38–39 induction studies, 3: 476–478 Explosives, ion mobility spectrometry, 5: 103, 106 phase II enzyme induction, 3: 481 Exposure: toxicity studies, 2: 356, 366–375 pediatric drug clearance and exposure, 6: 562–563 Extravascular routes, ADME studies, 2: 4–5 pharmacokinetic modeling, coexposure models, 6: Ex vivo studies: 593–594 distribution mechanisms, 2: 135–136 physiologically-based pharmacokinetic modeling, plasma protein binding, ADME studies, 2: 32 tissue site predictions, 2: 664 Ezetimibe: Expressed enzymes, enzyme kinetics, in vitro dehydrogenation, 1: 11 studies, 3: 290–292 distribution calculation, plasma concentration-time Extensive metabolizers (EMs): data, 2: 619–620 dietary plant secondary metabolites, CYP glucuronidation, 1: 12, 6: 252–254 polymorphisms, 4: 492–494 Ezlopitant, cytochrome P450 enzymes: drug-drug interactions: aliphatic hydroxylation, 6: 56–57 CYP inhibition, 6: 100 dehydrogenation, 6: 60–61 therapeutic efficacy, CYP-mediated effects, 4: 441 Fab fragments, antibody structure, 2: 908 time- and dose-dependent CYP induction, 4: Facilitated diffusion, drug transport proteins, 438–439 pharmacogenetics, 4: 389–393 drug metabolism, 1: 29 Failure to adapt hypothesis, idiosyncratic psychotropic drugs, CYP2D6 metabolism, 6: drug-induced liver injury, 4: 599–600 461–463 False discovery rate (FDR), proteomics, label-free Extent of metabolism, quantitative analysis, 1: protein quantification, 4: 331–332 34–35 Familial high density lipoprotein (HDL) deficiency, Extraction efficiency: ABC transporter mutations, 2: 179–180 bioanalysis guidelines, 5: 484–486 Farnesoid X receptor (FXR): quality controls, research background, 5: 516–518 ABC transporter transcriptional regulation, 2: 174 Extraction ratios: drug conjugation and transport, 6: 225–226 710 INDEX

Farnesoid X receptor (FXR) (Continued) pediatric drug metabolism, 6: 561–562 genetically modified animal models, 3: 663–664 safety testing, stable metabolites, 3: 226–227 sulfotransferases, induction, 1: 544–545 Fibrate therapy, drug-drug interaction, statins, 2: toxicogenomics, cholestasis and hepatotoxicity, 4: 870–871 263–264 Fibrin deposition, idiosyncratic drug-induced Fasted simulated small intestinal fluid (FaSSIF), reactions, inflammation, 4: 603–604 solubility and dissolution assessment, oral Fibrosis, cirrhosis and, 6: 326–327 absorption, 3: 515–516 Fick’s law of diffusion, oral absorption, 2: 86–87 Fast evaporation, MALDI-MS samples, 5: 126 Field asymmetric ion mobility spectrometry Fecal analysis: (FAIMS), basic principles, 5: 35, 265–266 drug elimination, 6: 222–223 First-dimension isoelectric focusing, two-dimensional mass balance studies, animal studies, 2: 422–425 electrophoresis, proteomics applications, 4: 315 metabolite identification, 3: 129–130 First-in-human studies: Fed simulated small intestinal fluid (FeSSIF), biotransformation pathway predictions, 6: solubility and dissolution assessment, oral 194–195 absorption, 3: 515–516 cancer therapies: Felbamate: exploratory/phase 0 trials, 3: 38–39 bioactivation, 4: 76–77 future research issues, 3: 39–40 drug-drug interactions, 6: 484 drug discovery and development, exploratory hepatotoxicity: toxicology, 2: 770–777 induction, 4: 582–583 early drug development, clinical pharmacology, 3: risk assessment, 4: 183–185 101–102 toxicity studies, reactive metabolite toxicity toxicity testing, 3: 25–26 elimination and minimization, 6: 389–390 First ionization energy, inductively coupled plasma Felodipine, food-drug interactions, citrus juices, 4: mass spectrometry, 5: 288–289 496–499 First-order absorption rate constant (ka), solubility Fenestrations, capillary permeability, 2: 121–122 and dissolution assessment, oral absorption, Fenofibrate, administration formulation and method, rate-limiting steps, 3: 496–501 6: 612 First-pass effect: Fetal development: drug metabolism, anatomic sites, 1: 22–23 age-dependent drug metabolism: hepatic drug metabolism: alcohol dehydrogenase, 4: 464–465 cirrhosis, 6: 327 carboxylesterases, 4: 466 extraction ratios, 2: 485–486 CYP2C expression, 4: 456–458 liver transplant patients, 6: 333–334 CYP2D6 expression, 4: 458–459 intestinal metabolism, 2: 46 CYP2E1 expression, 4: 459–460 extraction ratios, 2: 480–484 CYP3A expression, 4: 460–462 oral absorption and, 2: 93–94 epoxide hydrolases, 4: 466–467 xenobiotic extraction, 3: 338 flavin-containing monooxygenases, 4: 462–464 oral chemotherapeutic agents, 6: 501–502 future research issues, 4: 472–474 Fish-odor syndrome, FMO polymorphisms, 6: 24 glutathione S-transferases, 4: 468–469 Fit-for-purpose PK/PD biomarkers: physiological factors, 4: 452–454 assay validation, 5: 591–593 research background, 4: 451–452 drug discovery and development, 5: 585–587 sulfotransferases, 4: 469–470 Fixed exponent animal studies, allometric scaling UDP glucuronosyltransferase, 4: 471–472 pharmacokinetics, 2: 497–501 drug metabolism: Fixed-sequence study design, drug-drug interactions, cytochrome P450 enzymes, CYP3A7, 1: 261 6: 129–136 maternal:fetal barrier, 2: 123–124 FK3453 drug candidate, clinical programs, 1: 349 hepatic drug metabolism, 6: 317–318 Flavin-containing amine oxidases (FAOs), pregnancy drug metabolism: classification, 1: 373–375 drug-metabolizing enzymes, 2: 948–951 Flavin-containing monooxygenases (FMOs): transporter functions, 2: 943–945 academic drug development, ADMET concepts, 1: sulfotransferase effects, 1: 535–536 281–283 whole-body autoradiography, placental transfer age-dependent drug metabolism, 4: 462–464 and drug penetration, 5: 377 basic properties, 1: 275–279 Fexofenadine: bioactivation, 4: 64–71 extrahepatic metabolism, 2: 354–356 aryl piperazines, 4: 66, 68–69 herb-drug interactions, St. John’s wort, 6: 286 4-fluoro-N-methylanilines, 4: 69–71 INDEX 711

thiocarbonyls, 4: 65–67 plasma protein binding, 2: 545–546 biotransformation, 6: 12 Fluorescent immunoassay (FIA), basic principles, 5: pathway predictions, in vitro studies, 6: 185 400–401 polymorphisms, 6: 24 19 Fluorine magnetic resonance spectroscopy: chiral sulfoxide molecules, sulfide oxidation to, 4: metabolite identification, 3: 157 356–357 sample preparation, 5: 345 drug candidate selection enhancement, 1: 284–287 Fluorofelbamate, toxicity studies, reactive metabolite drug discovery and development: toxicity elimination and minimization, 6: metabolic stability, in vitro studies, 3: 55–56 389–390 phases and processes, 1: 279–281 4-Fluoro-N-methylanilines, bioactivation, 4: 69–71 drug-disease-drug interactions, 4: 637–638 Fluorometric-based assays, hepatic drug metabolism, drug optimization, 1: 298–299 CYP enzyme inhibition, 3: 362–365 enzyme kinetics, in vitro studies, 3: 289–290 Fluoroquinolones, human drug metabolism, extrahepatic metabolism, 2: 340–341 structure-toxicity relationships, 6: 380–381 future research issues, 1: 299 5-Fluorouracil: genetically modified animal models, 3: 649 drug-drug interactions, clinical perspectives, 6: idiosyncratic drug-induced liver injury, sulindac, 91–92 4: 606–607 oral chemotherapeutic prodrugs, 6: 519 non-nucleophile-mediated metabolism, 1: 298 phase I metabolism: nucleophile-mediated metabolism, 1: 287–298 amine/xanthine oxidases, 2: 268–269 aliphatic secondary amines, 1: 297 capecitabine prodrug, 6: 363 aliphatic tertiary amines, 1: 296–297 tegafur, ADME studies, 2: 843 amines, 1: 292 Fluoxetine: cyclic amines, 1: 295 CYP2C9 metabolism, 6: 464–465 hydrazines, 1: 293 CYP2D6 metabolism, 6: 461–462, 465 hydroxylamines, 1: 293–295 Flupentixol, CYP2D6 metabolism, 6: 462 primary amines, 1: 297–298 Flurazepam, phase I metabolism, 6: 357 pyrrolidines, 1: 296 Flutamide: sulfoxides, 1: 292 cytochrome P450 enzymes, bioactive metabolites, theioethers, 1: 290–292 4: 12–15 thioamides, 1: 289 mitochondrial superoxide drug reactions, 4: 577 thiols, 1: 289–290 reductive bioactivation, 4: 90–91 thiones, 1: 287–288 Fluvoxamine, CYP1A2 metabolism, 6: 466 pediatric drug metabolism, 6: 548–549 Fold change, drug-drug interactions, cytochrome pharmacogenetics, 4: 386 P450 induction, 6: 159–160 phase I metabolism: Fold change (FC): catalytic cycle, 2: 266–267 drug-drug interactions, intestinal metabolism, 4: clopidogrel and prasugrel, 6: 365–366 419–420 oxidation, 2: 265–267 proteomics, label-free protein quantification, 4: species differences in metabolism, 1: 146–147 331–332 Flavonolignans, dietary supplement-drug interaction, Fomepizole, pediatric drug metabolism, alcohol milk thistle, 4: 526–528 dehydrogenase catalysis, 6: 549–550 Flavoproteins, azo reductases, 1: 375–377 Food and Drug Administration (FDA). See also Flow cells, electrochemical liquid chromatography Regulatory issues mass spectrometry, overview, 5: 314 bioanalysis guidelines, 5: 469–473 Flow injection analysis (FIA): biotransformation, drug development and, 6: electrochemical array applications, 5: 322–323 37–39 electrochemical liquid chromatography mass dietary supplements regulation, 2: 794, 796–797, spectrometry, applications, 5: 316 806 quantitative analysis, 5: 76–77 intestinal absorption classifications, 2: 97–99 Flow-limited pharmacokinetics model, 2: 648 MIST guidelines, 4: 207–208 Flow rates: new drug development: electrospray ionization, high vs. low liquid flow, effects on research, 3: 89–91 5: 52 regulatory issues, 3: 91 turbulent-flow chromatography, sample radiation dosimetry, whole-body autoradiation preparation quality control, 5: 521–523 studies, 5: 381–383 Fluorescence measurement: safety testing, stable metabolites, 3: 223–227 metabolite identification, 3: 133–134 solute carrier transporter guidelines, 2: 230 712 INDEX

Food and Drug Administration (FDA). See also plasma protein and tissue binding, in vitro ADME Regulatory issues (Continued) studies, 3: 59 xenobiotic metabolism, hepatocyte assessment, plasma protein binding, 5: 658–660 draft guidance, 3: 433–435 in vivo studies, distribution mechanisms, 3: 599 Food-drug interactions. See also Dietary supplements Free energy relationship: aflatoxin production and toxicity, 2: 919–920 drug metabolism, 2: 249–256 early drug development: phase II metabolism, GST enzymes, 2: 281–283 clinical pharmacology, 3: 103–105 Free fraction. See Unbound fraction (fu) labeling issues, 3: 114 Free induction decay (FID): extrahepatic metabolism, 2: 354 metabolite identification, NMR spectroscopy, 3: food intake, 6: 289 158–159 grapefruit juice, 6: 289–296 nuclear magnetic resonance limitations, 5: cardiovascular drugs, 6: 291–293 336–337 central nervous system effects, 6: 293–295 two-dimensional nuclear magnetic resonance, 5: erythromycin, 6: 295 340–341 HIV-protease inhibitors, 6: 295 Fresh cell lines, xenobiotic metabolism, hepatocyte immunosuppressive drugs, 6: 295 assessment, in vitro studies, metabolic stability, oral contraceptives, 6: 295 3: 397–402 sildenafil, 6: 296 Front-loading toxicity testing, cancer therapy: green tea, 6: 296 cardiotoxicity screening, 3: 27–28 licorice, 6: 296 clinical trials or post marketing studies, 3: 30–31 oral absorption, 2: 88–89 cytotoxics, 3: 24 bioavailability determinants, 2: 472–475 drug discovery and development, 3: 25–28 oral chemotherapeutic agents, 6: 506–507 exploratory and phase 0 trials, 3: 38–39 phytochemical modulators, 4: 494–499 future research issues, 3: 39–40 citrus juices, 4: 496–499 hepatic toxicity screening, 3: 27 cruciferous vegetables, 4: 494–496 immunomodulatory drugs, 3: 31 in vivo studies, animal studies, 3: 597–598 molecular targets, 3: 28–29 Formaldehyde dehydrogenase, pediatric drug adverse event prediction, 3: 37–38 metabolism, 6: 549–550 multikinase inhibitors, 3: 35–36 Formalin-fixed paraffin-embedded (FFPE) tissue nonclinical studies, 3: 25–26 samples, imaging mass spectrometry, 5: research background, 3: 23–24 219–221 signaling pathways, 3: 32–35 antigen retrieval, 5: 222–226 epidermal growth factor, 3: 32–35 Forward-phase protein microarrays (FPAs), vascular endothelial factor, 3: 35 proteomics analysis, 4: 336–337 targeted therapies: Fospropofol, phase I metabolism, 6: 361 adverse event prediction, 3: 37–38 Fourier transform ion cyclotron resonance (FTICR), biomarkers, 3: 29–30 nonhybrid analyzers, 5: 188–189 molecular challenges, 3: 32 Fractional excretion, physiologically-based research background, 3: 24–25 pharmacokinetic modeling, renal metabolism, 2: Full transport proteins, basic properties, 2: 159–161 656–659 Fumarylacetoacetate hydrolase (Fah), Fractional mass filtering, metabolite identification, 3: chimeric/humanized liver models, 3: 629–630 143–146 Functional reserve, mitochondrial toxicity, 6: Fraction metabolized by primary enzyme (fmi): 429–431 drug-drug interactions, in vitro-in vivo correlation, Fundamental radiofrequency: 4: 414, 420–425 ion trap mass spectrometry, 5: 30–33 hepatic drug metabolism, CYP enzymes, total quadrupole ion trap mass spectrometry, 5: metabolism effects, 3: 355 153–154 Fraction of absorbed dose: quadrupole time-of-flight mass spectrometry, 5: 34 bioavailability studies: Furan analogs, cytochrome P450 enzymes, covalent hepatic extraction and uptake, 2: 484–486 modification, 4: 46–48 intestinal extraction, 2: 480–484 Furosemide, cardiovascular metabolism, 2: 871 oral absorption, bioavailability determinants, 2: Fused-core chromatography: 470–480 chiral columns, 5: 529–530 Fraction of unchanged drug, ADME studies, renal pelicular (fused-core) silica, 5: 533 clearance data, 2: 607 Futile cycling: Free drug hypothesis: drug metabolism, 1: 7–14 INDEX 713

UGT biotransformation, toxicity studies, 6: Gemfibrozil: 259–260 acyl glucuronide inhibition, 6: 259–260 Fα2N-4 cells, hepatic drug metabolism, CYP ADME studies, 2: 870–871 enzyme induction, 3: 377–378 Gender differences. See Sex differences in drug metabolism Gabapentin, drug-drug interactions, 6: 484 Gene expression. See also Pharmacogenetics Gadolinium compounds, inductively coupled plasma enzyme kinetics, in vitro studies, 3: 290–292 mass spectrometry, 5: 306 glutathione transferases: Gallium compounds, inductively coupled plasma human functional genomics, 1: 561 mass spectrometry, 5: 306 pseudogenes, 1: 563–564 Gamma absorption model, plasma toxicogenomics, 4: 252–253 concentration-time data, 2: 614–615 carcinogenicity prediction, 4: 258–260 γ-Glutamyltransferase, extrahepatic metabolism, 2: cholestasis and hepatotoxicity, 4: 263–264 339–340 hepatomegaly and hepatocellular hypertrophy, Ganaxolone, drug-drug interactions, 6: 493 4: 262 Ganglioside-induced differentiation-associated hepatotoxicity prediction, 4: 256–257 proteins (GDAPs), cytosolic glutathione oxidative stress and reactive metabolite transferases, classification, 1: 562–563 formation, 4: 265–266 Garlic: in vitro toxicity and drug metabolism studies, 4: dietary supplement-drug interactions, 4: 510–513 271–272 herb-drug interactions, 2: 816–818, 6: 286–287 UGT isoforms: Gas chromatography-mass spectrometry (GC-MS): UGT1A1, 1: 471–472 analytical standards, 5: 66 UGT1A3, 1: 475–476 chemical ionization, 5: 23–25 UGT1A4, 1: 477 electron ionization, 5: 23 UGT1A6, 1: 479 quadrupole devices, 5: 156–158 UGT1A7, 1: 481 research background, 5: 546 UGT1A8, 1: 482–483 Gas-phase electrophoretic molecular mobility UGT1A9, 1: 483–484 analyzer (GEMMA), ion mobility mass UGT1A10, 1: 485–486 spectrometry, 5: 267 UGT2B4, 1: 487 Gas-phase reactions, quadrupole ion trap mass UGT2B7, 1: 488–489 spectrometry, 5: 170–171 UGT2B10, 1: 492 Gastric emptying half-times: UGT2B15, 1: 493–494 intestinal metabolism, 2: 64–67 UGT2B17, 1: 495 solubility and dissolution assessment, oral xenobiotic metabolism, hepatocyte assessment, absorption, BCS classification, 3: 502–504 induction studies, 3: 415–419 Gastrointestinal drug metabolism. See Intestinal drug General fraction theorem, metabolite analysis, 2: metabolism 622–623 Gastrointestinal tract: General solubility equation (GSE), solubility intestinal metabolism: assessment, 3: 508–509 motility and transit times, 2: 64–67 Generic drug compounds, bioequivalence studies, 2: regional dimensions, 2: 60–64 463–470 linear dimensions, 2: 60 Genetically modified animal (GEMA) models: relative surface areas, 2: 63–64 chimeric-humanized liver models, 3: 628–630 surface areas, 2: 60–63 cytochrome P450, 3: 630–640 mass balance studies, human studies, dosimetry CYP1A, 3: 631–633 calculations, 2: 444–446 CYP2D6, 3: 633–635 oral absorption, 2: 85–89 CYP2E1, 3: 635–637 solubility and dissolution assessment, 3: CYP3A, 3: 637–640 496–501 drug-metabolizing enzymes, 3: 620–622 physiology, 2: 85–86 epoxide hydrolases, 3: 640–644 tumors, imaging mass spectrometry, 5: 240–243 microsomal epoxide hydrolase, 3: 640–642 in vivo studies, oral absorption and bioavailability, soluble epoxide hydrolase, 3: 642–644 3: 594–595 esterases, 3: 650–652 GC-rich sequencing, ABC transporters, 2: 174 cholinesterases, 3: 650–652 Gefitinib (IRESSA): flavin monooxygenases, 3: 649 oral chemotherapeutic agents, 6: 522 future research issues, 3: 677 proteomics analysis, 4: 335–336 humanized mice, 3: 628 714 INDEX

Genetically modified animal (GEMA) models: GSTA1, 1: 565, 569 (Continued) GSTA2, 1: 569 induction studies, 3: 623–624 GSTA3, 1: 569 knock-out (null) models, 3: 627–628 GSTA4, 1: 570 nomenclature, 3: 619 GSTA5, 1: 570 nuclear receptors, 3: 657–666 mu class, 1: 570–571 aryl hydrocarbon receptor, 3: 665–666 GSTM1, 1: 570 constitutive androstane receptor, 3: 659–661 GSTM2, 1: 570 farnesoic X-activated receptor, 3: 663–664 GSTM3, 1: 571 multiple nuclear receptor studies, 3: 664–665 GSTM4, 1: 571 peroxisome-proliferator-activated receptors, 3: GSTM5, 1: 571 661–663 omega class, 1: 574–575 pregnane X receptor, 3: 658–659 GST01, 1: 574–575 oxidases, 3: 644–649 GST02, 1: 575 alcohol and aldehyde dehydrogenases, 3: pi class, 1: 571–572 647–649 GSTP1, 1: 571–572 aldehyde oxidase, 3: 644–645 sigma class, 1: 573 monoamine oxidases, 3: 645–647 theta class, 1: 572–573 research background, 3: 617–619 GSTT1, 1: 572–573 sulfotransferase, 3: 656–657 GSTT2, 1: 573 transporters, 3: 625–626 zeta class, 1: 573–574 bile salt export pump, 3: 676–677 hepatic drug metabolism, 6: 317 breast cancer resistant protein, 3: 668–669 metabonomic identification, 4: 292–293 multidrug resistance protein, 3: 669–672 microsomal epoxide hydrolase, 1: 402–405 organic anion transporters, 3: 675–676 molybdenum-containing hydroxylases, 1: organic anion transporting polypeptides, 3: 312–315 672–674 monoclonal antibody analyses, 3: 459–460 organic cation transporters, 3: 674–675 pharmacogenetics, biotransformational, 6: 22–25 P-glycoproteins, 3: 666–668 phase I metabolism, clopidogrel and prasugrel, 6: UGTs, 3: 652–656 365–366 Genetic polymorphism. See also Pharmacogenetics physiologically-based pharmacokinetic modeling, carboxylesterases, 1: 441–442 whole body model, 2: 667–670 conjugation, transport and elimination soluble epoxide hydrolase, 1: 410 mechanisms, 6: 230–231 solute carrier transporters, 2: 228–230 cytochrome P450 enzymes: sulfotransferases, 1: 543–544 human drug-metabolizing enzymes, 1: 241–261 phase II metabolism, 6: 212–213 CYP1 family, 1: 241–248 toxicity studies, 6: 378–380 CYP1A subfamily (CYP1A1/CYP1A2), 1: UGT activity and, 6: 265–266 242–243, 247 UGT isoforms: CYP1B subfamily, 1: 247–248 pharmacogenetics, 1: 460–467 CYP2 family, 1: 248–259 UGT1A1, 1: 471–472 CYP2A subfamily, 1: 249–250, 251–250 UGT1A3, 1: 475–476 CYP2B subfamily, 1: 251–253 UGT1A4, 1: 477 CYP2C subfamily, 1: 253–256 UGT1A6, 1: 479 CYP2D subfamily, 1: 256–258 UGT1A7, 1: 481 CYP2E subfamily, 1: 258–259 UGT1A8, 1: 482–483 CYP3 family, 1: 259–261 UGT1A9, 1: 483–484 transcriptional gene regulation, 1: 226 UGT1A10, 1: 485–486 dose calculations and, 6: 617–618 UGT2B4, 1: 487 drug-drug interactions: UGT2B7, 1: 488–489 ADME studies, 2: 19 UGT2B10, 1: 492 predictive studies, 6: 169–170 UGT2B15, 1: 493–494 drug metabolism, 1: 29 UGT2B17, 1: 495 extrahepatic drug-metabolizing enzymes, 2: Genetic polymorphisms, ABC transporters: 344–349 basic principles, 2: 174–176 flavin-containing monooxygenases, 1: 286–287 disease states, 2: 179–181 glutathione transferase superfamily: SNP effects: alpha class, 1: 565–570 ABCB1, 2: 176–178 INDEX 715

ABCC1, 2: 178 enzyme-catalyzed xenobiotic conjugation, 4: ABCG2, 2: 178–179 108–121 Genomic biomarkers, pharmacodynamics studies, 2: acyl glucuronidation, 4: 109–118 699–701 benoxaprofen, 4: 115–117 Genotoxicity assays, exploratory toxicology, 2: diclofenac, 4: 117–118 773–775 arylhydroxamic acids, 4: 118–121 Genotyping, drug-drug interactions, 4: 421–422 2-acetylaminofluorene, 4: 119–121 Germander, ADME and toxicity studies, 2: 927 UGT enzymes, 2: 279–281 Gilbert’s syndrome: species differences, conjugation and, 6: 227–230 hepatic drug metabolism, 6: 324–325 substrate stereoselective metabolism, 4: 353 UGT isoforms, UGT1A1, 1: 475 toxicity prevention, 6: 261–262 UGT polymorphisms, 6: 24–25 uridine diphosphate clinical significance, 6: 265–266 (UDP)-glucuronosyltransferases (UGTs): phase II metabolism, 6: 209–210 absorption mechanisms, 6: 252–254 Gingko biloba, herb-drug interactions, 2: 818–820 bioactivation mechanisms, 6: 254–262 Ginkgo biloba: glucuronidation, toxicity prevention, 6: dietary supplement-drug interaction, 4: 513–516 261–262 herb-drug interactions, 6: 287 pharmacology, 6: 260–261 Ginseng: toxicity studies, 6: 254–260 dietary supplement-drug interaction, 4: 516–518 classification, 6: 244–245 herb-drug interactions, 6: 288 clearance mechanisms, glucuronidation, 6: ADME studies, American/Asian variants, 2: 813 262–264 Siberian ginseng, 2: 823 drug-drug interactions, 6: 269–270 Glaucoma, cytochrome P450 polymorphisms, patient factors, 6: 264–269 CYP1B subfamily, 1: 247–248 drug-drug interactions, 6: 266–267 Glimepiride, drug-drug interactions, genetic polymorphism, 6: 265–266 clearance-dependent CYP induction, 4: glucuronidation inhibition, 6: 267–269 436–437 research background, 6: 243–244 Glomerular filtration rate (GFR): substrate specificity, 6: 245–251 age-dependent drug metabolism, 4: 453–454 tissue distribution, 6: 251–252 intrinsic vs. organ clearance, 2: 569–570 toxicity studies, 6: 254–260 pediatric drug metabolism, 6: 561–562 in vitro toxicity studies, 4: 230–231 physiologically-based pharmacokinetic modeling, Glucuronides, analysis and quantitation, 1: 471–472 renal metabolism, 2: 656–659 Glutathione (GSH): solute carrier transporters, 2: 221 ABC small molecule transport, ABCC subfamily, in vivo studies, renal clearance, 3: 608–609 2: 165–166 Glucocorticoid receptor (GR): adducts, covalent binding studies, limitations, drug conjugation and transport, 6: 225–226 4: 186 hepatic drug metabolism, CYP induction, 3: biotransformation and, 6: 6–7 374–378 conjugation, phase-II-enzyme-catalyzed sulfotransferases, induction, 1: 544–545 xenobiotics, 4: 129–140 β-Glucuronidase: S-acyl-glutathione thioester adducts, extrahepatic metabolism, 2: 342–343 carboxylic-acid-containing drugs, 4: uridine diphosphate 139–140 (UDP)-glucuronosyltransferases, 1: 470–471 bromobenzene, 4: 133–134 Glucuronidation: ethylene dibromide episulfonium ion formation, drug-drug interactions, drug-metabolizing 4: 130–131 enzymes, 6: 156, 163 hexachlorobutadiene-induced nephrotoxicity, 4: food-drug interactions, cruciferous vegetables, 4: 136–137 495–496 3,4-methylenedioxymethamphetamine-induced hepatic drug metabolism, Gilbert’s syndrome, 6: neurotoxicity, 4: 131–133 324–325 α-naphthylisothiocyanate-induced intrahepatic induction mechanisms, 6: 268–269 cholestasis, 4: 137–138 inhibition mechanisms, 6: 267–269 sevoflurane-induced nephrotoxicity, 4: 134–136 metabolic pathways, 4: 105–108 in vitro toxicity studies, 4: 240–243 metabolite identification, 3: 149–150 drug-induced oxidative stress: pediatric drug metabolism, 6: 551–553 cellular defense, 3: 183 phase II metabolism, 6: 207–210 status disruption, 3: 185 716 INDEX

Glutathione (GSH) (Continued) food-drug interactions, cruciferous vegetable glutathione transferase conjugation, 1: 559–560 induction, 4: 494–496 hepatic drug metabolism, in children, 6: 318 function and nomenclature, 1: 563 metabolic pathways, 4: 106–108 genes, 1: 563–565 oxidation, sulfotransferase kinetics, 1: 540–541 alternative splicing, 1: 565 reactive metabolite bioactivation, thiol derivatives, pseudogenes, 1: 563–564 5: 631–635 genetic polymorphism, 1: 565–575 safety testing, reactive metabolites, 3: 228–237 glutathione conjugation, ticrynafen-induced hepatotoxicity, 4: 576 phase-II-enzyme-catalyzed xenobiotics, 4: toxicity studies: 129–140 conjugate formation, 6: 392–393 S-acyl-glutathione thioester adducts, reactive metabolite toxicity elimination and carboxylic-acid-containing drugs, 4: minimization, 6: 386–390 139–140 reactive metabolite trapping, 6: 379–380 bromobenzene, 4: 133–134 in vitro toxicity studies, adduct and reactive ethylene dibromide episulfonium ion formation, metabolite formation, 4: 230–231, 240–242 4: 130–131 Glutathione S-transferase (GST) superfamily: hexachlorobutadiene-induced nephrotoxicity, 4: age-dependent drug metabolism, 4: 467–469 136–137 biotransformational pathways, 6: 11–12 3,4-methylenedioxymethamphetamine-induced covalent binding studies, limitations, 4: 186 neurotoxicity, 4: 131–133 cytosolic GSTs: α-naphthylisothiocyanate-induced intrahepatic genetics, 1: 561 cholestasis, 4: 137–138 human functional genomics: sevoflurane-induced nephrotoxicity, 4: 134–136 alpha class, 1: 565–570 GST-deficient mice studies, 1: 579 GSTA1, 1: 565, 569 hepatic drug metabolism, nutritional status, 6: 319 GSTA2, 1: 569 historical perspective, 1: 561–562 GSTA3, 1: 569 human functional genomics: GSTA4, 1: 570 classification, 1: 562–563 GSTA5, 1: 570 gene families, 1: 561 classification, 1: 562–563 genetic polymorphism: function and nomenclature, 1: 563 alpha class, 1: 565–570 genes, 1: 563–565 GSTA1, 1: 565, 569 alternative splicing, 1: 565 GSTA2, 1: 569 pseudogenes, 1: 563–564 GSTA3, 1: 569 genetic polymorphism, 1: 565–575 GSTA4, 1: 570 historical perspective, 1: 561–562 GSTA5, 1: 570 mu class, 1: 570–571 mu class, 1: 570–571 GSTM1, 1: 570 GSTM1, 1: 570 GSTM2, 1: 570 GSTM2, 1: 570 GSTM3, 1: 571 GSTM3, 1: 571 GSTM4, 1: 571 GSTM4, 1: 571 GSTM5, 1: 571 GSTM5, 1: 571 omega class, 1: 574–575 omega class, 1: 574–575 GST01, 1: 574–575 GST01, 1: 574–575 GST02, 1: 575 GST02, 1: 575 pi class, 1: 571–572 pi class, 1: 571–572 GSTP1, 1: 571–572 GSTP1, 1: 571–572 sigma class, 1: 573 sigma class, 1: 573 structure and function, 1: 575–579 theta class, 1: 572–573 active site and catalysis, 1: 577–579 GSTT1, 1: 572–573 crystal structures, 1: 575–577 GSTT2, 1: 573 theta class, 1: 572–573 zeta class, 1: 573–574 GSTT1, 1: 572–573 overview, 1: 559–560 GSTT2, 1: 573 structure and function, 1: 575–579 zeta class, 1: 573–574 active site and catalysis, 1: 577–579 drug-disease-drug interactions, 4: 639 crystal structures, 1: 575–577 extrahepatic metabolism, 2: 337–338 intestinal metabolism, Caco-2/TC7 cell line age and gender factors, 2: 344, 350 comparisons, 3: 339–341 INDEX 717

metabolic pathways, 4: 106–108 erythromycin, 6: 295 phase II metabolism, 2: 281–283, 6: 213–214 HIV-protease inhibitors, 6: 295 plant secondary metabolites, 4: 488–494 immunosuppressive drugs, 6: 295 precision-cut tissue slices, phase II induction oral contraceptives, 6: 295 studies, 3: 478–481 overview, 4: 496–499 pregnancy drug metabolism, 2: 947–951 sildenafil, 6: 296 xenobiotic metabolism, hepatocyte assessment, intestinal metabolism, 2: 480–481 induction, 3: 410–419 irreversible inhibition, 6: 29–30 Glycation reaction, UGT enzyme bioactivation, Graphic data, enzyme kinetics, 1: 87–88 toxicity studies, 6: 255–260 Green tea: Glycine: food-drug interactions, 6: 296 benzoic acid conjugation, 6: 217–218 herb-drug interactions, 2: 820 conjugation, mitochondrial acyl-coA:glycine Grepafloxacin, DNA binding, 2: 515 N-acyltransferase, 1: 603–605 Growth factors, pharmacodynamics mechanisms, 2: Glycolipids, MALDI-MS analysis, 5: 129–130 691–692 Glycopeptides/glycoproteins, MALDI-MS Growth hormone, sex-dependent hepatic drug procedures, 5: 128–129 metabolism, 1: 108–110 Glycosylation, peptide and protein therapeutics, 2: molecular determinants, 1: 110–112 905–906 Growth models, pharmacodynamics, disease Gold compounds: progression, 2: 726–727 inductively coupled plasma mass spectrometry, 5: G-site binding, phase II metabolism, GST enzymes, 303–304 2: 281–283 micellar electrokinetic chromatography, 5: Guanylate-cyclase receptors, pharmacodynamics 428–429 mechanisms, 2: 691–692 Goldenseal, dietary supplement-drug interaction, 4: Gut-blood barrier hypothesis, sulfotransferase 518–520 sulfation, 1: 541–542 Gonadal hormones, sex-dependent hepatic drug Gyrolab nanoscale assay, basic principles, 5: 401 metabolism, 1: 107–108 Go/No-Go decisions, early drug development: Half-life predictions: biopharmaceutical considerations, 3: 98 absolute bioavailability calculations, 2: 459–460 clinical pharmacology, 3: 102–105 human hepatic clearance, 1: 58–59 decision-making studies, 3: 105–109 peptide and protein therapeutics, 2: 901–904 IND-enabling development, 3: 92–93 posttranslational modification, 2: 905–907 nonclinical studies, 3: 98–99 serum protein fusion, 2: 904–905 research background, 3: 89–91 pharmacokinetic/toxicokinetic profiles, 2: 588 Good laboratory practice/good clinical practice Half-maximal rate of inactivation (KI), enzyme (GLP/GCP): kinetics, irreversible inhibition, 1: 91–94 assay transfers and changes, 5: 501–502 Half-transport proteins, basic properties, 2: 159 bioanalysis guidelines, 5: 472–473 Haloperidol: herb-drug interactions: CYP1A2 metabolism, 6: 467 adulterants and contaminants, 4: 505–506 CYP2D6 metabolism, 6: 463 phytochemical content variability, 4: 503 ketone reduction to secondary alcohol, 4: 354–355 MIST guidelines, human studies, 4: 217–218 phase I metabolism, ketone reduction, 2: 276–278 new drug development, 3: 91 Halothane: quantitative analysis, nano-ESI mass spectrometry, age-dependent drug metabolism, CYP2E1 5: 76–77 expression, 4: 459–460 Good manufacturing practices (GMPs), hepatotoxicity, 4: 573–574 bioavailability estimations, 2: 461–462 idiosyncratic adverse drug reactions, 6: 434 G-protein-coupled receptors, pharmacodynamics reactive metabolites, irreversible binding, 3: mechanisms, 2: 690–691 186–188 Graft responses, liver transplant, host size and, 6: reduction, 1: 11 332–333 structure-toxicity relationships, 6: 381–382 Grapefruit juice: Halperidol, pyridinium ion conversion, 1: 11 cardiovascular metabolism, verapamil, 2: 879 Hamilton-pool method, MIST analysis guidelines, dose calculations and, 6: 615–616 plasma availability and pooling strategy, 4: food-drug interactions, 6: 289–296 211–212 cardiovascular drugs, 6: 291–293 Hanes-Woolf plot: central nervous system effects, 6: 293–295 enzyme kinetics, 3: 296–297 718 INDEX

Hanes-Woolf plot (Continued) clearance mechanisms, 2: 762–763 physiologically-based pharmacokinetic modeling, age-dependent factors: enzyme-transporter biochemistry, 2: 646–647 CYP2C expression, 4: 456–458 Hapten hypothesis: CYP3A expression, 4: 460–462 idiosyncratic adverse drug reactions, 6: 424–425 physiological factors, 4: 453–454 idiosyncratic drug-induced liver injury, 4: 598 bioactivation, 4: 63–65 toxicity studies, 6: 378–379 bioavailability studies, 2: 484–486 Haptenization: biotransformational polymorphisms, 6: 22–25 adverse drug reactions, 4: 63–65 biotransformation pathway predictions, research covalent drug-protein adducts, hypersensitivity background, 6: 179–180 reactions, 4: 161–164 cirrhosis and, 6: 325–331 Hard reactions: anesthesia, 6: 330–331 reactive metabolites: cascular architecture and hepatic blood supply, ADME studies, 2: 28 6: 326–327 idiosyncratic adverse drug reactions, 6: 434 clearance reduction, 6: 329 irreversible binding to cellular macromolecules, drug response, 6: 330 3: 186–188 first pass and bioavailability, 6: 327 safety testing, reactive metabolites, 3: 228–237 hepatic enzymes, 6: 328–329 Helicobacter pylori therapy, cytochrome P450 protein binding and volume distribution, 6: enzymes, CYP2C19, 1: 255 327–328 Hematologic reactions, idiosyncratic adverse drug renal impairment, 6: 329–330 reactions, 6: 421–423 clearance mechanisms, 2: 142, 6: 312–317 agranulocytosis, 6: 422–423 ADME studies, 2: 762–763 anemia, 6: 421–422 bile formation and biliary excretion, 6: 317 aplastic anemia, 6: 423 in elderly, 6: 318–319 thrombocytopenia, 6: 422 fetal and newborn clearance, 6: 317–318 Heme biosynthesis, constitutive androstane receptor liver transplantation, 6: 333–334 transcription, 1: 213 nutritional status, 6: 319 Hemopoietic prostaglandin D synthase (HPGDs), physiological changes, 6: 317–320 polymorphisms, 1: 573 pregnancy, 6: 319–320 Hemostatic system, idiosyncratic drug-induced rate-limiting step, 2: 564–568 reactions, inflammation, 4: 603–604 cytochrome P450 enzymes: Henderson-Hasselbalch equation: CYP1A2, 1: 242, 247 drug distribution and, 2: 109–112 CYP2A subfamily, 1: 249–250 drug metabolism, 2: 249–256 CYP2B6, 1: 251 HepaRG cells: CYP2C9, 1: 254–255 enzyme kinetics, 3: 294 CYP2C19, 1: 255 hepatic drug metabolism, CYP enzyme induction, CYP2E, 1: 259–260 3: 376–378 CYP3A5, 1: 261 Heparin, thrombocytopenia reaction, 6: 422 CYP3A7, 1: 261 Hepatic bioavailability (FH): future research issues, 3: 380 cirrhosis, hepatic drug metabolism, 6: 327 predictive studies, metabolism and drug-drug drug-drug interactions, CYP induction, 4: interactions: 430–433 induction, 3: 371–379 Hepatic blood flow: FαN-4 cells, 3: 377–378 gastrointestinal absorption, 2: 54–59 HepaRG cells, 3: 376–377 pediatric drug metabolism, 6: 555–556 human hepatocytes, 3: 375–376 pharmacokinetic predictive studies, 2: 496 reporter gene assay, 3: 372, 374–375 species differences in, 2: 593–594 in vivo studies, 3: 378–379 Hepatic clearance (CLH), xenobiotic metabolism, inhibition, 3: 359–371 hepatocyte assessment: reversible inhibition, 3: 359–365 hepatobiliary transport, 3: 422–428 time-dependent inhibition, 3: 365–367 in vitro studies, metabolic stability, 3: 399–402 in vivo inhibition, 3: 367–371 Hepatic couplets, xenobiotic metabolism, hepatocyte metabolic stability, 3: 353–355 assessment, hepatobiliary transport, 3: 421–422 research background, 3: 351–352 Hepatic drug metabolism. See also Drug-induced total metabolism, 3: 355 liver injury (DILI); Intestinal drug metabolism in vivo pharmacokinetics, 3: 355–358 ADME studies, 2: 25–28 in vitro-in vivo correlation studies, 6: 77–79 INDEX 719 cytokines, 4: 645–649 HNFα, 1: 112 dose calculations based on, 6: 614 hormonal determinants, cytochrome P450s, 1: drug-drug interactions: 107–110 anticonvulsants, 6: 475–476 human cytochrome P450s, 1: 106–107 CYP induction, 4: 430–433 molecular determinants, 1: 110–112 in vitro-in vivo correlation, 4: 415–425 rat cytochrome P450s, 1: 105–106 drug transporters, 4: 643–644 STAT5b tyrosine phosphorylation, 1: 110–111 elimination pathways, impairment effects, 6: SLC transporters, 2: 210–211 224–225 toxicogenomics: enzyme kinetics, in vitro/in vivo correlation, 3: mechanical analysis using, 4: 266–270 305–307 oxidative stress and reactive metabolite human studies predicting, 1: 58–59 formation, 4: 265–266 inflammation: transporter mechanisms, 6: 219–220 chemokines and cytokines, 4: 629 UGT enzymes, UGT1A9, 1: 485 drug-disease-drug interactions, research vectorial transport, 2: 553–554 background, 4: 625 in vitro toxicity studies, 4: 235–239 intrinsic vs. organ clearance, 2: 569–570 future models, 4: 246–247 liver anatomy and blood supply, 6: 308–312 intestinal metabolism vs., 4: 226–233 liver disease: xenobiotics, hepatocyte assessment: alcoholism, 6: 322–323 CYP induction, 3: 409–419 cholestatic disease, 6: 323–324 endpoint measurement, 3: 413–417 future research issues, 6: 339 in vitro-in vivo correlations, 3: 417–419 Gilbert’s syndrome, 6: 324–325 CYP inhibition studies, 3: 405–409 herb-drug interactions, 6: 338–339 FDA draft guidance, 3: 433–434 parenchymal disease, 6: 321–322 drug-metabolizing enzymes, 3: 433–434 pathology, 6: 320–321 transporters, 3: 434 research background, 6: 307–308 hepatobiliary transport, 3: 419–428 liver surgery and regeneration, 6: 331–332 cryopreserved hepatocytes, 3: 425 liver transplantation and, 6: 332–338 hepatic couplets, 3: 421–422 absorption mechanisms, 6: 333 primary culture, 3: 423–425 clearance mechanisms, 6: 333–334 primary hepatocytes, 3: 422–423 graft vs. recipient size, 6: 332–333 small interfering RNA, 3: 425–427 immunosuppressants, 6: 334–338 suspension hepatocytes, 3: 423 antiproliferative agents, 6: 337–338 transporter-mediated drug-drug interaction, 3: azathioprine, 6: 338 419–421 cyclosporine, 6: 336–337 in vitro/in vivo correlation, 3: 427–428 immunophilin-binding agents, 6: 335–337 hepatotoxicity studies, 3: 428–433 mycophenolate mofetil, 6: 337–338 future toxicity models, 3: 432–433 sirolimus, 6: 337 in vitro assays, primary hepatocytes, 3: steroids, 6: 334–335 430–432 tacrolimus, 6: 335–336 metabolic profiling, 3: 403–404 posttransplant metabolism, 6: 333–334 metabolic stability, drug candidate, 3: 396–402 protein binding, 6: 333 fresh/cryopreserved suspensions, 3: 397–401 pediatric populations: in vitro-in vivo correlations, 3: 401–402 cytochrome P450 enzymes, 6: 541–547 metabolite identification, 3: 404–405 hepatic blood flow, 6: 555–558 research background, 3: 393–396 liver size relative to body weight, 6: 557–559 Hepatic microsteatosis: phase I metabolism, 6: 539–540 biomarkers, drug-induced liver injury, 4: 188–192 protein binding, 6: 554–555 mitochondrial toxicity, 6: 430–431 pharmacokinetic modeling, 6: 590–591 Hepatitis, hepatic drug metabolism, 6: 321–322 physiologically-based pharmacokinetic modeling, Hepatobiliary transport, xenobiotic metabolism, 2: 650–652 hepatocyte assessment, 3: 419–428 in pregnancy, 2: 937 cryopreserved hepatocytes, 3: 425 reactions and pathways, 6: 312 hepatic couplets, 3: 421–422 sex differences in, 1: 102–112 primary culture, 3: 423–425 future research issues, 1: 112 primary hepatocytes, 3: 422–423 gonadal hormones, 1: 107–108 small interfering RNA, 3: 425–427 growth hormone, 1: 108–110 suspension hepatocytes, 3: 423 720 INDEX

Hepatobiliary transport, xenobiotic metabolism, in vitro-in vivo correlations, 3: 401–402 hepatocyte assessment (Continued) metabolite identification, 3: 404–405 transporter-mediated drug-drug interaction, 3: research background, 3: 393–396 419–421 Hepatomegaly, toxicogenomics and, 4: 261–262 in vitro/in vivo correlation, 3: 427–428 Hepatotoxicity. See also Drug-induced liver injury Hepatocellular hypertrophy, toxicogenomics and, 4: (DILI); Hepatic drug metabolism 261–262 acetaminophen: Hepatocyte nuclear factors (HNFs): drug-drug interactions, 4: 3–4 drug conjugation and transport, 6: 225–226 idiosyncratic drug reactions, 4: 576 transcriptional regulation, 4: 650 metabolism and oxidative stress, 3: 192–193 Hepatocytes: amodiaquine-induced, 4: 581–582 acetaminophen bioactivation, oxidative stress, 3: animal studies: 194–198 drug-inflammation interaction, 4: 605–612 ADME studies: inflammatory stress hypothesis, 4: 607–610 CYP induction, 2: 30–31 model comparisons, 4: 610–612 DNA microarrays, 3: 321–324 sulindac, 4: 606–607 permeability and transporters, 2: 25 future research issues, 4: 612–613 biotransformation pathway predictions, in vitro inflammatory response, 4: 601–605 studies, 6: 185–186 hemostatic system and hypoxia, 4: 603–604 cytochrome P450 enzymes, in vitro-in vivo neutrophils, 4: 604–605 correlation studies, 6: 77–79 reactive oxygen species, 4: 605 drug-drug interactions: tumor necrosis factor-α, 4: 602–603 CYP inhibition, 6: 94–101 proposed mechanisms, 4: 597–601 enzyme induction, 1: 64–65 danger hypothesis, 4: 599 NME-precipitated CYP induction, 6: 109–111 failure to adapt hypothesis, 4: 599–600 transporters and NME disposition, 6: 125–126 hapten hypothesis, 4: 598 enzyme kinetics, 3: 292–293 inflammatory stress hypothesis, 4: 600–601, hepatic drug metabolism: 607–608 CYP enzyme induction, 3: 375–378 metabolic polymorphism hypothesis, 4: in vivo human pharmacokinetics, 3: 356–358 597–598 human hepatic clearance predictions, 1: 58–59 mitochondrial dysfunction hypothesis, 4: 599 metabolic stability, in vitro studies, 3: 353–355 multiple determinant hypothesis, 4: 600 solute carrier proteins, in vitro studies, 2: 217 research background, 4: 595–597 xenobiotics, hepatic metabolism assessment: biomarkers, metabonomic identification, 4: CYP induction, 3: 409–419 298–299 endpoint measurement, 3: 413–417 bromobenzene, 4: 133–134 in vitro-in vivo correlations, 3: 417–419 cancer therapy, screening techniques, 3: 27 CYP inhibition, 3: 405–409 covalent drug-protein adducts, prevention FDA draft guidance, 3: 433–434 strategies, 4: 165–186 drug-metabolizing enzymes, 3: 433–434 covalent binding evaluation, hepatotoxicity transporters, 3: 434 prediction, 4: 176–179 hepatobiliary transport, 3: 419–428 limitations of covalent binding studies, 4: cryopreserved hepatocytes, 3: 425 185–186 hepatic couplets, 3: 421–422 reactive intermediate formation, minimization primary culture, 3: 423–425 of, 4: 165–176 primary hepatocytes, 3: 422–423 dual A2A/A1 receptor antagonist small interfering RNA, 3: 425–427 optimization, 4: 174–176 suspension hepatocytes, 3: 423 leukotriene receptor agonist optimization, 4: transporter-mediated drug-drug interaction, 3: 174 419–421 SERM optimization, 4: 173–174 in vitro/in vivo correlation, 3: 427–428 taranabant optimization, 4: 172–173 hepatotoxicity studies, 3: 428–433 risk assement, covalent binding data, 4: future toxicity models, 3: 432–433 179–185 in vitro assays, primary hepatocytes, 3: anticonvulsants, 4: 183–185 430–432 buspirone, 4: 181–182 metabolic profiling, 3: 403–404 paroxetine, 4: 182 metabolic stability, drug candidate, 3: 396–402 propranolol, 4: 179–181 fresh/cryopreserved suspensions, 3: 397–401 raloxifene, 4: 182–183 INDEX 721

sudoxicam, 4: 183 regulatory issues, 2: 796, 807 diclofenac, 4: 84 research background, 2: 793–796 drug-drug interactions, CYP-mediated induction, St. John’s wort, 2: 823–825 4: 443–444 saw palmetto, 2: 822 electrochemical array with mass spectrometry, Siberian ginseng, 2: 823 metabolomics, 5: 325–326 transporter-associated absorption, 2: 809–811 electrochemical liquid chromatography mass underlying mechanisms, 2: 809–812 spectrometry, reactive intermediates, 5: US herb use, 2: 812–826 319–320 valerian, 2: 825 flutamide, reductive bioactivation, 4: 90–91 biotransformation and, 6: 6 HLA genetic markers for, 4: 190–192 conjugation and transport, 6: 226–227 idiosyncratic drug-induced reactions: consequences of, 4: 487 halothane-induced toxicity, 4: 573–574 drug-drug interaction comparisons, 6: 280–281 isoniazid-induced toxicity, 4: 574–575 echinacea, mechanisms, 6: 286 mechanisms, 4: 569–570 Echinacea spp., dietary supplement-drug ticrynafen-induced toxicity, 4: 575–576 interaction, 4: 507–510 mitochondrial toxicity, 6: 429–431 garlic, 6: 286–287 α-naphthylisothiocyanate intraheptatic cholestasis, dietary supplement-drug interactions, 4: 4: 137–138 510–513 toxicogenomics: Gingko biloba, mechanisms, 6: 287 cholestasis and, 4: 262–264 ginkgo biloba, dietary supplements, 4: 514–516 hepatomegaly and hepatocellular hypertrophy, ginseng: 4: 261–262 dietary supplement-drug interaction, 4: prediction studies, 4: 256–257 516–518 in vitro toxicity screening, 4: 235–239 mechanisms, 6: 288 future models, 4: 246–247 hepatic drug metabolism, liver disease, 6: sandwich culture, 4: 246 338–339 withdrawal of drugs for, 4: 159–160 interbatch potency consistency, 2: 808 xenobiotics: kava kava: metabolism: dietary supplement-drug interaction, 4: assessment, 3: 428–433 521–522 future toxicity models, 3: 432–433 mechanisms, 6: 288 in vitro assays, primary hepatocytes, 3: milk thistle: 430–432 dietary supplement-drug interaction, 4: hepatobiliary transport, 3: 421–428 526–528 Herb-drug interactions: mechanisms, 6: 288 ADME studies: phytochemical modulators: aloe, 2: 812–813 content variability, 4: 502–503 assessment, 2: 807–809 DSHEA guidelines and dietary supplements, 4: bitter orange, 2: 813 499–500 black cohosh, 2: 813–814 enteric CYP3A/ABC content/activity, 4: cranberry, 2: 814 500–501 curcumin, 2: 814–815 pharmacogenetics, 4: 501 CYP induction and metabolism, 2: 812 prediction and interpretation uncertainty, 4: CYP inhibition and metabolism, 2: 811–812 500–503 danshen, 2: 815 synergistic mechanisms, 4: 501–502 dong quai, 2: 815–816 research background, 6: 279–280 echinacea, 2: 816 St. John’s wort, 6: 281–286 evening primrose oil, 2: 816 anticancer drugs, 6: 283 future research issues, 2: 825–826 anti-HIV drugs, 6: 283–284 garlic, 2: 816–818 cardiovascular drugs, 6: 284–286 ginger, 2: 8181 central nervous system effects, 6: 284 Gingko biloba, 2: 818–820 fexofenadine, 6: 286 ginseng, 2: 813 immunosuppressive drugs, 6: 282–283 green tea, 2: 820 oral contraceptives, 6: 283 kava kava, 2: 820–821 proton pump inhibitors, 6: 286 licorice, 2: 821 theophylline, 6: 286 milk thistle, 2: 821–822 in vivo human studies, 4: 504–505 722 INDEX hERG binding assay, toxicity studies, 2: 775 normalized response, 5: 61 Heteroactivation enzyme kinetics, 1: 86–87, 3: nuclear magnetic resonance and, 5: 342–343 301–302 plasma protein binding estimation, 2: 543–544 Heteroatoms: qualitative analysis, 5: 75–76 cytochrome P450 oxidations, 1: 190–193 quality controls: biotransformation, 6: 59–60 buffer selection, 5: 527–528 hydroxylation, 6: 57–59 research background, 5: 516–518 dealkylation, cytochrome P450 enzymes, phase I quantitative analysis, 5: 76–77 metabolism, 2: 261–265 sample introduction, 5: 53–54 Heterocycle reduction, AO/XOR-mediated reactions, selective reaction monitoring, 5: 555–557 1: 329–331 simultaneous fraction collection, 5: 68–69 N-Heterocycles, oxidation, AO/XOR-mediated sulfotransferase, sulfation assays, 1: 538 reactions, 1: 315–320 High permeability (HP) compounds, solubility and Heteronuclear experiments, metabolite identification, dissolution assessment, oral absorption: 3: 161–162 BCS classification, 3: 501–504 Heteronuclear multiple bond correlation (HMBC), BDDCS classification, 3: 504–507 multidimensional analysis, 5: 341 rate-limiting steps, 3: 498–501 Heteronuclear multiple quantum coherence (HMQC), High resolution magic angle spinning (HR-MAS), multidimensional analysis, 5: 341 metabonomics analysis, 4: 285 Heteronuclear single quantum coherence (HSQC), High resolution mass spectrometry (HR-MS): multidimensional analysis, 5: 341 basic principles, 5: 31–32, 34–36 Heterotropic cooperativity: metabolite identification, 5: 39–45 cytochrome P450 catalytic cycle, substrate MIST analysis guidelines, 4: 212–215 binding, 1: 184–186 reactive metabolite bioactivation, glutathione in vitro toxicity studies, positive cooperativity, 4: derivatives, 5: 633–635 228–233 selectivity, 5: 65–66 Hexachlorobutadiene, nephrotoxicity induction, 4: High solubility (HS) compounds, solubility and 136–137 dissolution assessment, oral absorption: High amplitude short time excitation (HASTE), BCS classification, 3: 501–504 quadrupole ion trap mass spectrometry, BDDCS classification, 3: 504–507 resonant excitation, ion activation, 5: 168–169 High temperature liquid chromatography (HTLC), High content screening (HCS), biomarkers, development of, 5: 533–535 drug-induced liver injury, 4: 188–192 High throughput quantitative mass spectrometry: High energy solids, solubility and dissolution ambient ionization methods, 5: 567–570 assessment, oral absorption, 3: 534–535 applications, 5: 555–557 High field asymmetric waveform ion mobility basic principles, 5: 548, 550 spectrometry, basic principles, 5: 265–266 bioinformatics, 5: 564–565 High mass accuracy and resolution, ion mobility laser-based ionization methods, 5: 566–567 mass spectrometry-mass spectrometry mass analyzer tuning and selection, 5: 552–555 integration, 5: 277–280 multicolumn parallel chromatography: High performance ion mobility mass multiple ESI sources, 5: 562–563 spectrometry-mass spectrometry, basic single ionization source, 5: 560–562 principles, 5: 276–277 multiplexed systems, 5: 558–559 High performance liquid chromatography (HPLC): non-LC-based techniques, 5: 565 bioanalytical applications, 5: 4 sample pooling, 5: 551–552 carryover regulations, 5: 486 sample preparation, 5: 551–552 chiral columns, 5: 529–530 serial higher throughput, 5: 557–558 early drug development, animal-to-human staggered parallel chromatography, 5: 563–564 transition, 3: 94 staggered parallel dual column reconditioning, 5: electrochemical flow cells, 5: 314 560 flow rates, 5: 52 High-throughput screening (HTS): hybrid silica particles, 5: 528–529 ADME studies, hybrid mass spectrometry, 5: metabolite identification, 3: 130–146 178–180 NMR combined with, 3: 162–164 blood-brain barrier penetration, in vitro studies, radiometric quantification, 3: 164–166 tissue binding, 3: 573–574 monolithic columns, 5: 530 drug-drug interactions, predictive studies, 6: nano-electrospray ionization mass spectrometry, 5: 165–168 47–48 CYP450, 6: 166–167 INDEX 723

limitations, 6: 168 Human anti-rabbit antibody (HARA), in silico assessment, 6: 168 immunoassays, 5: 407 UGTs, 6: 167 Human BioMolecular Research Institute (HBRI), hepatic drug metabolism: flavin-containing monooxygenases, academic CYP enzyme induction, 3: 374–378 drug development, 1: 282–283 CYP enzyme inhibition, 3: 359–365 Human equivalent dose (HED), early drug plasma protein binding, 2: 545–546 development, clinical pharmacology, 3: solubility and dissolution assessment, oral 101–102 absorption, 3: 514–515 Human functional genomics, glutathione transferase dissolution measurement, 3: 528 superfamily, cytosolic GSTs: Hill coefficient, enzyme kinetics, sigmoidal kinetics, alpha class, 1: 565–570 1: 82–83 GSTA1, 1: 565, 569 Hill equation: GSTA2, 1: 569 enzyme kinetics, sigmoidal kinetics, 1: 82–83 GSTA3, 1: 569 pharmacodynamics, 2: 685–686 GSTA4, 1: 570 Histological analysis: GSTA5, 1: 570 image analysis, mass spectrometry: classification, 1: 562–563 integration of, 5: 229–230 function and nomenclature, 1: 563 research background, 5: 216 genes, 1: 563–565 intestinal metabolism, 3: 336 alternative splicing, 1: 565 Histone deacetylase inhibitors, oral chemotherapeutic pseudogenes, 1: 563–564 agents, 6: 523 genetic polymorphism, 1: 565–575 HIV therapies: historical perspective, 1: 561–562 abacavir, 4: 77–79 mu class, 1: 570–571 food-drug interactions, grapefruit juice, 6: 295 GSTM1, 1: 570 herb-drug interactions: GSTM2, 1: 570 garlic, 6: 287 GSTM3, 1: 571 St. John’s wort, 2: 824, 6: 283–284 GSTM4, 1: 571 pediatric drug metabolism, drug-drug interactions, GSTM5, 1: 571 6: 566 omega class, 1: 574–575 phase I metabolism, drug-drug interactions, 6: 368 GST01, 1: 574–575 protease inhibitors, drug-drug interactions, GST02, 1: 575 therapeutic efficacy, 4: 442 pi class, 1: 571–572 HNF4α: GSTP1, 1: 571–572 cytochrome P450 genes, transcriptional regulation, sigma class, 1: 573 receptor cross talk, CYP2C9, 1: 219 structure and function, 1: 575–579 sex-dependent hepatic drug metabolism, 1: active site and catalysis, 1: 577–579 110–112 crystal structures, 1: 575–577 Homogenates, blood-brain barrier penetration, in theta class, 1: 572–573 vitro studies, tissue binding, 3: 573–752 GSTT1, 1: 572–573 Homogeneous immunoassays, basic principles, 5: GSTT2, 1: 573 402 zeta class, 1: 573–574 Homogenization factor, mass balance studies, animal Human leukocyte antigen (HLA) markers, hepatic studies, 2: 425 and skin toxicity, 4: 190–192 Homotropic cooperativity, cytochrome P450 Human liver microsomes (HLMs): catalytic cycle, substrate binding, 1: 184–186 ADME studies: Hormonal agents, oral chemotherapeutic agents, 6: hepatic metabolism, 2: 25–28 523–524 pharmacokinetics, 3: 78–80 Hormonal determinants: in silico studies, 3: 65–69 pregnancy drug metabolism, 2: 945–951 biotransformation pathway predictions, in vitro sex-dependent hepatic drug metabolism, 1: studies, 6: 183–185 107–110 cytochrome P450 enzymes, in vitro-in vivo H-site, phase II metabolism, GST enzymes, 2: correlation studies, 6: 77–79 282–283 drug-drug interactions, 4: 422–423 HSP90, aryl hydrocarbon receptor transcription, 1: CYP induction, 6: 158–160 214–215 CYP inhibition, 6: 94–101 Human anti-mouse antibody (HAMA), NME pharmacokinetics and risk assessment, 6: immunoassays, 5: 407 124–125 724 INDEX

Human liver microsomes (HLMs) (Continued) dietary supplement-drug interaction, St. Johns enzyme kinetics, in vitro studies, 3: 288–290 wort, 4: 530–532 hepatic drug metabolism, in vivo human distribution mechanisms, in vivo studies, 2: pharmacokinetics, 3: 356–358 137–138 metabolic stability, in vitro studies, 3: 353–355 DNA microarrays: monoclonal antibody analyses, 3: 448–451 ADME studies, 3: 321–324 pediatric drug metabolism, milligram microsomal toxicogenomics, 3: 324–328 protein per gram liver, 6: 559 drug discovery and development, 3: 19–21 early drug development, animal studies transition uridine diphosphate to, 3: 93–99 (UDP)-glucuronosyltransferases: elimination pathways, 6: 222–225 albumin effect, 1: 468–469 hepatic clearance prediction, 1: 58–59 research background, 1: 458 hepatic drug metabolism, in vivo in vitro studies, enzyme inhibition, 5: 8 pharmacokinetics, 3: 355–358 Human molybdenum cofactor sulfurase (HMCS), liver slices: molybdenum-containing hydroxylases, 1: CYP induction studies, 3: 475–476 314–315 phase II enzyme induction, 3: 480–481 Human serum albumin (HSA): mass balance studies: equilibrium dialysis, 2: 539–540 case study, 2: 448–450 high performance affinity chromatography, 2: dosimetry calculations, 2: 441–446 543–544 effective dose, 2: 445–446 pediatric drug metabolism, 6: 555–558 gastrointestinal tracts, 2: 444–445 plasma protein binding: organs and tissues, 2: 445 distribution mechanisms, 2: 118–119 experimental design, 2: 447–448 research background, 2: 532–536 research background, 2: 440–441 Human studies. See also First-in-human studies microdosing bioanalysis: ADME studies: accelerator mass spectrometry, 5: 602–614 DNA microarrays, 3: 321–324 liquid chromatography-mass spectometry, 5: metabolite prediction, 2: 13–15 614–618 pharmacokinetic prediction, 2: 12–13 positron emission tomography, 5: 618–620 allometric scaling pharmacokinetics: research background, 5: 599–602 animal studies, 2: 497–501 microsomal epoxide hydrolase, genetic nonlinear mixed effects modeling, 2: 508–509 polymorphism, 1: 402–405 in vitro studies, 2: 501–503 MIST guidelines: volume of distribution, 2: 503, 505–508 accelerator mass spectrometry, 4: 216 14 biotransformation pathway predictions, in vivo carbon 14 ( C) ADME study, 4: 215 studies, 6: 194–198 molybdenum-containing hydroxylases, 1: first-in-human studies, 6: 194–195 335–336 microtracer and accelerator mass spectrometry pharmacokinetic modeling, absorption and disposition kinetics, 2: 515–521 studies, 6: 196–198 physiologically-based pharmacokinetic modeling, radiolabeled studies, 6: 195–196 blood flow and tissue volume, 2: 640–641 carboxylesterases, 1: 429–432 phytochemicals, 4: 504–505 animal comparisons, 1: 446–448 plant secondary metabolite modulation, 4: substrate specificity, 1: 432–434 490–492 tissue distribution, 1: 438 preclinical PK-PD evaluation, 2: 778–780 clearance mechanisms, glucuronidation, 6: sex differences in drug metabolism, hepatic drug 262–264 metabolism, 1: 106–107 CYP1A enzymes, 1: 129 solubility and dissolution assessment, oral CYP1B enzymes, 1: 129 absorption, rate-limiting steps, 3: 498–501 CYP2A enzymes, 1: 129–131 soluble epoxide hydrolase, 1: 410 CYP2B enzymes, 1: 131–133 sulfotransferases, 1: 529–536 CYP2C enzymes, 1: 133–135 classification and nomenclature, 1: 530–532 CYP2D enzymes, 1: 135–137 fetal development, 1: 535–536 CYP2E metabolism, 1: 137–138 protein structure and function, 1: 531, 533 cytochrome P450 enzymes, 1: 169–172 tissue distribution, 1: 533–535 expression and activity, 6: 61–69 toxicity studies: nomenclature and classification, 6: 54–55 covalent binding, 6: 391–393 INDEX 725

future research issues, 6: 396 nuclear magnetic resonance, 5: 338 medicinal chemistry management, 6: 386–390 drug discovery and development, 5: prediction studies, 6: 391–393 346–350 reactive metabolites: 2H-Hydrogen, metabolite identification, NMR daily dose/low systemic exposure, 6: spectroscopy, 3: 158 393–395 Hydrogen atom extraction (HAT), phase I screening, 6: 379–380 metabolism: trapping, 6: 391–393 cytochrome P450 enzymes: research background, 6: 377–379 aliphatic oxidation, 2: 258–259 structure-toxicity relationships, 6: 380–386 heteroatom dealkylation and oxidation, 2: toxicophore prohibition, drug design, 6: 261–265 390–391 monoamine oxidase, 2: 269–271 in vivo models of drug metabolism, 1: 56–58 Hydrogen bonding: in vivo studies: ADME studies: clearance models, 3: 610 permeability, 2: 8–10 distribution mechanisms, animals as model for, pharmacokinetics, 3: 78–80 3: 599 drug discovery and development, Lipinski’s oral absorption and bioavailability, 3: 594–595 rule-of-five and, 3: 47–54 animal models as basis for, 3: 596–597 drug metabolism, 2: 248–256 research background, 3: 50–593 micellar electrokinetic chromatography: xenobiotic metabolism, hepatocyte assessment, in micellar pseudophases, 5: 426 vitro studies, metabolic stability, 3: 399–402 pseudostationary phase classification, 5: Hyberbolic saturation, enzyme kinetics, 431–432 Michaelis-Menten kinetics, 1: 79–81 Hydrogen/deuterium (H/D) exchange: Hybrid mass spectrometry: metabolite identification, 3: 150–151 drug discovery and development: quadrupole ion trap mass spectrometry, 5: 171 development stage studies, 5: 180–181 Hydrolysis, metabolite identification, 3: discovery stage studies, 5: 178–180 151–152 instrumentation, 5: 189–205 Hydrolytic metabolism: drug discovery and development, 5: 178–181 carboxylesterases: isotope pattern filtering, 5: 201–204 drug design, 1: 426 mass defect filtering, 5: 200–201 ester and amide drugs, 1: 424–426 metabolite detection software, 5: 204–205 species-specific reactions, 1: 446–447 metabolite fragmentation, 5: 197–200 uridine diphosphate-glucuronosyltransferases, 1: Orbitrap systems, 5: 195–197 442–443 Q-TOF systems, 5: 192–195 cytochrome P450 enzymes, ester/amide cleavage, QTRAP systems, 5: 189–192 6: 59 metabolite identification, 5: 31–36, 39–45 pediatric population, extrahepatic metabolism, 6: Hybridoma technology, monoclonal antibody 550–551 production, 3: 448 peptide and protein therapeutics, 2: 898–901 Hybrid silica particles, emergence of, 5: 528–529 principles of, 1: 3–14 Hydantoins, bioactivation, 4: 83 Hydroperoxides, enzyme-catalyzed reduction Hydrates, solubility and dissolution assessment, oral reactions, 1: 383–384 absorption, multicomponent formulation, 3: 536 Hydrophilic interaction chromatography (HILIC): Hydrazines: basic principles, 5: 530–531 aromatic, N-acetylation, 4: 127 sulfotransferase, sulfation assays, 1: 538 cytochrome P450 bioactivation, covalent Hydrophilic-lipophilic balance (HLB), solubility and modification, 4: 47–48 dissolution assessment, oral absorption, 3: flavin-containing monooxygenase metabolism, 1: 539–540 293 Hydrophobicity, micellar electrokinetic metabolite identification, 3: 147–150 chromatography, 5: 422 metabonomic analysis, 4: 299 Hydrophobic substrate binding sites, glutathione Hydrodynamic voltammograms, electrochemical transferase superfamily: liquid chromatography mass spectrometry, 5: ABC small molecule transport, 2: 165–166 315 pi class GSTs, 1: 571–572 1H-Hydrogen: 3-Hydroxyacetanilide (AMAP), hepatotoxicity metabolite identification, NMR spectroscopy, 3: prevention, reactive intermediate formation, 4: 157, 159–162 166–172 726 INDEX

Hydroxyeicosatetraenoic acid (HETEs), chiral inversion, 4: 358–359 cardiovascular drug metabolism, phase II metabolism, acyl coA synthetase, 2: drug-metabolizing enzymes, 2: 861–863 289–290 Hydroxyl alkyl-enzyme intermediate, epoxide toxicity studies, structure-toxicity relationships, 6: hydrolase, phase I metabolism, 2: 276 385 Hydroxylamines, flavin-containing monooxygenase IC50 parameter: metabolism, 1: 293–295 ADME studies, CYP inhibition, 2: 29–30 Hydroxylases, catalytic activity, 6: 54–56 drug-drug interactions: Hydroxylation: ADME studies, 3: 57–58 cytochrome P450 enzymes: CYP inhibition, 6: 94–101 aliphatic hydroxylation, 6: 56 inhibition mechanisms, 4: 406–413 α-carbon to hetero atom, 6: 57–59 noncompetitive inhibition, 4: 411 aromatic hydroxylation, 6: 56–57 uncompetitive inhibition, 4: 412–413 bioactive metabolites, aromatic/aliphatic drug-drug interactions (DDIs), in vitro-in vivo hydroxylation, 4: 11–15 correlation, 4: 413–425 oxidative ester/amide cleavage, 6: 59 enzyme kinetics, 1: 94–96 drug metabolism, 1: 7–14 hepatic drug metabolism, CYP enzyme inhibition, Hydroxymethylvinyl ketone (HMVK), reactive 3: 363–367 metabolite bioactivation, 5: 635–637 Idiosyncratic adverse drug reactions (IADRs): N-Hydroxy compounds, reduction reactions, 1: ADME studies, metabolite prediction, 2: 14–15 328–329 animal studies, 4: 571–582 Hydroxypyrimidine, oxidation, AO/XOR-mediated acetaminophen-induced hepatotoxicity, 4: 576 reactions, 1: 315–320 amodiaquine-induced hepatotoxicity and 4-Hydroxytamoxifen, phase I metabolism, agranulocytosis, 4: 581–582 tamoxifen, 6: 360 drug-induced liver injury: Hydroxyzine, cytochrome P450 enzymes, bioactive drug-inflammation interaction, 4: 605–612 metabolites, 4: 14–15 inflammatory stress hypothesis, 4: Hyperbaric oxygenation, carboplatin and, 2: 607–610 848–849 model comparisons, 4: 610–612 Hyperbilirubinemia, pediatric drug metabolism, 6: sulindac, 4: 606–607 555–558 future research issues, 4: 612–613 Hyperforin, St. Johns wort, dietary supplement-drug inflammatory response, 4: 601–605 interaction, 4: 529–532 hemostatic system and hypoxia, 4: Hypersensitivity reactions: 603–604 abacavir, 4: 77–79 neutrophils, 4: 604–605 covalent drug-protein adducts, 4: 161–164 reactive oxygen species, 4: 605 defined, 6: 404 tumor necrosis factor-α, 4: 602–603 idiosyncratic drug-induced reactions, 4: 566–570 proposed mechanisms, 4: 597–601 sulfonamide, animal model, 4: 573 danger hypothesis, 4: 599 Hypertension, cancer therapies, toxicity studies, 3: failure to adapt hypothesis, 4: 599–600 35–36 hapten hypothesis, 4: 598 Hyphenated techniques: inflammatory stress hypothesis, 4: chromatography-mass spectrometry, research 600–601, 607–608 background, 5: 546–548 metabolic polymorphism hypothesis, 4: nuclear magnetic resonance, 5: 341–343 597–598 Hypothetical grain method, microautoradiography, 5: mitochondrial dysfunction hypothesis, 4: 384–388 599 Hypoxia: multiple determinant hypothesis, 4: 600 idiosyncratic drug-induced reactions, research background, 4: 595–597 inflammation, 4: 603–604 felbamate-induced hepatotoxicity and aplastic reductive bioactivation, antitumor prodrugs, 4: anemia, 4: 582 92–94 halothane-induced hepatotoxicity, 4: 573–574 isoniazid-induced hepatotoxicity, 4: 574–575 Ibotenic acid, ADME and toxicity studies, 2: 925 mitochondrial superoxide heterozygote mouse Ibufenac: model, 4: 577 structure-toxicity relationships, 6: 385 nevirapine-induced skin rash, 4: 580–581 UGT enzyme bioactivation, 6: 256–260 D-penicillamine-induced autoimmunity, 4: 578 Ibuprofen: procainamide-induced lupus, 4: 579–580 INDEX 727

propylthiouracil-induced autoimmunity, 4: specific mechanistic hypotheses, 6: 432–433 578–579 research background, 4: 565–567 sulfonamide-induced hypersensitivity, 4: 573 skin rashes, 6: 417–419 ticrynafen-induce hepatotoxicity, 4: 575–576 drug reaction with eosinophilia and system autoimmunity, 6: 417 symptoms, 6: 419 multiple IDRs, 6: 435 hypersensitivity reactions, 6: 419 bioactivation, non-P450 enzymes, 4: 63–65 maculopapular rash, 6: 419 bioactivation and, 3: 181 Stevens-Johnson syndrome, 6: 419 characteristics and mechanisms, 4: 567–570 toxic epidermal necrolysis, 6: 419 covalent drug-protein adducts, 4: 160–165 urticaria, 6: 418–419 drug classification, IDR pattern as basis for, 6: Ifosfamide: 434–441 cytochrome P450 bioactivation, 4: 24–25 multiple reactions, 6: 435 metabonomics analysis, 4: 290 drug-induced liver injury: oral chemotherapeutic agents, 6: 518 drug classification based on, 6: 435–441 [I]:Ki ratio: metabolism role in, 6: 420–421 CYP enzyme inhibition, in vivo static prediction future research issues, 4: 583–584, 6: 441 model, 3: 368–370 hematologic reactions, 6: 421–423 drug-drug interactions: agranulocytosis, 6: 422–423 CYP inhibition, 6: 95–101 anemia, 6: 421–422 competitive/noncompetitive inhibition, 6: aplastic anemia, 6: 423 157–158 thrombocytopenia, 6: 422 NME clinical pharmacology, 6: 117–120 human drug metabolism: Image analysis: clinical characteristics, 6: 405–417 mass spectrometry, 5: 108–112 covalent binding, 6: 391–393 applications, 5: 233–250 drugs associated with, 6: 405–417 degenerative conditions, 5: 244–246 future research issues, 6: 396 drugs and tracers, 5: 246–248 medicinal chemistry management, 6: 386–390 metabolites, 5: 248–250 prediction studies, 6: 391–393 oncology, 5: 233–244 reactive metabolites: automation, 5: 233 daily dose/low systemic exposure, 6: data analysis, 5: 230–232 393–395 experimental protocols, 5: 226–232 risk assessment, 6: 404–405 future research issues, 5: 250–251 screening, 6: 379–380 histology integration, 5: 229–230 trapping, 6: 391–393 mass analyzers, 5: 228–229 research background, 6: 377–379, 403–404 methodology, 5: 218–233 structure-toxicity relationships, 6: 380–386 protein identification, 5: 226–228 toxicophore prohibition, drug design, 6: quantitation, 5: 229 390–391 research background, 5: 215–218 immune involvement, 3: 187–188 spatial resolution, 5: 226 immune-mediated mechanisms, 6: 423–428 targeted imaging analysis, 5: 232–233 antigen-presenting cell activation, 6: 428 tissue samples, 5: 219–221 danger hypothesis, 6: 425–427 matrix application, 5: 224–226 epigenetic effects, 6: 428 matrix selection, 5: 224 hapten hypothesis, 6: 424–425 preparation protocols, 5: 221–226 immune system balance disturbance, 6: 428 wash protocols, 5: 221–224 p-I hypothesis, 6: 427 tissue stretch, 5: 233 unfolded protein response, 6: 428 proteomics applications, 4: 317 viral reactivation, 6: 427 Imaging-based biomarkers, pharmacodynamics lupus-like syndrome, 6: 417 studies, 2: 701 multiple drug reactions, 6: 435 Imatinib: non-immune-mediated mechanisms, 6: 428–432 drug-drug interactions, steady-state administration inflammagen hypothesis, 6: 431–432 studies, 6: 131–136 metabolic idiosyncrasy, 6: 429 herb-drug interactions, St. John’s wort, 6: 283 mitochondrial toxicity, 6: 429–431 oral chemotherapeutic agents, 6: 521–522 prediction methods, 4: 582–583 Iminium ions: reactive metabolites, 4: 570–571 AO/XOR-mediated oxidation, 1: 321–324 risk assessment, 6: 433–434 two-electron oxidation, 4: 40–42 728 INDEX

Imino methide, two-electron oxidation, 4: 39–40 Immunoconjugated therapeutics, cancer therapies, Imipramine, CYP1A2 metabolism, 6: 466 development of, 3: 29 Immobilized pH gradient (IPG), two-dimensional Immunogenic complexes: electrophoresis, first-dimension isoelectric immunoassays, 5: 412 focusing, 4: 315 phase-II-enzyme-catalyzed xenobiotic conjugation, Immortalized cell lines, solute carrier proteins, in acyl glucuronidation, 4: 114–118 vitro studies, 2: 215 Immunoglobulin G (IgG): Immune-mediated reactions. See also Inflammation antibody recycling, neonatal Fc receptor, 2: idiosyncratic adverse drug reactions, 6: 423–428 909–911 antigen-presenting cell activation, 6: 428 immunogenicity, 5: 412 danger hypothesis, 6: 425–427 Immunoglobulin M (IgM): epigenetic effects, 6: 428 diclofenac glucuronidation, 4: 118 hapten hypothesis, 6: 424–425 immunogenicity, 5: 412 immune system balance disturbance, 6: 428 Immunohistochemistry, microautoradiography and, p-I hypothesis, 6: 427 5: 387–388 unfolded protein response, 6: 428 Immunomodulated therapeutics: viral reactivation, 6: 427 cancer therapies, 3: 29 idiosyncratic drug-induced reactions, 4: 567–570 toxicity studies, 3: 31 oral chemotherapeutic agents, 6: 525–526 Immunophilin-binding agents, liver transplantation, D-penicillamine, 4: 578 6: 335–337 procainamide-induced lupus, 4: 579–580 Immuno polymerase chain reaction (Immuno-PCR), propylthiouracil autoimmunity, 4: 578–579 basic principles, 5: 402 Immunoaffinity restricted access media (IA-RAM), Immunoradiometric assays (IRMAs), basic biofluid analysis, 5: 446–447 principles, 5: 399 Immunoallergic hepatitis, halothane hepatotoxicity, Immunosuppressants: 4: 573–574 biotransformation, inhibitors, 6: 28–29 Immunoassays: food-drug interactions, grapefruit juice, 6: 295 applications, 5: 408, 411–415 herb-drug interactions, St. John’s wort, 6: immunogenicity, 5: 412 282–283 pharmacodynamics, 5: 413–415 Immunosuppressants, liver transplantation, hepatic pharmacokinetics, 5: 411–412 drug metabolism and, 6: 334–338 current technologies, 5: 397–404 antiproliferative agents, 6: 337–338 defined, 5: 395–396 azathioprine, 6: 338 electrochemiluminescence, 5: 401 cyclosporine, 6: 336–337 enzyme immunoassay, 5: 399–401 immunophilin-binding agents, 6: 335–337 formats, 5: 404–407 mycophenolate mofetil, 6: 337–338 design of experiments, 5: 407 sirolimus, 6: 337 direct assays, 5: 405–406 steroids, 6: 334–335 selectivity, 5: 406–407 tacrolimus, 6: 335–336 soluble target assays, 5: 406 Inborn errors of metabolism, extrahepatic Gyrolab nanoscale assay, 5: 401 metabolism, 2: 350–354 homogeneous assays, 5: 402 Incubation conditions: immune polymerase chain reaction, 5: 402 in vitro studies, 1: 76–77 kinetics, 5: 404 xenobiotic metabolism, hepatocyte assessment, in liquid chromatography-mass spectrometry protein vitro studies, metabolic stability, 3: 397–402 analysis, 5: 402–404 Incurred sample reanalysis (ISR), regulatory radioimmunoassay, 5: 399 guidelines: research background, 5: 396–397 bioanalysis, 5: 470–472 surface plasmon resonance, 5: 401–402 failure analysis, 5: 494–497 validation: Indinavir: best practices, 5: 408–410 drug-drug interactions, therapeutic efficacy, guidelines and standards, 5: 407–408 CYP-mediated effects, 4: 442 Immunoblotting: herb-drug interactions, St. John’s wort, 6: monoclonal antibodies: 283–284 CYP 450 targeting, 3: 451–452 Indirect activation pathways, constitutive androstane human liver microsome analysis, 3: 450–451 receptor, transcriptional regulation, 1: 211–213 protein identification, 4: 318 Indirect capture assays, Her2/neu receptor, 5: 406 INDEX 729

Indirect response models, pharmacodynamics, 2: P-glycoprotein induction, 6: 162–163 712–715 risk assessment for, 6: 126–127 precursor dependence, 2: 727–729 drug-metabolizing enzymes, species differences in, Individualized drug therapy, dose calculations and, 1: 123, 125–126, 129–130 6: 618 genetically modified animal models, 3: 622–624 Induction studies: glucuronidation, 6: 268–269 ADME studies: metabolic drug interactions, 1: 20–21 CYP induction, 2: 30–31, 3: 59 precision cut tissue slices, drug metabolizing drug-drug interactions, 2: 17–18 enzymes: biotransformation, 6: 13–20 animal studies, 3: 472–475, 478–480 basic mechanisms, 6: 13–14 clinical and toxicological perspectives, 3: clinical consequences, 6: 19–20 469–470 cytochrome P450, 6: 14–17 cryopreservation, 3: 481–485 CYP2D6 noninduction, 6: 17 extrahepatic slices, 3: 476–478, 481 CYP2E1 and the proteasome, 6: 16 future research issues, 3: 485–486 cytoplasmic receptor mediation, 6: 16 human studies, 3: 475–476, 480–481 nuclear receptor mediation, 6: 15–16 phase I systems, 3: 471–478 receptor cross talk, 6: 18–19 phase II systems, 3: 478–481 sulfonyltransferases, 6: 17–18 preparation and culture protocols, 3: 470–471 transporters, 6: 18 research background, 3: 467–469 uridine diphospho-glucuronosyltransferases, 6: solute carrier transporters, regulatory guidelines, 17 2: 231 carboxylesterases, 1: 439–440 sulfotransferases, 1: 544–545 cytochrome P450 enzymes: translational research, CYP enzymes, 2: 755–756 ADME studies, 3: 59 whole-body autoradiography, 5: 375–376 hepatic drug metabolism, 6: 313–317 xenobiotic metabolism, hepatocyte assessment, predictive studies, 3: 371–379 FDA draft guidance concerning, 3: 434 FαN-4 cells, 3: 377–378 Inductively coupled plasma mass spectrometry HepaRG cells, 3: 376–377 (ICP-MS): human hepatocytes, 3: 375–376 applications, 5: 297–312 reporter gene assay, 3: 372, 374–375 gadolinium, 5: 306 in vivo studies, 3: 378–379 gallium, 5: 306–307 herb-drug interactions, 2: 812 gold compounds, 5: 303–304 mechanisms of, 1: 167–168 metal-containing drugs, 5: 298–308 translational research, 2: platinum-based drugs, 5: 298–303 755–756 ruthenium compounds, 5: 304–306 xenobiotic metabolism, hepatocyte assessment, titanium, 5: 307 3: 409–419 vanadium, zinc, rhodium, and osmium, 5: drug discovery and development: 307–308 oral drug development, 3: 10 capillary electrophoresis-ICP-MS integration, 5: screening procedures, 3: 14–15 293–297 drug-drug interactions, 1: 63–65 interfaces, 5: 294–295 ADME studies, DMEs, 2: 17–18 quantitative analysis, 5: 295–297 anticonvulsants, 6: 476–477, 481–482 future research issues, 5: 308 cytochrome P450 enzymes, 6: 158–160 instrumentation, 5: 288 future research issues, 4: 444–445 interference, 5: 288–289 NME-precipitated CYP induction, 6: laser ablation-ICP-MS integration, 5: 297 108–115 liquid chromatography-ICP-MS integration, 5: pharmacodynamics, 4: 439–444 290–293 therapeutic efficacy, 4: 439–441 organic solvents, 5: 291–292 toxicity effects, 4: 441–444 small bore columns and low flow nebulizers, 5: pharmacokinetics, 4: 430–439 293 clearance-dependent induction, 4: 434–437 quantitative analysis, 5: 289–290 route-dependent induction, 4: 433–434 research background, 5: 287–288 theoretical issues, 4: 430–433 Industrial ADME research, MIST guidelines, 4: time- and dose-dependent induction, 4: 206–207 437–439 Inferential analysis, a posteriori population research background, 4: 429 modeling, 6: 597–598 730 INDEX

Inflammagen hypothesis, idiosyncratic adverse drug Information-dependent acquisition (IDA), reactions, 6: 431–432 proteomics, multiple reaction monitoring, 4: Inflammasome, drug-disease-drug interactions, 4: 334–335 628 Infrared electrospray laser desorption ionization Inflammation: (IR-ELDI), basic principles, 5: 100–101 acetaminophen bioactivation, drug-induced liver Infrared laser-assisted desorption electrospray injury, 3: 194–198 ionization (IR-LADESI), basic principles, 5: cytochrome P450 genes, transcriptional regulation, 97–101 receptor cross talk, CYP1A1/2, 1: 216 Infrared multiphoton dissociation (IRMPD), cytokines, 4: 645–649 quadrupole ion trap mass spectrometry, 5: 170 disease-drug interactions, research background, 4: Infusion mass spectrometry, sample introduction, 5: 622–623 54 Infusion nano-electrospray ionization. See drug-disease-drug interactions, 4: 628–630 Nano-electrospray ionization (Nano-ESI) biomarkers, 4: 630 Inhalation mechanisms, pharmacokinetic modeling, central nervous system, 4: 641 6: 586–588 chronic diseases, 4: 629–630 Inhibition constant (K ): conjugation enzymes, 4: 638–639 i ADME studies, CYP inhibition, 2: 30 CYP1 subfamily regulation, 4: 631–632 drug-drug interactions: CYP2 subfamily regulation, 4: 632–635 competitive inhibition, 4: 408–409 CYP3 subfamily regulation, 4: 636 CYP inhibition, 6: 94–101 CYP4 subfamily regulation, 4: 637 competitive/noncompetitive inhibition, 6: cytokines and other mediators, 4: 629 157–158 drug transporters, 4: 641–645 inhibition mechanisms, 4: 406–413 extrahepatic tissues, 4: 644 uncompetitive inhibition, 4: 412–413 LPS model, 4: 643 in vitro-in vivo correlation, 4: 413–425 sterile inflammation, 4: 643 enzyme kinetics, substrate inhibition, 1: viral infection, 4: 643 84–86 extrahepatic metabolism, 4: 639–641 hepatic drug metabolism, CYP inhibition, PBPK flavin monooxygenases, 4: 637–638 model, 3: 370–371 intestinal metabolism, 4: 639–640 substrate inhibition, 3: 304 kidney metabolism, 4: 640–641 in vitro studies: lung metabolism, 4: 640 enzyme kinetics, 1: 94–96 research background, 4: 623–624 incubation conditions, 1: 77 drug-drug interactions, research background, 4: nonspecific microsomal binding, 1: 78 623 Inhibition ratio (IR), drug-drug interactions, in future drug metabolism research, 4: 651 vitro-in vivo correlation, 4: 417–425 idiosyncratic drug-induced liver injury, 4: Inhibition studies. See also Enzyme-inhibition (EI) 601–605 complex hemostatic system and hypoxia, 4: 603–604 ADME studies: CYP inhibition, 2: 29–30 neutrophils, 4: 604–605 drug-drug interactions, 2: 16–17 reactive oxygen species, 4: 605 biotransformation, 6: 27–32 tumor necrosis factor-α, 4: 602–603 anticancer agentse, 6: 31–32 innate immunity and, 4: 624–628 clinical relevance, 6: 30–32 acute-phase response and liver injury, 4: 628 conjugative inhibitors, 6: 30 4: cellular and molecular aspects, 624–625 cytochrome P450 inhibitors, 6: 27–29 pattern-recognition receptors, 4: 625–628 irreversible inhibitors, 6: 29–30 regulation mechanisms, 4: 649–651 rhabdomyolysis, 6: 31 posttranscriptional regulation, 4: 650–651 sedation, 6: 31 transcriptional regulation, 4: 649–650 sulfonation inhibitors, 6: 30 research background, 4: 621–624 torsades des pointes, 6: 30–31 Inflammatory stress hypothesis, idiosyncratic UGT inhibitors, 6: 30 drug-induced liver injury, 4: 600–601 carboxylesterases, 1: 434–438 sulindac, 4: 607–611 cytochrome P450 enzymes: Influx transporters: drug-drug interactions, 6: 93–101 biotransformation and, 6: 6–7 competitive and noncompetitive inhibition, 6: SLC transporters, 2: 210–211 156–158 INDEX 731

quantitative magnitude predictions, 6: molybdenum-containing hydroxylases: 98–101 AO inhibitors, 1: 331–333 surrogate selection, 6: 97–98 regulators and inducers, 1: 342–344 in vitro studies, 6: 93–97 XOR inhibitors, 1: 333–335 hepatic drug metabolism, 6: 313–317 in silico studies, drug-drug interactions, 3: predictive studies, 3: 359–371 260–261 inhibition, 3: 359–371 solute carrier proteins, drug-drug interactions, 2: reversible inhibition, 3: 359–365 223–225 time-dependent inhibition, 3: 365–367 stereoselectivity, drug-metabolizing enzymes, 4: in vivo inhibition, 3: 367–371 359–361 metabolic stability, 3: 353–355 sulfotransferases, reaction phenotyping, 1: 546 research background, 3: 351–352 translational research, CYP enzymes, 2: 754–755 reversible inhibition, 3: 359–365 UGT isoforms: time-dependent inhibition, 3: 365–367 UGT1A1, 1: 474 total metabolism, 3: 355 UGT1A3, 1: 476 in vivo inhibition, 3: 367–371 UGT1A4, 1: 477–478 in vivo pharmacokinetics, 3: 355–358 UGT1A6, 1: 480 herb-drug interactions, 2: 812 UGT1A7, 1: 482 translational research, 2: 754–756 UGT1A8, 1: 483 drug discovery and development: UGT1A9, 1: 484 CYP450 enzymes, 3: 15 UGT1A10, 1: 486 reaction phenotyping, 1: 59–61 UGT2B4, 1: 488 drug-drug interactions, 1: 61–63 UGT2B7, 1: 489 ADME studies, DMEs, 2: 16–17 UGT2B15, 1: 494 anticonvulsants, 6: 477 UGT2B17, 1: 496 basic mechanisms, 4: 406–413 in vitro studies: circulating metabolites, 4: 424 bioanalysis, 5: 7–8 competitive inhibition, 4: 408–409 toxicity studies, CYP inhibition and drug-drug cytochrome P450 enzymes, 6: 93–101 interactions, 4: 238, 240 competitive and noncompetitive inhibition, 6: whole-body autoradiography, 5: 375–376 156–158 xenobiotic metabolism, hepatocyte assessment, 3: quantitative magnitude predictions, 6: 405–409 98–101 FDA draft guidance concerning, 3: 433–435 surrogate selection, 6: 97–98 Inhibitor concentrations, drug-drug interactions, in in vitro studies, 6: 93–97 vitro-in vivo correlation, 4: 415–425 fraction metabolized, 4: 420–421 Inhibitor of autophagic proteolysis, lysosomal drug future research issues, 4: 425 distribution, 2: 511–513 genotypes, 4: 421–422 Inhibitory antibodies, drug discovery studies, intestinal metabolism, 4: 418–420 reaction phenotyping, 1: 59–61 mixed inhibition, 4: 413 Injured tumor cells, pharmacodynamics, multiple binding sites, 4: 424–425 time-dependent transduction, 2: 721 noncompetitive inhibition, 4: 409–411 Innate immunity: non-P450 metabolism, 4: 422–423 halothane hepatotoxicity, 4: 574 P-glycoprotein inhibition, 6: 162–163 inflammation and infection, 4: 624–628 pharmacokinetics, 4: 423–424 Inositol phosphate system, pharmacodynamics protein binding, 4: 422 mechanisms, 2: 690–691 research background, 4: 405–406 Insecticide detoxification, carboxylesterases, 1: 427 stereoselective inhibition, 4: 359–361 drug interactions, 1: 444–445 uncompetitive inhibition, 4: 411–413 In silico studies: in vitro-in vivo correlations, 4: 413–425 ADME, 2: 20, 23–24 enzyme kinetics, substrate inhibition, 3: 302–304 ADME studies: glucuronidation, 6: 267–269 drug discovery and development, 3: 46–47 metabolic drug interactions, 1: 20–21 modeling techniques, 3: 65–69 microsomal epoxide hydrolase, 1: 402 applications, 3: 250, 253–268 mitochondrial acyl-coA:glycine N-acyltransferase, drug-metabolizing enzymes or transport 1: 605 proteins, 3: 263–264 mitochondrial medium chain acyl-CoA enzyme isoform-drug interactions, 3: 257–261 synthetases, 1: 602 inhibition mechanisms, 3: 260–261 732 INDEX

In silico studies (Continued) halothane hepatotoxicity, 4: 574 isoform-specific metabolism, 3: 257–260 Intermediate metabolites (IMs): metabolic rate prediction, 3: 254–257 cytochrome P450 enzymes, ethnic differences in physiologically based models, 3: 264–268 expression, 6: 76–77 transporters, 3: 262 dietary plant secondary metabolites, CYP biotransformation: polymorphisms, 4: 492–494 drug development and, 6: 36 drug metabolism, 1: 29 pathway predictions: drug metabolism and, 1: 4 research background, 6: 177–180 International Commission on Radiological Protection tools for, 6: 180–182 (ICRP), mass balance human studies, dose blood-brain barrier predictions and simulations, 3: calculations, 2: 441–446 576–577 International Conference on Harmonisation (ICH): computational models, 3: 576 bioanalysis guidelines, 5: 472–473 multiparameter optimization, 3: 576 biotransformation, drug development and, 6: PBPK models, 3: 577 37–39 drug discovery and development, 3: 268–274 MIST guidelines, 4: 207–208 ADME studies, 3: 46–47 safety testing, stable metabolites, 3: 224–227 drug discovery process, 2: 742–743 International Transporter Consortium (ITC), drug-drug interactions: transporter recommendations, 2: 98–99 CYP inhibition, 6: 94–101 Interstitial fluid, drug distribution and, 2: 114–116 predictive modeling and simulations, 6: 168 Interstitial fluid (ISF), blood-brain barrier future research issues, 3: 275–276 penetration, in vivo studies, 3: 565–572 high throughput quantitative mass spectrometry, Intestinal drug metabolism. See also Hepatic drug 5: 552 metabolism hybrid mass spectrometry, drug discovery and absorption kinetics: development, 5: 180 discontinuous absorption model, 2: 615–617 mass balance studies, animal studies, radiolabeled plasma concentration-time data, 2: 608–618 compounds, 2: 430–431 ADME studies, 2: 5 pediatric drug clearance and exposure, 6: 562–563 alimentary canal, 2: 46–54 research design and methodology, 6: 568–570 absorption sites and barriers, 2: 52–54 physiologically-based pharmacokinetic modeling, protective and absorptive interfaces, 2: 50–52 2: 571–574 anatomical and physical parameters, research problems, 3: 251, 253 background, 2: 45–46 research overview, 3: 248–250 bioavailability mechanisms, 2: 356 tools, 3: 252–253 biotransformation: toxicity testing, cancer therapy, 3: 26–27 mechanisms, 6: 6–7 In situ models, intestinal absorption, 2: 96–97 pathway predictions, in vitro studies, 6: 188 Insoluble materials, MALDI-MS samples, 5: 127 Caco-2 passage studies, 3: 343–345 In-source decay, biomolecules, MALDI-MS Caco-2/TC7 comparisons: characterization, 5: 136 cellular model, 3: 338–339 Instrument qualification, bioanalysis guidelines, 5: phase I enzymes, 3: 339 503 phase II enzymes, 3: 339–340 Intentional prodrugs, development of, 6: 360 transporters, 3: 340–341 Interfacial surfaces, inductively coupled plasma mass cell models, 3: 341–342 spectrometry-capillary electrophoresis chemical perspective, 3: 336 integration, 5: 294–295 CYP enzymes, 2: 317, 328–329 Interference, inductively coupled plasma mass distribution mechanisms, 2: 110–112 spectrometry, 5: 288–289 drug-disease-drug interactions, 4: 639–640 Interferons: drug-drug interactions, 6: 164–165 drug metabolizing enzymes and drug transporters, in vitro-in vivo correlation, 4: 418–420 4: 645–649 drug transporters, 4: 644–645 inflammation, drug-drug interactions, 4: 623 enterohepatic recirculation, 2: 72–73 Interleukin-1 variants, glutathione transferase enzyme kinetics, in vitro/in vivo concentration, 3: superfamily, omega class polymorphisms, 1: 307 575 extraction ratios, bioavailability studies, 2: Interleukins: 480–484 drug metabolizing enzymes and drug transporters, FDA classification systems, 2: 97–99 4: 645–649 first pass effects, 3: 338 INDEX 733

future research issues, 2: 73 Intrinsic activity of the agent, pharmacodynamics, cell models, 3: 345–346 concentration-effect relationship, 2: 705–706 gastrointestinal tract: Intrinsic clearance (CLint): motility and transit times, 2: 64–67 ADME: regional dimensions, 2: 60–64 calculation methods, 2: 26–28 linear dimensions, 2: 60 metabolic stability, 2: 10 relative surface areas, 2: 63–64 allometric scaling pharmacokinetics, in vitro surface areas, 2: 60–63 studies, 2: 501–503 herb-drug interactions, 4: 500–501 drug-drug interactions: histological perspective, 3: 336 CYP induction, 4: 430–433 longitudinal and transverse heterogeneities, 3: intestinal metabolism, 4: 419–420 337–338 in vitro-in vivo correlation, 4: 414–425 lumenal contents: drug-protein binding, 2: 534–536 bacterial flora and coprophagy, 2: 71 enzyme kinetics: bile and bile salts, 2: 70–71 biphasic kinetics, 1: 84 physicochemical characteristics, 2: 68–70 competitive inhibition, 1: 88–89 metabolic perspective, 3: 336 Michaelis-Menten kinetics, 1: 80–81 oral absorption: in vitro-in vivo correlation/extrapolation, 3: absorption assessment, 2: 94–97 305–307 absorption pathways, 2: 85–89 glucuronidation, 6: 262–264 basic principles, 2: 81–83, 93–94 hepatic drug metabolism, 2: 142 bioavailability determinants, 2: 470–480 metabolic stability, 3: 353–355 physicochemical properties, 2: 83–85 in vivo human pharmacokinetics, 3: 356–358 solubility and dissolution assessment, 3: CYP inhibition, 3: 368–370 496–501 human hepatic clearance predictions, 1: 58–59 transporters, 2: 89–93 organ clearance and, 2: 569–570 oral chemotherapeutic agents, 6: 501–508, physiologically-based pharmacokinetic modeling, 503–506 2: 572–574 pediatric population: enzyme-transporter biochemistry, 2: 646–647 hydrolytic enzymes, 6: 550–551 liver, 2: 650–652 sulfotransferases, 6: 554 sequential metabolism models, 2: 649 pharmacokinetic modeling, 6: 590–591 rate-limiting step, 2: 565–568 phase I metabolism, nabumetone, 6: 364–365 in silico prediction studies, metabolic rates, 3: physiologically-based pharmacokinetic modeling, 255–257 2: 653–656 xenobiotic metabolism, hepatocyte assessment, in pregnancy, 2: 937 in vitro studies, 3: 396–402 research background, 3: 335–336 Intrinsic dissolution rate (IDR), solubility and SLC transporters, 2: 209–210 dissolution assessment, oral absorption, 3: toxicity studies, 2: 356, 366–375 528–530 vascularity, 2: 54–59 Intrinsic factors, conjugation, transport and blood flow, 2: 54–55 elimination mechanisms, 6: 230–231 lymphatic flow, 2: 55–56 Intrinsic solubility: segregation routes, 2: 56–59 defined, 3: 509 in vitro toxicity screening, drug discovery and solubility and dissolution assessment, oral development: absorption, 3: 522 metabolic mechanisms, 4: 232–233 Inverse agonists: phase I/II metabolism, 4: 225–232 constitutive androstane receptor, transcriptional precision cut tissue slices, 4: 233–235 regulation, 1: 211–213 subcellular fractions, 4: 233 pharmacodynamics, 2: 694–695 in vivo studies, oral absorption and bioavailability, Investigational New Medicinal Product Dossier 3: 594–595 (IMPD), biotransformation, drug development Intracellular receptors, pharmacodynamics and, 6: 37–39 mechanisms, 2: 692 Investigative new drugs (INDs): Intrahepatic cholestasis, α-naphthylisothiocyanate, 4: animals-to-humans process, 3: 93–99 137–138 bioanalytical considerations, 3: 93 Intrasource separation, lipid characterization, 5: biopharmaceutical considerations, 3: 98 73–74 go/no-go decisions, 3: 98–99 734 INDEX

Investigative new drugs (INDs) (Continued) cytochrome P450 enzymes: nonclinical pharmacology and toxicology, 3: identification/mapping, 2: 28–29 93–98 induction, 2: 30–31 clinical pharmacology, 3: 99–115 inhibition, 2: 29–30 decision-making studies, 3: 105–109 drug discovery and development, 3: 11–14, drug-drug interactions, 3: 113–114 45–47, 54–60 first in human studies, 3: 101–102 compound progression, 3: 11–13 labeling issues, 3: 114–115 linear/nonlinear processes, 3: 13–14 metabolic disposition studies, 3: 110–111 metabolism, 2: 25–28 premarketing phase, NDA, 3: 114 permeability/transporters, 2: 24–25 radiolabeled studies (ADME), 3: 110 reactive intermediate trapping, 2: 28 research methods, 3: 102–104 solubility, 2: 24 in vitro drug metabolism/interaction studies, 3: transgenic mice, DDI prediction, 2: 31 111–112 allometric scaling pharmacokinetics, 2: 501–504 IND-enabling development, 3: 92–93 bioanalysis, 5: 5–10 overview of process, 3: 89–91 enzyme inhibition, 5: 7–8 regulatory issues, 3: 91 metabolic stability, 5: 7 research background, 3: 87–89 metabolite identification, 5: 8–10 In vitro-in vivo correlation/extrapolation permeability, 5: 6–7 (IVIVC/IVIVE): protein binding, 5: 8 ADME studies: bioequivalence studies, 2: 469–470 clearance mechanisms, 2: 762–763 biomarkers: DDI prediction failures, 2: 11–12 bioactivation, 3: 189–190 cytochrome P450 enzymes, extrapolation drug-induced liver injury, 4: 187–192 techniques, 6: 77–79 biotransformation, 1: 75–76 drug discovery and development, 3: 17–18 drug development and, 6: 36 drug-drug interactions: pathway predictions: clinical perspectives, 6: 91–92 expressed enzyme systems, 6: 187–188 CYP induction, 6: 113–115 hepatocytes, 6: 185–186 CYP inhibition, 6: 95–101 intestinal homogenates, 6: 188 mechanism-based inhibition, risk assessment, 6: liver slices, 6: 186–187 105–108 research background, 6: 177–180, 182 drug-drug interactions (DDIs): tissue-specific microsomes, 6: 182–185 circulating metabolites, 4: 424 tools and techniques, 6: 182–188 fraction metabolized, 4: 420–421 blood-brain barrier penetration, 3: 572–576 genotyping, 4: 421–422 brain tissue binding, 3: 573–574 inhibition mechanisms, 4: 413–425 permeability, 3: 572–573 intestinal metabolism, 4: 418–420 retroanalysis, Pfizer clinical candidates case multiple binding sites, 4: 424–425 studies, 3: 581–582 non-P450 metabolism, 4: 422–423 transporters, 3: 574–576 pharmacokinetics, 4: 423–424 confounding factors, 1: 76–78 protein binding, 4: 422 incubation conditions, 1: 76–77 enzyme kinetics, 3: 304–307 nonspecific microsomal binding, 1: 78 hepatic drug metabolism, in vivo organic solvents, enzyme effects, 1: 77–78 pharmacokinetics, 3: 355–358 covalent binding: molybdenum-containing hydrolases, 1: 344–345 hepatotoxicity prediction, 4: 176–179 solubility and dissolution assessment, oral limitations of, 4: 185–186 absorption, Biopharmaceutics Classification cytochrome P450 enzymes: System, 3: 501–504 CYP2B6, 1: 252 solute carrier proteins, 2: 216–217 transcriptional regulation, 1: 222–224 xenobiotic metabolism, hepatocyte assessment: distribution mechanisms, 2: 129–135 hepatobiliary transport, 3: 427–428 brain tissue distribution, 2: 134–135 induction studies, 3: 417–419 plasma protein binding, 2: 129, 132–133 metabolic stability, 3: 401–402 transporter studies, 2: 133–134 In vitro micronucleus (IVMN) assay, toxicity drug discovery and development: studies, 2: 774–775 ADME studies, 3: 45–47 In vitro studies: discovery phase, 1: 15 ADME studies, 2: 24–32 reaction phenotyping, 1: 59–61 INDEX 735 drug-drug interactions: physiologically-based pharmacokinetic modeling, combined approach to, 6: 163–166 tissue partition coefficient, 2: 642–645 CYP induction, 6: 108–115 phytochemicals, 4: 503–504 CYP inhibition studies, 6: 93–97 preclinical phase, 1: 15 enzyme inhibition, 1: 61–63 reactive metabolite bioactivation, trapping inhibition mechanisms, 4: 407–413 protocol, 5: 647 mechanism-based CYP inhibition, 6: 102–105 solubility and dissolution assessment, oral NME clinical pharmacology, 6: 115–120 absorption, dissolution measurements, 3: 525 NME-precipitated CYP induction: solute carrier proteins, 2: 197, 215–217 assay platforms, 6: 109–111 toxicity studies: endpoint measurement, 6: 111–112 covalent binding, 4: 243–244 risk assessment based on, 6: 112–113 CYP inhibition and potential drug-drug preclinical assessmdent, 6: 153 interactions, 4: 238–240 research background, 6: 89–90 gastrointestinal tract: drug metabolism, 1: 31, 44–50 metabolic mechanisms, 4: 232–233 cellular systems, 1: 47–48 phase I/II metabolism, 4: 225–232 enzymes, 1: 44–45 precision cut tissue slices, 4: 233–235 organ perfusion, 1: 49–50 subcellular fractions, 4: 233 organ slices, 1: 48–49 hepatic metabolism and toxicity, 4: 235–238 subcellular fractions, 1: 46–47 future research models, 4: 246–247 early drug development, drug-drug interactions, 3: micronucleus assay, 2: 774–775 111 mitochondrial membrane permeability, 4: 245 4: enzyme kinetics, 3: 288–294 overview, 4, 223–225 oxidative stress, 4: 244–245 expressed enzymes, 3: 290–292 primary hepatocytes, sandwich culture, 4: 246 HepaRG cells, 3: 294 reactive metabolite formation, 4: 240–243 hepatocytes, 3: 292–293 toxicogenomics applications, 4: 270–272 human liver microsomes, 3: 288–290 toxicity testing, cancer therapy, 3: 26–27 liver slices, 3: 293 UGT isoforms, 1: 461, 467–471 S9 fraction, 3: 293 albumin effect, 1: 468–469 flavin-containing monooxygenases, academic drug β-glucuronidase, 1: 470–471 development, 1: 283 protein-protein interactions, 1: 469–470 hepatic drug metabolism: xenobiotic metabolism, hepatocyte assessment: CYP enzymes: hepatotoxicity, 3: 430–432 inhibition, 3: 359–371 research background, 3: 393–396 total metabolism effects, 3: 355 In vivo studies: CYP induction, 3: 372–378 ADME studies, 2: 32–33 human clearance, 1: 58–59 DNA microarrays, 3: 321–324 metabolic stability, 3: 353–355 drug discovery and development, 3: 45–47 high throughput mass spectrometry, 5: 548–550 pharmacokinetics, 3: 59–61 intestinal absorption, 2: 94–96 allometric scaling pharmacokinetics, 2: 501–503 metabolite identification, 3: 126–128 bioactivation, NAC conjugate biomarkers, 3: NMR spectroscopy, 3: 154–156 190–192 molecular-based assays: bioanalysis, 5: 10–13 future research issues, 3: 328 metabolite identification, 5: 12–13 metabolic liability of drug candidates: pharmacokinetics, 5: 10–12 DNA microarrays, 3: 318–328 biotransformation: ADME studies, 3: 320–324 drug development and, 6: 36 bioinformatics, 3: 327–328 pathway predictions: toxicogenomics, 3: 324–327 animal studies, 6: 188–194 protein microarrays, 3: 316–318 radiolabeled compounds, 6: 190–194 research background, 3: 315–316 species selection, 6: 188–189 molybdenum-containing hydroxylases: unlabeled compounds, 6: 189–190 AO inhibitors, 1: 331–333 human studies, 6: 194–198 XOR inhibitors, 1: 333–335 first-in-human studies, 6: 194–195 pediatric drug metabolism, 6: 566–570 microtracer and accelerator mass phase-II-enzyme-catalyzed xenobiotic conjugation, spectrometry studies, 6: 196–198 acyl glucuronidation, 4: 113–118 radiolabeled studies, 6: 195–196 736 INDEX

In vivo studies (Continued) intestinal absorption, 2: 96–97 research background, 6: 177–180 metabolite identification, 3: 128–130 blood-brain barrier penetration, 3: 566–572 NMR spectroscopy, 3: 154–156 cerebrospinal fluid surrogate, 3: 567–569 metabonomics, metabolite identification, 4: microdialysis, 3: 569–570 288–290 PET imaging, 3: 570–572 MIST guidelines, metabolism, 3: 611 preclinical neuro pharmacokinetics, 3: 566–567 mitochondrial acyl-coA:glycine N-acyltransferase, retroanalysis, Pfizer clinical candidates case glycine conjugation, 1: 603–605 studies, 3: 581–582 molybdenum-containing hydroxylases: covalent binding, hepatotoxicity prediction, 4: AO inhibitors, 1: 333 176–179 XOR inhibitors, 1: 335 discovery phase of drug development, 1: 15 oral absorption, 3: 593–598 distribution, 3: 598–603 animal studies: animal studies, extrapolation to humans, 3: 599 bioavailability, 3: 595–596 CNS penetration, preclinical species, 3: food-drug interactions, 3: 597–598 600–602 as human models, 3: 596–597 free drug hypothesis, 3: 599 human bioavailability studies, 3: 593–595 passive drug movement barriers, 3: 599–600 phase-II-enzyme-catalyzed xenobiotic conjugation, preclinical studies, 3: 602–603 acyl glucuronidation, 4: 113–118 distribution mechanisms, 2: 135–138 physiologically-based pharmacokinetic modeling, human studies, 2: 137–138 tissue partition coefficient, 2: 642–645 preclinical animals and ex vivo organs, 2: phytochemicals: 135–136 animal studies, 4: 504 DNA microarrays: human studies, 4: 504–505 ADME studies, 3: 321–324 preclinical phase, 1: 15 toxicogenomics, 3: 324–328 safety testing, stable metabolites, 3: 223–227 drug discovery and development, ADME studies, solute carrier proteins, 2: 197, 217–220 3: 45–47 toxicity testing, cancer therapy, 3: 26–27 drug-drug interactions, inhibition mechanisms, 4: toxicogenomics applications, 4: 270–272 407–413 in vitro toxicity screening, adverse outcome drug metabolism, 1: 31, 50–58 prediction using, 4: 244 human studies, 1: 56–58 Ion channels, pharmacodynamics mechanisms, 2: preclinical animal studies, 1: 50–51 688–689 species differences, 1: 51–52 Ion current stability, nano-electrospray ionization, 5: transgenic/chimeric mice, 1: 52–56 59–60 drug metabolism research: Ion cyclotron resonance (ICR), Orbitrap analyzer animal studies, 3: 611–613 (LTQ Orbitrap) instrumentation, 5: 195–197 research background, 3: 591–593 Ion emission mechanism (IEM), electrospray early drug development, drug-drug interactions, 3: ionization, 5: 49 111–112 Ion-ion reactions, quadrupole ion trap mass excretion and elimination, 3: 603–611 spectrometry, 5: 171–172 active transporters, 3: 609 Ionizable solutes, micellar electrokinetic aldehyde oxidase, 3: 607–608 chromatography, 5: 424 allometric scaling of clearance, 3: 603–605 Ionization constants (pKa), drug discovery and biliary elimination, 3: 609–610 development, 2: 749–750 clearance processes, 3: 605–610 Ionization state: CYP metabolism, 3: 606–607 ADME effects, 2: 6–7 drug metabolism, 3: 605 ambient ionization mass spectrometry, 5: 77–78 human clearance, 3: 610 biofluid analysis, turbulent-flow chromatography, passive clearance, 3: 608–609 5: 458–462 renal elimination, 3: 608 compounds, electrospray ionization sensitivity UGTs, 3: 607 and, 5: 50–51 flavin-containing monooxygenases, academic drug dissolution, 3: 511–512 development, 1: 283 distribution mechanisms, 2: 109–112 hepatic drug metabolism: electrical discharge ionization techniques, 5: CYP enzyme induction, 3: 371, 378–380 93–97 CYP enzyme inhibition, 3: 367–371 gas chromatography-mass spectrometry: human pharmacokinetics, 3: 355–358 chemical ionization, 5: 23–25 INDEX 737

electron ionization, 5: 23 metabolic drug interaction, 1: 21 inductively coupled plasma mass spectrometry, reactive metabolites, cellular macromolecule interferences, 5: 288–289 binding, 3: 186–188 mass spectrometry and, 5: 88–89, 88–90 Isoelectric focusing (IEF), two-dimensional metabolite identification, 3: 136–146 electrophoresis: oral absorption and bioavailability, 2: 83–85 basic principles, 4: 313–315 quadrupole ion trap mass spectrometry: first-dimension focusing, 4: 315 ion activation, 5: 167–170 Isoflurane, structure-toxicity relationships, 6: ion isolation, 5: 166–167 381–382 manipulation, 5: 162–164 Isomers: single quadrupole mass spectrometry, 5: 25–27 carbohydrate characterization, nano-ESI Ion mobility mass spectrometry (IMS-MS): spectrometry, 5: 74–75 basic principles, 5: 34–36 stereoselectivity, 4: 346–351 differential mobility analyzer, 5: 266–267 Isoniazid: drift tube IMS, 5: 262–264 N-acetylation, 4: 127 explosives applications, 5: 103, 106 hepatotoxicity, animal models, 4: 574–575 future research issues, 5: 280–281 idiosyncratic adverse drug reactions, metabolic high field asymmetric waveform and differential idiosyncrasy, 6: 429 mobility IMS, 5: 265–266 pharmacogenetics, 4: 378 mass spectometry integration, 5: 267–274 phase II metabolism, N-Acetyltransferases, 6: information content, 5: 271–274 216–217 instrumentation, 5: 268–269 Isoquinoline substrates, AO/XOR-mediated orthogonality and peak capacity, 5: 269–270 reactions, 1: 317–320 speed of analysis, 5: 270–271 Isothiocyanates, food-drug interactions, cruciferous research background, 5: 257–258 vegetables, 4: 494–496 tandem methods, 5: 274–280 Isotope cluster techniques, metabolite identification, high mass accuracy and resolution, metabolite 3: 152–153 identification, 5: 277–280 Isotope-code affinity tag (ICAT), proteomics high performance modes, 5: 276–277 application, 4: 322–324 scanning modes, 5: 274–276 Isotope dilution analysis (IDA), platinum techniques, 5: 258–262 compounds, inductively coupled plasma mass traveling wave IMS, 5: 264–265 spectrometry, 5: 298 Ion-molecule reactions, quadrupole ion trap mass Isotope labeling. See Stable-isotope labeling spectrometry, 5: 171 Isotope pattern filtering: Ion-pair reagents, quality control, 5: 535 hybrid instrumentation, 5: 201–204 Ion spray, defined, 5: 49–50 metabolite identification, 3: 63–65 Ion suppression/enhancement, sample preparation, high resolution mass spectrometry, 5: 42–45 quality control, 5: 519–520 Isotopes: Ion trap mass spectrometry: accelerator mass spectrometry, microdose studies, basic principles, 5: 29–33 5: 603–614 metabolite identification, 2: 767–768, 3: 136–146 nuclear magnetic resonance, 5: 338 Irinotecan: quantitative whole-body radiography, limitations carboxylesterases, 1: 443–445 of, 5: 368–370 dose calculations, 6: 617–618 Isozymes/isoforms: glucuronidation, 6: 253–254 drug-drug interactions, in silico studies, 3: herb-drug interactions, St. John’s wort, 6: 283 259–261 UGT biotransformation, 6: 11 drug metabolism, 1: 23–29 toxicity studies, 6: 259–260 Itopride, flavin-containing monooxygenases: UGTs, ADME studies, 2: 847–848 biotransformational polymorphisms, 6: 24 Iron-oxygen complexes, cytochrome P450 catalytic metabonomic analysis, 1: 287 cycle, 1: 186–188 Itraconazole, dose calculations and, 6: 615–616 heteroatom oxidations, 1: 191–193 Irreversible effects models, pharmacodynamics, 2: JAK/STAT pathway, cancer therapies, epidermal 721–724 growth factor receptor, 3: 33–35 Irreversible inhibition: Jaundice, pediatric drug metabolism, 6: 551–553 biotransformation, 6: 29–30 JC-1 dye, in vitro toxicity screening, mitochondrial drug-drug interactions, 1: 61–63, 4: 406–413 membrane permeability, 4: 245 enzyme kinetics, 1: 91–94 J-coupling, nuclear magnetic resonance, 5: 335–336 738 INDEX c-June N-terminal kinase (JNK), idiosyncratic inhibition mechanisms, 4: 406–413 drug-induced reactions: noncompetitive inhibition, 4: 410–411 reactive oxygen species, 4: 605 uncompetitive inhibition, 4: 411–413 tumor necrosis factor-α, 4: 603 in vitro-in vivo correlation, 4: 413–425 Junk DNA, microsomal epoxide hydrolase, 1: enzyme kinetics: 406–407 autoactivation (sigmoidal) kinetics, 3: 299–300 biphasic kinetics, 1: 84, 3: 299–300 Kava kava: competitive inhibition, 1: 88–89 dietary supplement-drug interaction, 4: 521–522 heteroactivation kinetics, 1: 87 herb-drug interactions, 2: 820–821 Michaelis-Menten kinetics, 1: 79–81 mechanisms, 6: 288 mixed inhibition, 1: 90–91 Kelch-like ECH-associated protein (Keap 1), noncompetitive inhibition, 1: 89 biomarkers, drug-induced liver injury, 4: sigmoidal kinetics, 1: 81–83 188–192 substate depletion, 3: 297–298 Ketoconazole: substrate inhibition, 1: 84–86 aryl piperazine bioactivation, 4: 66, 68–69 in vitro/in vivo correlation, 3: 305–307 biotransformation, 6: 28–29 flavin-containing monooxygenases, drug candidate idiosyncratic adverse drug reactions, metabolic selection, 1: 286–287 idiosyncrasy, 6: 429 human hepatic clearance, 1: 58–59 Ketones: sulfotransferases: metabolite identification, 3: 147–150 enzyme kinetics, 1: 541 reduction to secondary alcohol, 4: reaction phenotyping, 1: 545–546 354–355 in vitro studies: Ketoreductase, phase I metabolism, 2: nonspecific microsomal binding, 1: 78 276–278 parameters, 1: 75–76 “Key and lock” hypothesis, stereoselectivity, 4: xenobiotic metabolism, hepatocyte assessment, 348–351 in vitro studies, 3: 396–402 Kidney: Knime software, translational drug discovery, physiologically-based pharmacokinetic modeling, ADME studies, 2: 745–746 2: 656–659 Knock-in and knock-in/knock-out mice: solute carrier transporters in, 2: 210–211, aryl hydrocarbon receptor model, 3: 666 213–214 constitutive androstane receptor, 3: 661 Kinetic isotope effect: CYP1A expression, 3: 632–633 mass balance studies, animal studies, radiolabeled CYP2D6 expression, 3: 634–635 compounds, 2: 430–431 3: rate limiting effects, cytochrome P450, 1: CYP2E1 expression, 636–637 189–190 CYP3A expression, 3: 637–639 Kinetic parameters: development of, 3: 628 ion mobility mass spectrometry, 5: 258–262 organic anion transporter polypeptide models, ligand-binding assays, 5: 404 3: 674 solubility: peroxisome-proliferator-activated receptors, 3: 663 defined, 3: 509 pregnane X receptor model, 3: 659 solubility and dissolution assessment, oral soluble epoxide hydrolase expression, 3: 644 absorption, assays, 3: 518–521 UGT1A expression, 3: 653–655 sulfotransferase, 1: 538–539 Knockout mice: in vitro studies, 1: 75–76 acetylcholinesterase expression, 3: 650–651 drug-drug interactions, mechanism-based CYP alcohol dehydrogenase expression, 3: 648 inhibition, 6: 102–105 aldehyde dehydrogenase expression, 3: 648–649 Km values: aryl hydrocarbon receptor model, 3: 665–666 carboxylesterases, species-specific reactions, 1: bile sale export pump model, 3: 676–677 447 breast cancer resistance protein model, 3: clearance mechanisms, glucuronidation, 6: 24 668–669 drug clearance, 1: 17–21 butyrylcholinesterase expression, 3: 651–652 drug-drug interactions: constitutive androstane receptor model, 3: competitive inhibition, 4: 408–409 660–661 CYP inhibition, 6: 94–101 CYP1A expression, 3: 631–633 competitive and noncompetitive inhibition, 6: cytokine research, 4: 648–649 156–158 farnesoid X receptor model, 3: 664 INDEX 739

flavin-containing monooxygenase expression, 3: Lamotrigine: 649 drug-drug interactions, 6: 485 microsomal epoxide hydrolase expression, 3: glucuronidation induction, 6: 268–269 641–642 glucuronidation inhibition, 6: 268 monoamine oxidase expression, 3: 645–647 hepatic drug metabolism, pregnancy, 6: 320 multidrug resistance (MDR) 1/2 protein models, skin reactions to, 4: 164–165 3: 669–670 UGT isoforms, UGT1A4, 1: 478 multidrug resistance (MDR) 3 (MRP3) protein Lapatinib: model, 3: 671 Lipinski’s rule-of-five and, 3: 53–54 multidrug resistance (MDR) 4 (MRP4) protein oral chemotherapeutic agents, 6: 523 model, 3: 671–672 Laplace transform: organic anion transporter models, 3: 672–674, 676 absorption kinetics, Loo-Riegelman (L-R) method, organic cation transporter models, 3: 674–675 2: 613–614 peroxisome-proliferator-activated receptor model, metabolite analysis, 2: 622–623 3: 662–663 Large intestine, anatomy and function, 2: 49–52 P-glycoprotein model, 3: 667–668 Large molecules, bioanalysis, regulatory guidelines, pregnane X receptor model, 3: 658–659 5: 504–507 research background, 3: 618–619, 627–628 Laser ablation, inductively coupled plasma mass soluble epoxide hydrolase expression, 3: 643–644 spectrometry integration, 5: 297 solute carrier proteins, in vivo studies, 2: 218–219 Laser ablation electrospray ionization (LAESI): sulfotransferase expression, 3: 657 basic principles, 5: 97–101 UGT1A expression, 3: 652–653 image analysis, 5: 109–112 Krumdieck automatic slicer, cryopreserved precision Laser-assisted desorption electrospray ionization cut tissue slices, 3: 482–485 techniques, basic principles, 5: 97–101 Laser desorption, historical development, 5: Label-free protein quantification, proteomics 120–123 analysis, 4: 325–332 Laser diode thermal desorption-atmospheric pressure mass spectrometry analysis, 4: 327 ionization, high throughput mass spectrometry, protein identification, 4: 327–329 5: 565 protein quantification, 4: 329–331 Laser-induced fluorescence (LIF), micellar quality assurance and control, 4: 332 electrokinetic chromatography, 5: 433–434 sample preparation, 4: 326–327 Laser sources, MALDI-MS instrumentation, statistical analysis, 4: 331 5: 123 Labeling issues: Lasofoxifene: clinical pharmacology: ADME studies, 2: 34–35 administration formulation and methods, 6: 612 aromatic hydroxylation of CYP450 enzymes, 6: age factors, 6: 612 57–58 dose recommendations, 6: 611–612 Latin square design, bioequivalence studies, 2: ethnic differences, 6: 618 464–465 future research issues, 6: 619 Lead optimization and identification: genetic polymorphism, 6: 617–618 drug discovery and development, 1: 14–15, 3: 8 hepatic impairment, 6: 614 drug discovery process, 2: 742–743, 746–757 individualized drug therapy, 6: 618 permeability and drug transport, 2: 751–753 metabolic pathways, 6: 614–616 pharmacokinetics and ADME studies, 2: renal impairment, 6: 613 746–749 research background, 6: 609–610 physico-chemical properties, 2: 748–751 size and weight factors, 6: 613 toxicity testing, anticancer drugs, 3: 26–28 early drug development, 3: 114–115 Leflunomide, cytochrome P450 enzymes, active Lability reduction, metabolite identification, 3: metabolic actions, 4: 18–23 122–123 Lenalidomide, oral chemotherapeutic agents, 6: 525 Lacosamide, drug-drug interactions, 6: 485 Letrozole, CYP2A6, ADME studies, 2: 843–844 Lactate dehydrogenase (LDH), xenobiotic Leukotriene receptor antagonists: metabolism, hepatocyte assessment, drug-drug interactions, CYP inhibition, 6: hepatotoxicity assays, 3: 430–432 100–101 L-amino acid oxidases (LAAO), classification, 1: enantiomeric stereoselectivity, toxic antipodes, 4: 375 364–365 Lamivudine, herb-drug interactions, St. John’s wort, optimization of, 4: 174–175 6: 284 Levetiracetam, drug-drug interactions, 6: 485–486 740 INDEX

Levorotatory compounds, stereoselectivity, 4: Linear solvation energy relationships (LSERs), 346–351 micellar electrokinetic chromatography, Licorice: pseudostationary phases, 5: 431–432 food-drug interactions, 6: 296 Linear trap quadrupole-Fourier transform (LTQ-FT) herb-drug interactions, 2: 821 mass spectrometry, basic principles, 5: 32, 34 Lidocaine, ADME studies, 2: 875–876 Linear velocity, sub-2-μm chromatography, 5: 532 Life span studies, amino acid conjugation, 1: Lineweaver-Burk plot: 605–606 drug-drug interactions: Ligand-binding assays (LBAs): noncompetitive inhibition, 4: 410–411 applications, 5: 408, 411–415 uncompetitive inhibition, 4: 411–413 immunogenicity, 5: 412 enzyme kinetics, double reciprocal plot, 3: 296 pharmacodynamics, 5: 413–415 physiologically-based pharmacokinetic modeling, pharmacokinetics, 5: 411–412 enzyme-transporter biochemistry, 2: 646–647 current technologies, 5: 397–404 Linkage analysis, idiosyncratic drug reactions, 4: 583 defined, 5: 395–396 Linkage disequilibrium: electrochemiluminescence, 5: 401 ABC transporters, 2: 174–176 enzyme immunoassay, 5: 399–401 glutathione transferase superfamily, omega class formats, 5: 404–407 polymorphisms, 1: 575 design of experiments, 5: 407 Lipid characterization: direct assays, 5: 405–406 MALDI-MS analysis, 5: 129–130 selectivity, 5: 406–407 nano-electrospray ionization, 5: 72–74 soluble target assays, 5: 406 Lipid Formulation Classification System (LFCS), Gyrolab nanoscale assay, 5: 401 solubility and dissolution assessment, oral homogeneous assays, 5: 402 absorption, 3: 539–540 immune polymerase chain reaction, 5: 402 Lipid-lowering agents, ADME studies, 2: 866–871 kinetics, 5: 404 gemfibrozil, 2: 870–871 liquid chromatography-mass spectrometry protein statins, 2: 866–870 analysis, 5: 402–404 Lipid metabolism: radioimmunoassay, 5: 399 carboxylesterases, 1: 426 research background, 5: 396–397 constitutive androstane receptor transcription, 1: surface plasmon resonance, 5: 401–402 213 validation: peroxidation and ROS propagation, 3: 185 best practices, 5: 408–410 solubility and dissolution assessment, oral guidelines and standards, 5: 407–408 absorption, formulation strategies, 3: Ligand-binding domain (LBD), pregnane X receptor, 539–540 cytochrome P450, transcriptional regulation, 1: Lipinski’s rule-of-five: 206–211 ADME, 2: 6–10 Ligand-binding pocket (LBP), constitutive drug design and, 3: 47–54 androstane receptor, transcriptional regulation, oral absorption and bioavailability, 2: 85 1: 211–213 translational drug discovery, 2: 745–746 Ligand-gated channels, pharmacodynamics Lipitor. See Atorvastatin mechanisms, 2: 689 Lipophilicity: Limit of detection (LOD), proteomics, multiple ADME effects, 2: 6 reaction monitoring, 4: 334–335 distribution mechanisms, 2: 109–112 Linear drug discovery: drug discovery and development: hepatic metabolic stability, 3: 353–355 oral drug properties, 3: 7–8 oral drug development, 3: 13–14 translational research, 2: 750–751 Linear effect concentration model, intestinal absorption, in vitro studies, 2: 94–96 pharmacodynamics, 2: 707 mitochondrial sequestration, 2: 513–514 Linear fitting, bioanalysis guidelines, response plasma protein binding, drug discovery and calibration, 5: 476–481 development, 5: 670–671 Linear furanocoumarins, food-drug interactions, 4: Lipopolysaccharides (LPS): 496–499 drug-disease-drug interactions: Linear quadrupole ion traps: CYP2A, 4: 633 nonhybrid analyzers, 5: 185–186 CYP2B, 4: 633 QTRAP instrumentation, 5: 190–192 CYP2C, 4: 634 quadrupole ion trap mass spectrometry, 5: CYP2D, 4: 635 164–166 CYP2E1, 4: 635 INDEX 741

CYP3 subfamily, 4: 636 sample pooling, 5: 551–552 CYP4 subfamily, 4: 637 sample preparation, 5: 551–552 flavin-containing monooxygenases, 4: 637–638 serial higher throughput, 5: 557–558 glutathione S-transferases, 4: 639 staggered parallel chromatography, 5: 563–564 sterile inflammation, 4: 631–632 staggered parallel dual column reconditioning, uridine diphosphate-glucuronosyltransferases, 4: 5: 560 638 image analysis: drug transporters, 4: 643 protein identification, 5: 226–228 idiosyncratic drug-induced reactions, 4: 569–570 spatial resolution, 5: 226 drug-inflammation interaction, species immunoassays and, protein analysis, 5: 402–404 comparisons, 4: 610–612 inductively coupled plasma mass spectrometry hemostasis and hypoxia, 4: 604 integration, 5: 290–293 inflammagen hypothesis, 6: 431–432 metal-based drugs, 5: 307 inflammatory stress hypothesis, 4: 600–601 organic solvents, 5: 291–292 sulindac, 4: 608–610 platinum compounds, 5: 299–301 tumor necrosis factor-α, 4: 602–603 ruthenium compounds, 5: 304–306 transcriptional regulation, 4: 649–650 small bore columns and low flow nebulizers, 5: Liquid chromatography mass spectrometry 293 (LC-MS/MS): ion trap mass spectrometry, 5: 31–33 ADME studies, 2: 764–768 mass balance studies, animal studies, 2: 424–425 ion trap instrumentation, 2: 767–768 metabolite identification, 3: 132–133, 5: 37, 39 metabolite identification, 2: 765–767 NMR and, 3: 162–164 quantitative bioanalysis, 2: 765 on-line electrochemical techniques, 5: 313–326 tandem mass spectrometers, 2: 767–768 microdose studies, 5: 614–618 time-of-flight mass spectrometry, 2: 768 advantages and limitations, 5: 615 basic principles, 5: 25 analysis and sample preparation, 5: 616 monolithic chromatography, 5: 455–457 cost issues, 5: 617 bioanalysis regulations, 5: 472 examples, 5: 617–618 contaminants, 5: 492–493 instrumentation, 5: 615–616 extraction efficiency, 5: 484–486 sensitivity, 5: 616 larger molecules, 5: 504–507 multiple experiments, extended analysis, 5: 65 biofluid analysis: multiplexing technology, 5: 535–536 on-line SPE, 5: 449–451 nano-electrospray ionization mass spectrometry, research background, 5: 445–447 comparisons, 5: 47–48 turbulent-flow chromatography, 5: 457–462 normalized response, 5: 60–61 biomarker assays, data quality, 5: 590–593 nuclear magnetic resonance and, 5: 331–332 biotransformation pathway predictions, in vivo on-line electrochemical techniques, metabolite animal studies, 6: 189–190 characterization: clinical trials, drug development, 1: 15–16 array techniques, 5: 321–326 compound tuning, automation, 5: 67 flow injection analysis, 5: 322–323 data quality, research background, 5: 517 metabolomics, 5: 323–326 drug-drug interactions, inhibition mechanisms, 4: quantitative bioanalysis, complex matrices, 5: 407–413 323 dynamic range, 5: 61–63 electrochemistry principles, 5: 315 early drug development, animal-to-human flow cells, 5: 314 transition, 3: 94 flow injection analysis, 5: 316, 322–323 electrospray ionization and, 5: 50 metabolism mimicry, 5: 320–321 flow rates, 5: 52 pre- and postcolumn electrochemistry, 5: 316 hepatic drug metabolism, CYP enzyme inhibition, reactive intermediates, EC generation and 3: 361–365 analysis, 5: 318–320 high throughput techniques, 5: 548, 550 research background, 5: 313–314 applications, 5: 555–557 semipreparative EC synthesis, 5: 316–317 bioinformatics, 5: 564–565 plasma protein binding, drug discovery and mass analyzer tuning and selection, 5: 552–555 development, 5: 664–665 multicolumn parallel chromatography: proteomics application, 4: 322–336 multiple ESI sources, 5: 562–563 data interpretation, 4: 335 single ionization source, 5: 560–562 label-free protein quantification, 4: 325–332 multiplexed systems, 5: 558–559 MRM transition determination, 4: 332–334 742 INDEX

Liquid chromatography mass spectrometry disease: (LC-MS/MS) (Continued) dose calculations based on, 6: 614 peptide selection, 4: 332 hepatic drug metabolism: quantification and data analysis, 4: 334–335 alcoholism, 6: 322–323 quantitative applications, 4: 335–336 cholestatic disease, 6: 323–324 stable-isotope-labeled protein quantification, 4: future research issues, 6: 339 323–325 Gilbert’s syndrome, 6: 324–325 targeted analysis techniques, 4: 332–335 herb-drug interactions, 6: 338–339 quadrupole devices, 5: 156–158 parenchymal disease, 6: 321–322 qualitative analysis, 5: 75–76 pathology, 6: 320–321 quantitative analysis, 5: 76–77 research background, 6: 307–308 research background, 5: 545–548 herb-drug interactions, 6: 338–339 safety testing: slices: reactive metabolites, 3: 227–237 biotransformation pathway predictions, in vitro stable metabolites, 3: 224–227 studies, 6: 186–187 sample introduction, 5: 52–54 CYP induction studies: sample preparation quality control, ion animal studies, 3: 472–475 suppression/enhancement, 5: 519–520 human studies, 3: 475–476 signal averaging, 5: 64 enzyme kinetics, 3: 293 simultaneous fraction collection, 5: 67–69 phase II enzyme induction: toxicity studies, reactive metabolite trapping, 6: animal studies, 3: 479–480 379 human studies, 3: 480–749 Liquid chromatography-nuclear magnetic resonance, surgery and regeneration, hepatic drug basic principles, 5: 342–343 metabolism, 6: 331–332 Liquid chromatography-nuclear magnetic toxicity (See Hepatotoxicity) resonance-mass spectrometry, basic principles, transplant, in vitro toxicity studies, intestinal drug 5: 342–343 metabolism, 4: 229 Liquid extraction surface analysis (LESA), overview, transplantation, hepatic drug metabolism and, 6: 5: 77–78 332–338 Liquid-liquid extraction, sample preparation quality absorption mechanisms, 6: 333 control: clearance mechanisms, 6: 333–334 orthogonality, 5: 520–521 graft vs. recipient size, 6: 332–333 supported liquid extraction, 5: 524 immunosuppressants, 6: 334–338 Liquid matrices, MALDI-MS samples, 5: 127 antiproliferative agents, 6: 337–338 Liquid scintillation counting (LSC): azathioprine, 6: 338 microdose studies, 5: 602–614 cyclosporine, 6: 336–337 organ dissection and homogenization, 5: 364–366 immunophilin-binding agents, 6: 335–337 tissue distribution studies, 5: 361–364 mycophenolate mofetil, 6: 337–338 Lisdexamfetamine (LDX), pediatric drug sirolimus, 6: 337 metabolism, 6: 551 steroids, 6: 334–335 Lisinopril, herb-drug interactions, garlic, 6: 287 tacrolimus, 6: 335–336 Liver. See also Drug-induced liver injury (DILI); posttransplant metabolism, 6: 333–334 Hepatic drug metabolism protein binding, 6: 333 anatomy and blood supply, 6: 308–312 Liver-specific transporter 1 (LST-1), cirrhosis, 6: 326–327 pathophysiology, 2: 202–205 pediatric drug metabolism, liver size relative to Liver X receptor (LXR): body weight, 6: 557–559 sulfotransferases, induction, 1: 544–545 cirrhosis, hepatic drug metabolism, 6: 325–331 translational drug research, human PK-PD anesthesia, 6: 330–331 evaluation, 2: 778–779 cascular architecture and hepatic blood supply, Log drug concentrations, distribution calculation, 2: 6: 326–327 140–142 clearance reduction, 6: 329 Log-linear effect concentration model, drug response, 6: 330 pharmacodynamics, 2: 707 first pass and bioavailability, 6: 327 Longitudinal heterogeneity, intestinal metabolism, 3: hepatic enzymes, 6: 328–329 337 protein binding and volume distribution, 6: Loop storage, metabolite identification, 3: 163–164 327–328 Loo-Riegelman (L-R) method, absorption kinetics, renal impairment, 6: 329–330 plasma concentration-tme data, 2: 613–614 INDEX 743

Loratidine: toxicogenomics, carcinogenicity prediction, 4: 260 cytochrome P450 enzymes, dealkylation reaction, Lung metabolism, drug-disease-drug interactions, 4: 4: 15–16 640 metabolic pathway, 1: 6 Lupus: Losartan: drug-disease-drug interactions, CYP2D, 4: 635 ADME studies, 2: 880–881 procainamide-induced lupus, 4: 579–580 cytochrome P450 enzymes, bioactive metabolites, Lupus-like syndrome, drug-induced reactions, 6: 417 4: 13–15 LY335979 P-gp inhibitor, ABC transport Low barrier hydrogen bonding, phase I metabolism, modulation, 2: 173 carboxylesterases, 2: 272–274 Lyphatic flow, gastrointestinal absorption, 2: 55–56 Low-density lipoprotein cholesterol (LDL-C), drug Lysosomes, drug distribution pharmacokinetics, 2: discovery and development, 5: 578–580 510–513 Lower limit of quantitation (LLOQ): Lysyl oxidase (LOX), classification, 1: 369–370 bioanalysis guidelines, 5: 471–472 carryover regulations, 5: 486 Macrocyclic trichothecene (MT) mycotoxins, ADME response calibration, 5: 475–481 and toxicity, 2: 927–928 sample reanalysis, 5: 494–497 Maculopapular rash, idiosyncratic adverse drug specificity and selectivity, 5: 490–491 reactions, 6: 419 standards, 5: 479–481 Magnesium ions, sulfotransferase kinetics, 1: system suitability and response changes, 5: 540–541 493–494 Magnetic resonance imaging (MRI): data quality, research background, 5: 516–518 blood-brain barrier penetration, in vivo studies, 3: microdose studies, LC-MS/MS, 5: 615–618 570–572 quantitative analysis, nano-ESI techniques, 5: distribution mechanisms, in vivo studies, 2: 138 76–77 Mahler’s enzyme, mitochondrial medium chain sample preparation, quality control, 5: 518–524 acyl-CoA synthetases, amino acid conjugation, Low flow nebulizers, inductively coupled plasma 1: 598–602 mass spectrometry-liquid chromatography Major histocompatibility complex (MHC): integration, 5: 293 drug-induced liver injury, 6: 420–421 Low permeability (LP) compounds, solubility and idiosyncratic adverse drug reactions, reactive dissolution assessment, oral absorption, 3: metabolite location, 6: 433–434 498–501 Maleylacetoacetate isomerase, 1: 573–574 BCS classification, 3: 501–504 Mammary gland, distribution barrier, 2: 123–124 BDDCS classification, 3: 504–507 Manganese ions, sulfotransferase kinetics, 1: drug development and, 3: 530–531 540–541 Low solubility (LS) compounds, solubility and Mass analyzer instrumentation: dissolution assessment, oral absorption: high throughput quantitative mass spectrometry, BCS classification, 3: 501–504 5: 552–555 BDDCS classification, 3: 504–507 hybrid mass analyzers, 5: 189–205 drug development and, 3: 530–531 drug discovery and development, 5: 178–181 Low systemic exposure, reactive metabolites, IADR isotope pattern filtering, 5: 201–204 mitigation, 6: 393–395 mass defect filtering, 5: 200–201 Low temperature plasma (LTP) probes, electrical metabolite detection software, 5: 204–205 discharge ionization techniques, 5: 96–97 metabolite fragmentation, 5: 197–200 LTQ Orbitrap, basic principles, 5: 32, 34 Orbitrap systems, 5: 195–197 Lucifer yellow passage, intestinal metabolism Q-TOF systems, 5: 192–195 models, passage study protocols, 3: 343–345 QTRAP systems, 5: 189–192 Lumenal contents, intestinal metabolism: imaging mass spectrometry, 5: 228–229 bacterial flora and coprophagy, 2: 71 inductively coupled plasma mass spectrometry, 5: bile and bile salts, 2: 70–71 288 physicochemical characteristics, 2: 68–70 ion mobility mass spectrometry, 5: 266–267 Lumenal epithelium: mass spectrometry integration, 5: 268–269 intestinal absorption sites and barriers, 2: 52–53 MALDI-MS techniques, 5: 123–125 surface area, 2: 60–62 microdose studies, LC-MS/MS, 5: 615–616 Lung cancer: nonhybrid mass analyzers, 5: 182–189 glutathione transferase superfamily, mu class FTICR mass analyzers, 5: 188–189 GSTs, 1: 570–571 LIT (2D trap), 5: 185–186 imaging mass spectrometry, 5: 236–237 quadrupole mass filter, 5: 182 744 INDEX

Mass analyzer instrumentation (Continued) hybrid and high resolution techniques, 5: 31–32, time-of-flight mass analyzers, 5: 186–188 34–36 triple quadrupole ion trap, 5: 183–185 imaging studies, 5: 108–112 quadrupole ion trap mass spectrometry, 5: 155 applications, 5: 233–250 Mass balance studies: degenerative conditions, 5: 244–246 animal studies: drugs and tracers, 5: 246–248 clinical goals and aims, 2: 417 metabolites, 5: 248–250 pharmacokinetic parameters, 2: 431–434 oncology, 5: 233–244 preclinical studies: automation, 5: 233 case study, 2: 435–438 data analysis, 5: 230–232 experimental design, 2: 418–430 experimental protocols, 5: 226–232 biliary excretion, 2: 427–428 future research issues, 5: 250–251 blood and plasma matrices, 2: 422 histology integration, 5: 229–230 carcass and carbon dioxide exhalation, 2: mass analyzers, 5: 228–229 428–430 methodology, 5: 218–233 dose, administration route, and protein identification, 5: 226–228 formulation, 2: 420–421 quantitation, 5: 229 excreta and cage wash, 2: 422–425 research background, 5: 215–218 matrix selection, 2: 421–430 spatial resolution, 5: 226 species selection, 2: 418–420 targeted imaging analysis, 5: 232–233 tissues and organs, 2: 425–427 tissue samples, 5: 219–221 research issues and methodology, 2: 438–440 matrix application, 5: 224–226 5: radiolabeled compounds, use, selection criteria matrix selection, 224 preparation protocols, 5: 221–226 and limitations, 2: 430–431 wash protocols, 5: 221–224 research backgound, 2: 415–416 tissue stretch, 5: 233 elimination pathways, 6: 223 ion mobility mass spectrometry integration, 5: future research issues, 2: 450 267–274 human studies: information content, 5: 271–274 case study, 2: 448–450 instrumentation, 5: 268–269 dosimetry calculations, 2: 441–446 orthogonality and peak capacity, 5: effective dose, 2: 445–446 269–270 gastrointestinal tracts, 2: 444–445 speed of analysis, 5: 270–271 organs and tissues, 2: 445 metabolite identification, 3: 63–65, 134–146 experimental design, 2: 447–448 biological matrices, 3: 139–146 research background, 2: 440–441 instrumentation and scanning, 3: 134–138 in vivo models, 1: 57–58 ionization, 3: 138–139 membrane-limited pharmacokinetics model, 2: 648 metabolite structure, 1: 33–34 preclinical animal studies, 1: 51 metabonomics analysis, 4: 282–283, 285–287 Mass defect filtering (MDF): nuclear magnetic resonance and, 5: 332–333 biotransformation pathway predictions, in vivo plasma protein binding, drug discovery and animal studies, 6: 189–190 development, 5: 668 hybrid instrumentation, 5: 200–201 proteomics analysis: metabolite identification, 3: 138–146 drug discovery and development, 4: 335–336 high resolution mass spectrometry, 5: 41–45 label-free protein quantification, 4: 327 MIST analysis, high-resolution mass spectrometry, research background, 5: 87–88 4: 212–215 Mass therapy, pharmacogenetic testing and, 6: Mass measurements, high resolution mass 25–26 spectrometry, 5: 39–45 Mass-to-charge values, ion mobility mass Mass-selective instability, quadrupole ion trap mass spectrometry-mass spectrometry integration, 5: spectrometry, 5: 161–162 272–274 Mass spectrometry (MS). See also specific MS Maternal:fetal barrier, distribution mechanisms, 2: techniques, e.g., Gas chromatography mass 123–124 spectrometry Mathematical models, pharmacodynamics, 2: bioanalytical applications, 5: 4 703–704 derivatization reactions, metabolite identification, delayed effect models, 2: 707–721 5: 36–38 disease progression models, 2: 724–727 general principles, 5: 21–23 irreversible effects models, 2: 721–724 INDEX 745

reversible effect models, 2: 705–707 protein detection, 4: 317 tolerance and rebound models, 2: 727–729 Q-TOF instrumentation, 5: 192–195 Mathieu stability diagram, quadrupole ion trap mass quadrupole ion trap mass spectrometry, spectrometry, 5: 153–156 nonresonance excitation, 5: 169–170 ion manipulation, 5: 162–164 reactivity, 5: 125 Matrix-assisted laser desorption electrospray research background, 5: 87–88 ionization (MALDESI): sample preparation, 5: 125–127 absorptivity, 5: 125 second-generation techniques, 5: 131–134 applications and methodology, 5: 137–141 carbon nanotubes, 5: 132–133 bacterial identification, 5: 139 desorption/ionization on silicon, 5: 131–132 drug delivery systems, 5: 140–141 room temperature ionic liquid matrices, 5: small molecule analysis, 5: 140 133–134 basic principles, 5: 97–101 solid matrices, 5: 126 biomolecular characterization, 5: 134–137 solubility, 5: 125 in-source decay, 5: 136–137 time-of-flight (TOF) analyzers, 5: 186–188 post-source decay, 5: 136 volatility, 5: 125 carbohydrates, 5: 129 Matrix effects: desorption, 5: 125 ambient ionization methods, 5: 570 future research issues, 5: 141–142 bioanalysis guidelines: glycolipids, 5: 129–130 basic components, 5: 482–484 glycopeptides/glycoproteins, 5: 128–129 response calibration, 5: 476–481 historical overview, 5: 119–123 sample preparation, quality control, ion image analysis, 5: 109–112 suppression/enhancement, 5: 519–520 Matrix-assisted laser/desorption ionization mass Matrix-enhanced selected ion monitoring (ME-SIM), spectrometry (MALDI-MS): imaging mass spectrometry, 5: 249–250 ADME studies, tissue distribution, 3: 62 Matrix factor, bioanalysis guidelines, 5: 482–484 distribution mechanisms, in vivo studies, 2: 136 Matrix selection: high throughput mass spectrometry, 5: 565 electrochemical array, complex matrices, laser-based ionization methods, 5: 566–567 quantitative bioanalysis, 5: 323 image analysis: imaging mass spectrometry, 5: 224 spatial resolution, 5: 226 Matrix suppression: tissue samples, 5: 219–221 electrospray ionization, 5: 51 imaging analysis: nano-electrospray ionization, 5: 58–59 data analysis, 5: 230–232 Maximal velocity (Vmax): mass analyzer instrumentation, 5: 228–229 drug-drug interactions: matrix selection and preparation, 5: 224–226 competitive inhibition, 4: 408–409 oncology, 5: 233–244 noncompetitive inhibition, 4: 410–411 brain tumors, 5: 233–234 uncompetitive inhibition, 4: 412–413 breast cancer, 5: 234–236 in vitro-in vivo correlation, 4: 413–425 gastrointestinal tract tumors, 5: 240–243 enzyme kinetics: intratumor heterogeneity, 5: 243–244 biphasic kinetics, 1: 84 lung cancer, 5: 236–237 competitive inhibition, 1: 88–89 ovarian cancer, 5: 237 heteroactivation kinetics, 1: 87 prostate cancer, 5: 237–240 Michaelis-Menten kinetics, 1: 79–81 overview, 5: 218–233 mixed inhibition, 1: 90–91 protein identification, 5: 226–228 noncompetitive inhibition, 1: 89 quantitation, 5: 229 sigmoidal kinetics, 1: 81–83 sample preparation, 5: 221–226 substrate inhibition, 1: 84–86 instrumentation, 5: 123–125 in vitro/in vivo correlation, 3: 305–307 laser sources, 5: 123 in vitro studies, 1: 75–76 lipids, 5: 129 xenobiotic metabolism, hepatocyte assessment, in liquid matrices, 5: 127 vitro studies 394–400 mass analyzers, 5: 123–125 Maximum absorbable dose (MAD): matrix properties, 5: 125 ADME studies, 2: 5 nucleic acids, 5: 130–131 pharmacokinetics, 3: 74–80 peptides and proteins, 5: 127–128 solubility and dissolution assessment, oral proteomics, two-dimensional electrophoresis: absorption: peptide mass fingerprinting, 4: 318–319 rate-limiting steps, 3: 496–501 746 INDEX

Maximum absorbable dose (MAD) (Continued) Median values, ADME studies, pharmacokinetics, 3: research background, 3: 493–495 79–80 Maximum inactivation rate constant (kinact), enzyme Mediatiors, pharmacodynamics mechanisms, 2: 687 kinetics, irreversible inhibition, 1: 91–94 Medium chain acyl-CoA synthetases (ACSMs), Maximum inhibitor hepatic input concentration amino acid conjugation, 1: 597–602 ([I]in), drug-drug interactions, in vitro-in vivo inhibitors, 1: 602 correlation, 4: 415–425 structure-activity relationships, 1: 600–602 Maximum inhibitor systemic plasma concentration substrates, 1: 599–600 ([I]max), drug-drug interactions, in vitro-in vivo Medium-chain dehydrogenase/reductase (MDR) correlation, 4: 415–425 superfamily, alcohol dehydrogenase, Maximum life span potential (MLP): bioactivation, 4: 75–79 allometric scaling pharmacokinetics, animal Melanin binding: studies, 2: 498–501 drug discovery and development, biomarkers, 5: pharmacokinetic predictive studies, 2: 495–496 585–587 Maximum likelihood estimation, a posteriori whole-body autoradiography, drug discovery and population modeling, 6: 597–598 development, 5: 372–375 Melanocortin-4 receptor (MC4R) agonist, safety Maximum plasma concentration (Cmax): ADME studies, noncompartmental analysis, 2: testing, reactive metabolites, 3: 229–237 602–603 Melphalan, phase II metabolism, pharmacokinetics/toxicokinetics profiles, 2: 585 glutathione-S-transferases, 6: 213–214 Maximum safe starting dose (MSSD), early drug Membrane-associated proteins in eicosanoid and development, clinical pharmacology, 3: glutathione metabolism (MAPEG), gluthathione 101–102 transferases, 1: 561 Maximum tolerated dose (MTD), early drug Membrane-based transporter assays: ADME studies, 2: 25 development, clinical pharmacology, 3: 102 distribution mechanisms, 2: 133–134 Mean residence time (MRT): solute carrier proteins, in vitro studies, 2: 217 drug clearance, 1: 16–17 Membrane-bound GSTs, phase II metabolism, 6: 214 pediatric drug metabolism, 6: 542–543 Membrane-bound sulfotransferases, classification and radiation dosimetry, whole-body autoradiation nomenclature, 1: 530–532 studies, 5: 381–383 Membrane-limited pharmacokinetics model, 2: Mechanism-based inhibition (MBI): 647–648 covalent binding studies, limitations, 4: 185–186 Menthofuran, pulegone ring closure to, 1: 6–7 cytochrome P450 enzymes, 2: 755 Meperidine, cytochrome P450 bioactivation, active bioactivation, 4: 42–48 metabolites, 4: 21–23 covalent modification, 4: 45–48 Mephenytoin, cytochrome P450 bioactivation, active quasi-irreversible inactivation, 4: 43–45 metabolites, 4: 21–23 in vitro toxicity studies, 4: 240 6-Mercaptopurine: drug-drug interactions, 1: 62–63, 4: 406–413 ADME studies, 2: 848 ADME studies, DMEs, 2: 16–17 drug-drug interactions, allopurinol, 6: 91–92 CYP enzymes, 3: 57–58 Mercapturate conjugates, bioactivation, in vivo NAC hepatic drug metabolism, 3: 365–367 conjugators, 3: 190–192 new molecular entities, CYP inactivation, 6: Mercapturic-acid pathway, 101–108 3,4-methylenedioxymethamphetamine CYP turnover half-life, 6: 107–108 bioactivation, 4: 131–133 in vitro-in vivo extrapolation studies, 6: Meso Scale Discovery (MSD)-based assays: 105–107 electrochemiluminescence, 5: 401 in vitro studies, 6: 102–105 overview of, 5: 395–396 enzyme kinetics, 1: 91–94 Metabolic acidosis, pediatric drug metabolism, plant secondary metabolites, human studies, 4: alcohol dehydrogenase catalysis, 6: 549–550 490–492 Metabolic defense mechanisms, plant-animal translational research, 2: 756–757 “warfare,” 4: 487–488 xenobiotic metabolism, hepatocyte assessment, Metabolic hot spot, drug clearance, 1: 18 induction and, 3: 416–419 Metabolic idiosyncrasy, idiosyncratic adverse drug Mechanism biomarkers, drug discovery and reactions, 6: 429 development, 5: 579–580 Metabolic intermediates, safety testing, reactive Media loss assays, hepatic drug metabolism, in vivo metabolites, 3: 229–237 human pharmacokinetics, 3: 357–358 Metabolic pathways: INDEX 747

dose calculations based on, 6: 614–616 xenobiotic metabolism, hepatocyte assessment, 3: metabonomics analysis, 4: 291–292 403–404 Metabolic polymorphism hypothesis, idiosyncratic Metabolism-transporter interplay, drug metabolism, drug-induced liver injury, 4: 597–598 1: 30 Metabolic rate (MR): Metabolite formation assay: atypical reactions, 3: 297–304 hepatic metabolic stability, 3: 353–355 autoactivation (sigmoidal) kinetics, 3: 300–301 xenobiotic metabolism, hepatocyte assessment, in biphasic kinetics, 3: 299–300 vitro studies, metabolic stability, 3: 396–402 heteroactivation, 3: 301–302 Metabolite inhibitor (MI) complex, cytochrome P450 partial inhibition, 3: 303 enzymes, quasi-irreversible inactivation, 4: substrate inhibition, 3: 302–304 43–45 Eadie-Hofstee plot, 3: 296 Metabolite-intermediate (MI) complex, drug-drug Hane-Woolf plot, 3: 296–297 interactions, enzyme inhibition, 1: 62–63 limitations, 3: 297 Metabolites: Lineweaver-Burk double reciprocal plot, 3: 296 ADME studies: Michaelis-Menten kinetics, 3: 294–296 human studies, 2: 13–15 research background, 3: 287–288 identification techniques, 3: 62–65 in silico prediction studies, 3: 254–257 bioanalysis guidelines, multiple analyte assays, 5: substrate depletion methods, 3: 297–298 498–500 in vitro-in vivo correlations, 3: 304–307 biotransformation, drug development and, 6: in vitro studies, 3: 288–294 37–39 expressed enzymes, 3: 290–292 cardiovascular drug metabolism, CYP metabolites, HepaRG cells, 3: 294 2: 862–863 chemical transformation and, 1: 6–14 hepatocytes, 3: 292–293 cytotoxic synthesis, 3: 24 human liver microsomes, 3: 288–290 drug discovery and development, structure liver slices, 3: 293 elucidation, 3: 124–126 S9 fraction, 3: 293 drug-drug interactions, circulating metabolites, 4: Metabolic soft spot, drug clearance, 1: 18 424 Metabolic stability: drug metabolism, basic principles, 2: 248–256 ADME, 2: 10 endogenous metabolites, imaging mass bioanalysis, in vitro studies, 5: 7 spectrometry, 5: 248–249 drug discovery and development: fragmentation information, hybrid instrumentation, oral absorption, 3: 9, 15–16 5: 197–201 in vitro studies, 3: 55–56 identification: hepatic drug metabolism, in vitro studies, 3: bioanalysis guidelines, 5: 480–481 353–355 biological matrices, 3: 139–146 oral absorption, bioavailability studies, 2: chemical derivatization, 3: 146–150 475–476 chemically reactive metabolites, 3: 123 platinum drugs, inductively coupled plasma mass chromatographic separation, 3: 131–133 spectrometry, 5: 299 clearance routes, 3: 123 xenobiotic metabolism, hepatocyte assessment, 3: cross-species comparisons, 3: 125 396–402 derivatization reactions, mass spectrometry, 5: Metabolic switching, drug clearance, 1: 18 36–38 Metabolism-based inhibition, 1: 21 detection, 3: 133–134 Metabolism mechanisms: electrochemical array techniques, 5: 321–326 defined, 2: 5–6 electrochemical liquid chromatography mass dietary supplements, absorption effects, 2: spectrometry: 797–805 electrochemistry principles, 5: 315 drug discovery and development, in vitro studies, flow cells, 5: 314 3: 55–56 flow injection analysis, 5: 316, 322–323 herb-drug interactions, CYP inhibition, 2: metabolism mimicry, 5: 320–321 811–812 pre- and postcolumn electrochemistry, 5: 316 intestinal metabolism, 3: 336 reactive intermediates, EC generation and pharmacokinetic modeling, 6: 590–592 analysis, 5: 318–320 plasma concentration-time data, 2: 622–626 research background, 5: 313–314 profiling and identification, 2: 35 semipreparative EC synthesis, 5: 316–317 translational research, 2: 754–755 enzymatic hydrolysis, 3: 151–152 748 INDEX

Metabolites (Continued) ketone reduction, secondary alcohol formation, HPLC-MS analysis, 3: 130–146 4: 354–355 HPLC-NMR, 3: 162–164 sulfide to chiral sulfoxide oxidation, 4: 356–357 human clearance pathways, 3: 125–126 tertiary amine to N-oxide oxidation, 4: 357 hybrid/high resolution mass spectrometry, 5: structure elucidation, 1: 33–34 31–36, 39–45 tandem mass spectrometry identification, 2: hydrogen/deuterium exchange, 3: 150–151 767–768 imaging mass spectrometry, 5: 246–248 time-of-flight mass spectrometry identification, 2: ionization studies, 3: 138–139 768 ion trap mass spectrometry, 5: 30–33 toxicity, 1: 19–20 lability reduction, 3: 122–123 translational drug research, safety of, 2: 758 liquid chromatography-mass spectrometry, 5: in vitro studies, bioanalysis, 5: 8–10 37, 39 in vivo studies: mass spectrometry, 3: 134–138 bioanalysis, 5: 12–13 NMR spectroscopy, 3: 153–164 preclinical animal studies, 1: 50–51 characterization strategies, 3: 162 species differences, 1: 52 experimental design, 3: 158–162 xenobiotic metabolism, hepatocyte assessment, nuclei, 3: 156–158 identification, 3: 504–505 sample preparation, 3: 154–156 Metabolites in Safety Testing (MIST) guidelines: pharmacologically active metabolites, 3: 124 accelerator mass spectrometry-based human QTRAP instrumentation, 5: 191 ADME studies, 4: 216 quantitative analysis, 3: 164–167 ADME development modifications, 4: 208–210 research background, 3: 121 bioanalysis guidelines, response calibration, 5: sample generation and workup, 3: 126–130 479–481 biotransformation, drug development and, 6: in vitro samples, 3: 126–128 37–39 in vivo samples, 3: 128–130 biotransformation pathway predictions, research software tools, 5: 204–205 background, 6: 179–180 stable isotope labeling, 3: 152–153 drug discovery and development, 2: 594–596 structure elucidation, 3: 121–122 drug-drug interactions, 4: 424 drug development, 3: 124–126 ADME studies, 2: 19–20 xenobiotic metabolism, hepatocyte assessment, elimination pathways, 6: 223–225 3: 404–405 FDA/ICH guidelines harmonization, 4: 207–208 ion trap mass spectrometry, identification, 5: future research issues, 4: 218 30–33 human carbon-14 ADME study, 4: 215 liquid chromatography mass spectrometry implementation strategies, 4: 216–218 identification, 2: 765–767 industrial ADME research and, 4: 206–207 mass balance studies, animal studies, 2: 425 multiple analyte assays, 5: 498–500 metabonomic identification, 4: 288–290 nonradioactive metabolite quantitation, 4: nuclear magnetic resonance characterization, 5: 210–215 333–338 high resolution mass spectrometry methods, 4: drug discovery and development, 5: 350–353 212–215 sample preparation, 5: 345 plasma availability and pooling strategy, 4: pharmacokinetics modeling, compartmental 210–212 analysis, 2: 622–623 nuclear magnetic resonance, 5: 350–353 pharmacological activity, 1: 19 overview, 4: 205–206 phase I metabolism: stable metabolites, 3: 222–227 conjugation mechanisms, 6: 355–356 strategic initiatives, 4: 208–210 drug-metabolite-bioactivation continuum, 6: 355 translational drug research, regulatory issues, 2: plasma analysis, MIST guidelines, 4: 209–210 758 quantitative chromatographic assays, interference in vivo studies, 3: 611 with, 5: 536–537 metabolite identification, 5: 12–13 safety testing, 3: 222–227 Metabolomics: stereoselectivity, drug metabolism, 4: 353–358 cardiovascular drugs, 2: 865–866 chiral reduction, carbon-carbon double bond, 4: electrochemical array with mass spectrometry, 5: 355–356 323–326 enantiotopic moiety to chiral metabolite pharmacodynamics studies, 2: 700–701 oxidation, 4: 357–358 Metabonomics: INDEX 749

analytical platforms, 4: 282–288 Methylenedioxyphenyl compounds, dietary data processing, 4: 286–288 supplements, drug interaction, 4: 518–526 mass spectrometry, 4: 285–286 goldenseal, 4: 518–520 nuclear magnetic resonance, 4: 284–285 kava kava, 4: 521–522 drug metabolism studies, 4: 288–293 piperine/black pepper, 4: 522–524 human polymorphism identification, 4: Schisandra spp., 4: 524–526 292–293 Methyl isocyanate (MIC), hepatotoxicity, 4: 138 metabolic pathway elucidation, 4: 291–292 Methyloxime adducts, reactive metabolite metabolite identification, 4: 288–290 bioactivation, 5: 643–645 future research issues, 4: 299–300 Methylphenidate, phase I metabolism, research background, 4: 281–282 carboxylesterases, 2: 271–274 toxicity studies, 4: 293–299 1-Methyl-4-phenyl-pyridinium (MPP+), safety biomarker identification, 4: 296–299 testing, stable metabolites, 3: 225–227 toxicity mechanisms, 4: 299 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity screening, 4: 294–296 (MPTP): MetaDrug™, biotransformation pathway prediction, iminium ion oxidation, 1: 322–326 6: 180–182 monoamine oxidase bioactivation, 4: 71–74 Metal-based drugs, inductively coupled plasma mass safety testing, stable metabolites, 3: 225–227 spectrometry: whole-body autoradiography, melanin binding, 5: applications, 5: 297–312 374–375 gadolinium, 5: 306 α-Methylstyrene: gallium, 5: 306–307 epoxidation, 1: 10 gold compounds, 5: 303–304 glutathione addition, 1: 12 metal-containing drugs, 5: 298–308 hydrolysis, 1: 13 platinum-based drugs, 5: 298–303 Methyltransferases (MTs), phase II metabolism, 2: ruthenium compounds, 5: 304–306 290–293, 6: 214–216 titanium, 5: 307 METPRO processing, drug discovery and vanadium, zinc, rhodium, and osmium, 5: development, hybrid mass spectrometry, 5: 307–308 179–180 capillary electrophoresis-ICP-MS integration, 5: Mianserin: 293–297 CYP2D6 metabolism, 6: 462 interfaces, 5: 294–295 stereoselective metabolic activation, 4: 365–366 quantitative analysis, 5: 295–297 Mibefradil: future research issues, 5: 308 biotransformation pathway predictions, in vitro instrumentation, 5: 288 studies, 6: 185 interference, 5: 288–289 drug-drug interactions, 6: 90–92 laser ablation-ICP-MS integration, 5: 297 substrate inhibition, 3: 304 liquid chromatography-ICP-MS integration, 5: Micellar electrokinetic chromatography (MEKC): 290–293 control and retention prediction, 5: 425 organic solvents, 5: 291–292 detection and sensitivity enhancement, 5: small bore columns and low flow nebulizers, 5: 432–434 293 future research issues, 5: 439–440 quantitative analysis, 5: 289–290 microfluidic mixing, 5: 434–436 research background, 5: 287–288 migration patterns and resolution, 5: 422–424 Metaprolol, cardiovascular drug metabolism, 2: 877 ionizable solutes, 5: 424 MetaSite tools, in silico studies, 3: 69 uncharged solutes, 5: 422–424 Methadone: pseudostationary phases, 5: 426–432 drug-drug interactions, route-dependent CYP classification, 5: 431–432 induction, 4: 434 micellar pseudophases, 5: 426–427 substrate stereoselective metabolism, 4: 353 mixed micelles, 5: 430 Methionine sulfoxide reductase (MSR), idiosyncratic organic modifiers, 5: 430–431 drug-induced liver injury, sulindac, 4: 606–607 polymeric and nanoparticle phases, 5: Methoxylamine, metabolite identification, 3: 427–430 147–150 research background, 5: 421–422 α-Methyldopa, drug-induced anemia, 6: 421–422 two-dimensional separations, 5: 437–439 3,4-Methylenedioxymethamphetamine (MDMA): Micellar selectivity triangle, micellar electrokinetic biotransformation, irreversible inhibitors, 6: 29–30 chromatography, pseudostationary phases, 5: neurotoxicity, 4: 131–133 431–432 750 INDEX

Micelle-forming surfactants, solubility and accelerator mass spectrometry, 5: 602–614 dissolution assessment, oral absorption, 3: biotransformation and conjugate formation, 5: 524–525 612–613 formulation strategies, 3: 539 carbon-14 measurement, 5: 604–606 Micelle-water partition coefficients, micellar drug discovery and development, 5: 606–610 electrokinetic chromatography, 5: 425 drug-ligand binding and subcellular localization, Michaelis-Menten equation: 5: 614 clearance mechanisms, glucuronidation, 6: 264 pharmacokinetics, 5: 611–612 drug clearance, 1: 17 reactive metabolite determination, 5: 614 drug-drug interactions: bioavailability estimations, 2: 462 competitive inhibition, 4: 409 comparison of techniques, 5: 620–622 in vitro-in vivo correlation, 4: 413–425 definitions, 5: 600–602 elimination kinetics, 2: 629–633 liquid chromatography-mass spectometry, 5: enzyme kinetics, 1: 78–81, 3: 294–296 614–618 in vitro-in vivo correlation/extrapolation, 3: advantages and limitations, 5: 615 304–307 analysis and sample preparation, 5: 616 human hepatic clearance predictions, 1: 58–59 cost issues, 5: 617 pediatric drug metabolism, alcohol dehydrogenase examples, 5: 617–618 catalysis, 6: 550 instrumentation, 5: 615–616 physiologically-based pharmacokinetic modeling, sensitivity, 5: 616 enzyme-transporter biochemistry, 2: 646–647 positron emission tomography, 5: 618–620 xenobiotic metabolism, hepatocyte assessment, in blood-brain barrier tracing, 5: 619 vitro studies, 3: 396–402 targeted cancer therapy, 5: 619–620 Microarrays: research background, 5: 599–602 DNA microarrays, 3: 318–328 Microfluidic micellar electrokinetic chromatography, ADME studies, 3: 320–324 basic principles, 5: 435–436 bioinformatics, 3: 327–328 MicroRNAs (miRNAs), toxicogenomics, 4: 253 toxicogenomics, 3: 324–327 Micro solid-phase extraction: electrochemical liquid chromatography mass biofluid analysis, 5: 451–452 spectrometry, 5: 321–322 sample preparation quality control, 5: 521 hepatotoxicity screening, 3: 27 Microsomal epoxide hydrolase (mEH), 1: 395–407 human drug metabolism, structure-toxicity biological function, 1: 396–397 relationships, 6: 381 expression regulation, 1: 405–407 mitochondrial toxicity, 6: 430–431 alternative promoters, 1: 405–406 molecular-based assays, future research issues, 3: transcription, 1: 405 328 transposable elements, 1: 406–407 protein microarrays, 3: 316–318 genetically modified animal models, 3: 640–642 proteomics, 4: 336–337 genetic polymorphisms, 1: 402–404 research background, 3: 315–316 stereoselectivity, detoxification pathways, 4: 365 toxicogenomics: substrates and inhibitions, 1: 397–402 carcinogenicity prediction, 4: 258–260 environmental/xenoiotic, 1: 397–399 DNA microarrays, 3: 324–327 inhibitors, 1: 402 hepatomegaly and hepatocellular hypertrophy, pharmacological properties, 1: 399–402 4: 261–262 summary/pharmacological implications, 1: 407 translational drug discovery, computational Microsomal gluthatione transferases, genetics, 1: 561 modeling, 2: 743–746 Microsomal protein per gram liver (MPPGL): Microautoradiography (MARG): pediatric drug metabolism, 6: 559 drug discovery and development, 5: 386–388 pharmacokinetic modeling, 6: 590 history and basic principles, 5: 383–385 Microsomes: strengths and limitations, 5: 385–386 ADME studies, hepatic metabolism, 2: 25–28 tissue distribution studies, 5: 361–364 age-dependent drug metabolism, physiological Microdialysis: factors, 4: 453–454 blood-brain barrier penetration, in vivo studies, 3: aristolochic acid ADME and toxicity, 2: 920–922 569–570 biomarkers, bioactivation, 3: 189–190 distribution mechanisms, in vivo studies, 2: biotransformation pathway predictions, in vitro 137–138 studies, tissue-specific, 6: 182–185 plasma protein binding estimation, 2: 544–545 drug discovery studies, reaction phenotyping, 1: Microdose studies: 59–61 INDEX 751

drug-drug interactions, CYP inhibition, 6: 94–101 Mitochondrial membrane permeability, in vitro drug metabolism, 1: 23 toxicity screening, 4: 245 monoclonal antibody analyses: Mitochondrial membrane potential, in vitro toxicity chemical inhibitor specificity and potency, 3: screening, reactive metabolite formation, 4: 243 460–462 Mitochondrial sequestration, pharmacokinetic endobiotic metabolism, 3: 459–460 predictive studies, 2: 513–514 human liver microsomes, 3: 450–451 Mitochondrial superoxide drug reactions, liver microsomes, 3: 448–450 heterozygous mouse model, 4: 577 polyclonal antibodies, 3: 462 Mitochondrial toxicity, idiosyncratic adverse drug polymorphisms, 3: 459 reactions, 6: 429–431 research background, 3: 447–448 Mitochondrial transporters, 2: 201 single and combinatorial analyses, 3: Mitogen-activated protein kinase: 454–455 drug-disease-drug interactions, inflammation, 4: single CYP450 metabolism, 3: 455–459 626–628 synopsis and critique, 3: 463–464 idiosyncratic drug-induced reactions, tumor α in vitro models, 1: 46–47 necrosis factor- , 4: 603 hepatotoxicity prediction, 4: 177–179 Mitomycin C/CB, reductive bioactivation, 4: 92–94 human hepatic clearance predictions, 1: 58–59 Mitoxantrone resistance protein, 2: 91–92 pediatric drug metabolism, milligram microsomal Mixed function oxidases, catalytic activity, 6: 54–56 protein per gram liver, 6: 559 Mixed inhibition: in vitro studies, nonspecific binding, 1: 78 drug-drug interactions, 1: 61–63, 4: 413 in vitro toxicity screening, 4: 233–235 enzyme kinetics, 1: 90–91 xenobiotics metabolism, hepatocyte assessment, 3: Mixed micelles, micellar electrokinetic chromatography, 5: 430 394–396 MK-0571 compound, enantiomeric stereoselectivity, Microtracer studies, biotransformation pathway toxic antipodes, 4: 364–365 predictions, in vivo human studies, 6: 197–198 Model for End-Stage Liver Disease (MELD), 6: 325 Microtubule polymerization, cancer therapy, 3: 24 Molecular-based assays: Midazolam: future research issues, 3: 328 drug-drug interactions, probe substrates, 6: metabolic liability of drug candidates: 119–120 DNA microarrays, 3: 318–328 herb-drug interactions: ADME studies, 3: 320–324 St. John’s wort, 6: 284 bioinformatics, 3: 327–328 in vivo human studies, 4: 505 toxicogenomics, 3: 324–327 phase I metabolism, active metabolites, 6: 357 protein microarrays, 3: 316–318 in vitro toxicity studies, 4: 226–227 research background, 3: 315–316 Milk thistle: Molecular determinants: dietary supplement-drug interaction, 4: 526–528 ABC protein function, 2: 171–172 herb-drug interactions, 2: 821–822, 6: 288 ADME studies, in silico studies, 2: 20, 23–24 “Mimicry” of metabolism, electrochemical liquid ADME studies, pharmacokinetics and, 3: chromatography mass spectrometry, 5: 320–321 72–80 Minoxidil, phase I metabolism, conjugation and, 6: biopharmaceuticals, 2: 896 355–356 cytochrome P450 enzymes: Mirtazapine, CYP1A2 metabolism, 6: 466 CYP2A subfamily, 1: 249–250 Mitochonchondrial glutathione transferases, genetics, CYP2B subfamily, 1: 251–253 1: 561 CYP2C subfamily, 1: 253–256 Mitochondrial acyl-coA:glycine N-acyltransferase distribution mechanisms, 2: 112 (GLYAT), amino acid conjugation, 1: 602–605 drug-drug interactions, NME-precipitated CYP inhibitors, 1: 605 induction, 6: 108–115 structure-activity relationships, 1: 603 sex-dependent hepatic drug metabolism, 1: in vivo conjugation, 1: 603–605 110–112 xenobiotic substrates, 1: 603 in silico studies, 3: 253 Mitochondrial cytochrome P450 enzyme structure, Molecular dynamics, in silico studies, drug-drug 1: 164–165 interactions, 3: 259–261 Mitochondrial dysfunction hypothesis: Molecular targeted therapies, cancer therapies, 3: bioactivation and oxidative stress, 3: 185 28–29 nefazodone case study, 3: 199–200 front-loading challenges, 3: 32 idiosyncratic drug-induced liver injury, 4: 599 preclinical ADR event prediction, 3: 37–38 752 INDEX

Molecular weight: pediatric drug metabolism, 6: 549 ADME effects, 2: 6 phase I metabolism, 2: 269–271 dissolution, 3: 512 Monoamine oxidase A/B: distribution mechanisms, 2: 112 bioactivation, 4: 71–74 Lipinski’s rule-of-five, drug design and, 3: classification, 1: 374 48–54 genetically modified animal models, 3: 646–647 metabolite identification, 3: 140–141 Monoamine transporters, pregnancy drug Molybdenum cofactor (MoCo): metabolism, 2: 943 amine/xanthine oxidases, phase I metabolism, 2: Monoclonal antibodies: 267–269 allele specificity, 3: 452–453 structure and function, 1: 310–311 antibody recycling, neonatal Fc receptor, 2: Molybdenum-containing hydroxylases: 910–911 clinical implications, 1: 345–349 enantiomer specificity, 3: 453–454 BIBX1382, 1: 348 epitope specificity, 3: 452 BK3453, 1: 349 immunoassays, selection criteria, 5: 398–399 carbazeran, 1: 345, 348 immunoblotting MAbs, 3: 451–452 RO1 metabolite, 1: 348 microsomal drug metabolism: SGX523, 1: 348–349 chemical inhibitor specificity and potency, 3: zaleplon, 1: 348 460–462 future research issues, 1: 349–350 endobiotic metabolism, 3: 459–460 genetics, 1: 312–315 human liver microsomes, 3: 450–451 human distribution, 1: 335–336 liver microsomes, 3: 448–450 inhibitors, 1: 331–335 polyclonal antibodies, 3: 462 AO inhibitors, 1: 331–335 polymorphisms, 3: 459 non-human distribution, 1: 336–338 research background, 3: 447–448 overview, 1: 305–306 single and combinatorial analyses, 3: 454–455 structure and function, 1: 306–312 single CYP450 metabolism, 3: 455–459 catalytic mechanisms, 1: 310–312 synopsis and critique, 3: 463–464 classification, 1: 308–310 multifunctional cytochrome P450, 3: 462–463 monomeric unit, 1: 308–309 pharmacokinetics and targeting mechanisms, 2: in vitro-in vivo correlation, 1: 344–345 911–912 xenobiotic biotransformations, 1: production technologies, 3: 448 315–331 structure, 2: 909 aldehyde oxidation, 1: 320–321 Monolithic chromatography, biofluid analysis, 5: aromatic N-heterocycle oxidation, 1: 315–320 455–457 heterocycle reduction, 1: 329–331 Monolithic columns, basic principles, 5: 530 N-hydroxy reduction, 1: 328–329 Monooxygenases, catalytic activity, 6: 54–56 iminium ion oxidation, 1: 321–324 Monte Carlo simulation: nitrate/nitrite reduction, 1: 326–327 drug metabolism and interactions, 6: 582–583 nitroreduction, 1: 324–326 hepatic drug metabolism, CYP inhibition, in vivo N- and sulfoxide reduction, 1: 327–328 studies, 3: 368–370 reduction, 1: 324 physiologically-based pharmacokinetic modeling, XOR/AO activity variation, 1: 338–344 6: 585–586 ethnic differences, 1: 344 Montelukast, ADME studies, 3: 51 ontogenic expression, 1: 343–344 Morphine: regulators and inducers, 1: 342–343 age-dependent drug metabolism, UDP Monkey studies: glucuronosyltransferase, 4: 471–472 cytochrome P450 enzymes, 6: 74–76 drug-drug interactions, therapeutic efficacy, 4: 441 in vivo studies, oral absorption and bioavailability, pediatric drug metabolism, 6: 552–553 3: 597 pharmacodynamics mechanisms, 2: 688–689 Monoamine oxidase (MAO): phase I metabolism, active metabolites, 6: 358 bioactivation, 4: 71–74 stereoselectivity, 4: 350–351 dopamine, 4: 72–74 UGT biotransformation, 6: 260–261 tetrahydropyridines, 4: 71–72 UGT isoforms, UGT2B7, 1: 491–492 biotransformational pathways, 6: 11–12 Morphine-6-glucuronide, phase II metabolism, 6: extrahepatic metabolism, 2: 341–342 210 toxicity studies, 2: 374–375 Motility measurements, intestinal metabolism, 2: genetically modified animal models, 3: 644–647 64–67 INDEX 753

Mouse studies. See also Transgenic mice; specific mitochondrial superoxide drug reactions, models, e.g., Knockout mice heterozygous mouse model, 4: 577 ADME studies: mitochondrial toxicity, 6: 430–431 DNA microarrays, 3: 321–324 solute carrier proteins, in vivo studies, 2: 218–220 drug-drug interactions, 2: 31 Mouth, anatomy and function, 2: 47–48 cytochrome P450 enzymes, 6: 69–71 mRNA molecules: in vitro-in vivo correlation studies, 6: 78–79 toxicogenomics, 4: 252–253 cytokines, 4: 648–649 xenobiotic metabolism, hepatocyte assessment, DNA microarrays: induction studies, 3: 415–419 ADME studies, 3: 321–324 MS3 scan, QTRAP instrumentation, 5: 190 toxicogenomics, 3: 324–328 mTOR inhibitors. See Serine-threonine kinase genetically modified animal models: (mTOR) inhibitors chimeric-humanized liver models, 3: 628–630 Mucosae, anatomy and function, 2: 50–52 cytochrome P450, 3: 630–640 Multicolumn parallel chromatography: CYP1A, 3: 631–633 multiple ESI sources, 5: 562–563 CYP2D6, 3: 633–635 single ionization source, 5: 560, 562 CYP2E1, 3: 635–637 Multicomponent solids, solubility and dissolution CYP3A, 3: 637–640 assessment, oral absorption, 3: 535–537 drug-metabolizing enzymes, 3: 620–622 Multidrug and toxicant extrusion (MATE) epoxide hydrolases, 3: 640–644 transporters: microsomal epoxide hydrolase, 3: 640–642 distribution and pathophysiology, 2: 202–205 soluble epoxide hydrolase, 3: 642–644 isoforms, 2: 208 esterases, 3: 650–652 in kidney, 2: 214 cholinesterases, 3: 650–652 nomenclature and structure, 2: 198–201 flavin monooxygenases, 3: 649 research background, 2: 197 future research issues, 3: 677 vectorial transport, 2: 550–558 humanized mice, 3: 628 in vivo studies, 2: 219–220 induction studies, 3: 623–624 Multidrug resistance, genetically modified animal knock-out (null) models, 3: 627–628 models, 3: 666–677 nomenclature, 3: 619 Multidrug resistance (MDR) 1/2 proteins: nuclear receptors, 3: 657–666 ABC transporters: aryl hydrocarbon receptor, 3: 665–666 cancer drug resistance, 2: 168 constitutive androstane receptor, 3: 659–661 single nucleotide polymorphisms, 2: 178 farnesoic X-activated receptor, 3: 663–664 small molecule transport, 2: 165–166 multiple nuclear receptor studies, 3: 664–665 substrate binding specificity, 2: 161–165 peroxisome-proliferator-activated receptors, biotransformation, 6: 7 3: 661–663 “phase 3” activation, 6: 12–13 pregnane X receptor, 3: 658–659 cardiovascular drug metabolism, 2: 864–865 oxidases, 3: 644–649 angiotensin receptor blockers, 2: 881 alcohol and aldehyde dehydrogenases, 3: drug-disease-drug interactions, 4: 640 647–649 drug transporters, 4: 642–645 aldehyde oxidase, 3: 644–645 efflux transporters, oral absorption mechanisms, 2: monoamine oxidases, 3: 645–647 89–91 research background, 3: 617–619 FDA guidelines concerning, 2: 97–98 sulfotransferase, 3: 656–657 genetically modified animal models, 3: 669–672 transporters, 3: 625–626 herb-drug interactions, absorption mechanisms, 2: bile salt export pump, 3: 676–677 809–811 breast cancer resistant protein, 3: 668–669 multidrug resistance protein-4, carboxylesterase multidrug resistance protein, 3: 669–672 transport, 1: 444–445 organic anion transporters, 3: 675–676 oral absorption, 2: 91–92 organic anion transporting polypeptides, 3: oral chemotherapeutic agents, intestinal ABCB1 672–674 efflux, 6: 503–506 organic cation transporters, 3: 674–675 pediatric drug metabolism, 6: 561–562 P-glycoproteins, 3: 666–668 pharmacogenetics, 4: 390–393 UGTs, 3: 652–656 physiologically-based pharmacokinetic modeling, glutathione transferase deficiency, 1: 579 2: 573–574 imaging mass spectrometry, disease states, 5: enzyme-transporter biochemistry, 2: 646–647 244–246 pregnancy drug metabolism and, 2: 938–945 754 INDEX

Multidrug resistance (MDR) 1/2 proteins (Continued) Multiplex analysis: reactive metabolite bioactivation, adverse drug high throughput quantitative mass spectrometry, reactions, 5: 629–630 5: 558–559 xenobiotic metabolism, hepatocyte assessment: immunoassays, 5: 414–415 hepatobiliary transport, 3: 419–428 liquid chromatography-mass spectometry, 5: induction, 3: 410–419 535–536 Multiexponential allometry (MA), allometric scaling Multitargeted inhibitors, development of, 3: 28 pharmacokinetics, animal studies, 2: 500–502 Muscimol, ADME and toxicity studies, 2: 925 Multikinase inhibitors, cancer therapies, toxicity Muscular disease, imaging mass spectrometry, 5: studies, 3: 35–36 244–246 Multiparameter optimization: Mutations: ADME studies, 3: 70–71 ABC transporters, diseases linked to, 2: 179–181 blood-brain barrier, in silico studies, 3: 576 cytochrome P450 enzymes, CYP1B subfamily, 1: Multiple analyte assays, bioanalysis guidelines, 5: 247–248 497–501 Mycophenolate mofetil (MMF): Multiple ascending dose (MAD): glucuronidation induction, 6: 269 assay transfers and changes, 5: 501–502 glucuronidation inhibition, 6: 268 bioanalysis guidelines, response calibration, 5: hepatic drug metabolism, liver transplant, 6: 478–481 337–338 MIST analysis guidelines, 4: 209–210 herb-drug interactions, St. John’s wort, 6: plasma availability and pooling strategy, 4: 282–283 210–212 oral absorption, bioavailability studies, 2: Multiple binding sites, drug-drug interactions, 4: 475–476 424–425 pediatric drug metabolism, 6: 552–553 Multiple bond correlation experiments, metabolite UGT polymorphisms, clinical significance, 6: identification, 3: 161–162 265–266 Multiple determinant hypothesis, idiosyncratic Mycophenolic acid (MPA), oral absorption, drug-induced liver injury, 4: 600 bioavailability studies, 2: 475–476 Multiple dosing (MD) studies, early drug Myeloperoxidase (MPO): development, clinical pharmacology, 3: 102 bioactivation, 4: 83–85 Multiple drug interactions: diclofenac, 4: 84 biotransformation and, 6: 6 ticlopidine, 4: 84–85 drug-drug interaction incidence and, 6: extrahepatic metabolism, 2: 342–343 152–153 human drug metabolism, structure-toxicity enantiomer stereoselectivity, 4: 361 relationships, 6: 380–381 idiosyncratic adverse drug reactions, two-electron oxidation, 4: 35–37 autoimmunity induction, 6: 435 Multiple reaction monitoring (MRM): Nabumetone, phase I metabolism, 6: 364–365 ADME in vivo studies, 3: 60–61 N-acetylcysteine (NAC), bioactivation: bioanalysis guidelines, specificity and selectivity, in vitro biomarkers, 3: 189–190 5: 491 in vivo biomarkers, 3: 190–192 metabolite identification, 3: 137–146 N-Acetyl-p-benzoquinone imine (NAPQ1): MIST analysis, high-resolution mass spectrometry, acetaminophen bioactivation, 4: 80–81 4: 214–215 oxidative stress, 3: 192–198 proteomics: drug-drug interactions, CYP-mediated induction, drug discovery and development, 4: 335–336 4: 443–444 LC/MS targeted studies, 4: 332–335 reactive intermediates: peptide selection, 4: 332 electrochemical liquid chromatography mass quantification and data analysis, 4: 334–335 spectrometry, 5: 319–320 stable-isotope-labeled protein quantification, 4: protein adduct detection, 5: 637–639 324–325 N-acetyltransferases (NATs): transition determination, 4: 332–333 arylamines: reactive metabolite bioactivation, glutathione N-acetylation, 4: 126–129 derivatives, 5: 631–635 drug-disease-drug interactions, 4: 639 sample preparation, quality control, ion pharmacogenetics, 4: 386–387 suppression/enhancement, 5: 519–520 cardiovascular drug metabolism, 2: 875 triple quadrupole/tandem mass spectrometry, 5: catalytic cycle, 2: 286–288 28–29 extrahepatic metabolism, 2: 336–337 INDEX 755

toxicity studies, 2: 374–375 drug-disease-drug interactions, research idiosyncratic adverse drug reactions, metabolic background, 4: 624 idiosyncrasy, 6: 429 idiosyncratic drug-induced liver injury: phase II metabolism, 2: 286–288, 6: 216–217 acetaminophen bioactivation, 3: 194–198 reactive metabolite bioactivation, adverse drug inflammatory response, 4: 601–605 reactions, 5: 628–630 Natural products, Lipinski’s rule-of-five and, 3: 54 toxicity studies, 6: 378–379 Natural toxins, ADME studies: NADPH. See Nicotinamide adenine dinucleotide aflatoxins, 2: 918–920 phosphate (NADPH) aristolochic acid, 2: 920–922 NADPH cytochrome P450 reductase: arsenic, 2: 922–923 bioactivation, 4: 90–91 germander, 2: 927 plant secondary metabolites, 4: 488–494 Ibotenic acid and muscimol, 2: 925–926 NADPH oxidoreductase (POR): pyrrolidizine alkaloids, 2: 926–927 azo reductases, 1: 378–379 research background, 2: 917–918 biotransformational polymorphism, 6: 22 selenium, 2: 923–925 nitro reductases, 1: 380–381 Nefazodone: NADPH-quinoneoxidoreductase (NQO1), reductive ADME studies, 2: 34 bioactivation, 4: 88–90 bioactivation and oxidative stress, 3: 198–200 Nano-electrospray ionization (Nano-ESI): bile salt export pump inhibition, toxicity applications, 5: 66–75 studies, 3: 198–199 analytical standards, 5: 66–67 mitochondrial dysfunction, 3: 199–200 automated compound tuning optimization, 5: 67 reactive metabolite formation and covalent 3: carbohydrate characterization, 5: 74–75 binding, 198–199 cytochrome P450 enzymes, active metabolic lipid characterization, 5: 72–74 reactions, 4: 20–23 noncovalent interactions, 5: 71–72 hepatotoxicity prevention strategies, 4: 181–182 proteomics, 5: 70–71 toxicity studies, structure-toxicity relationships, 6: simultaneous fraction collection with 382–383 LC/MS/MS, 5: 67–69 Negative food effect, oral absorption, bioavailability dynamic range, 5: 61–63 studies, 2: 473–475 future research issues, 5: 80–81 Nelfinavir, drug-drug interactions, therapeutic high resolution mass spectrometry selectivity, 5: efficacy, CYP-mediated effects, 4: 442 65–66 Neonatal Fc receptor (FcRn), antibody recycling, 2: ion current stability, 5: 59–60 909–911 liquid flow rates, 5: 52 Neonatal programming, sex-dependent hepatic drug matrix suppression, ionization, 5: 58–59 metabolism, androgens, 1: 107 multiple MS/MS, analysis time extension, 5: Neonates, biotransformation in, 6: 33 64–65 Nephrotoxicity: normalized response, 5: 60–61 aristolochic acid, 4: 88–90 overview, 5: 47–48 biomarkers, metabonomic identification, 4: pulled-glass capillaries, 5: 54–56 298–299 qualitative analysis, 5: 75–76 bromobenzene, 4: 133–134 quantitative analysis, 5: 76–77 hexachlorobutadiene-induced, 4: 136–137 sample quantity conservation, 5: 64 sevoflurane-induced, 4: 134–136 sensitivity, 5: 58 toxicogenomics studies, 4: 272 signal averaging, 5: 64 Nernst-Brunner equation, dissolution, 3: 511–512 single cell sampling, 5: 78–80 solubility and dissolution assessment, oral small molecule GLP bioanalysis, 5: 76–77 absorption, 3: 522–523 Nanoparticle pseudostationary phases, micellar surface area modification, 3: 532–533 electrokinetic chromatography, 5: 427–429 Neurodegenerative disease: α-Naphthylisothiocyanate, intraheptatic cholestasis, cytochrome P450 polymorphisms, CYP1B 4: 137–138 subfamily, 1: 247–248 Narrow therapeutic range (NTR), drug-drug imaging mass spectrometry, 5: 244–246 interactions: Neuromuscular blocking agents, cirrhosis and, 6: 331 drug-metabolizing enzymes, 6: 156 Neurotoxicity: predictive studies, 6: 154–155 metabonomic analysis, 4: 299 NAT enzymes. See N -acetyltransferases (NATs) 3,4-methylenedioxymethamphetamine-induced, 4: Natural killer cells: 131–133 756 INDEX

Neutral loss scan: sulfotransferases, reaction phenotyping, 1: high resolution mass spectrometry vs., 5: 43–45 545–546 ion mobility mass spectrometry-mass spectrometry toxicity screening, in vitro studies, early drug integration, 5: 275–276 discovery, 4: 225 triple quadrupole/tandem mass spectrometry, 5: in vitro studies, bioanalysis, 5: 4–10 28–29 whole-body autoradiography and, 5: 370–383 Neutrophils: melanin binding, 5: 372–375 drug-induced, 6: 422–423 radiation dosimetry predictions, 5: 381–383 idiosyncratic drug-induced reactions, 4: 604–605 New Drug Application (NDA): myeloperoxidase bioactivation, 4: 83–85 animals-to-humans process, 3: 93–99 Nevirapine: bioanalytical considerations, 3: 93 bioactivation, 3: 204–206 biopharmaceutical considerations, 3: 98 cytochrome P450 polymorphisms, CYP2B6, 1: go/no-go decisions, 3: 98–99 252 nonclinical pharmacology and toxicology, 3: herb-drug interactions, St. John’s wort, 6: 93–98 283–284 bioequivalence studies, 2: 464–465 skin reactions to, 4: 164–165, 580–581 clinical pharmacology, 3: 99–115 in vitro toxicity studies, 4: 230–231 decision-making studies, 3: 105–109 New chemical entities (NCEs): drug-drug interactions, 3: 113–114 ADME studies: first in human studies, 3: 101–102 CYP inhibition, 2: 29–30 labeling issues, 3: 114–115 drug-drug interactions, 2: 16–18 metabolic disposition studies, 3: 110–111 metabolite prediction, 2: 13–15 premarketing phase, NDA, 3: 114 physicochemical properties, 2: 6–10 radiolabeled studies (ADME), 3: 110 research background, 2: 3–4 research methods, 3: 102–104 in vitro studies, 2: 24–32 in vitro drug metabolism/interaction studies, 3: animals-to-humans process, 3: 93–99 111–112 bioanalytical considerations, 3: 93 clinical trials, drug development, 1: 16 biopharmaceutical considerations, 3: 98 IND-enabling development, 3: 92–93 go/no-go decisions, 3: 98–99 overview of process, 3: 89–91 nonclinical pharmacology and toxicology, 3: regulatory issues, 3: 91 93–98 research background, 3: 87–89 clinical pharmacology, 3: 99–115 New molecular entities (NMEs): decision-making studies, 3: 105–109 animals-to-humans process, 3: 93–99 drug-drug interactions, 3: 113–114 bioanalytical considerations, 3: 93 first in human studies, 3: 101–102 biopharmaceutical considerations, 3: 98 labeling issues, 3: 114–115 go/no-go decisions, 3: 98–99 metabolic disposition studies, 3: 110–111 nonclinical pharmacology and toxicology, 3: premarketing phase, NDA, 3: 114 93–98 radiolabeled studies (ADME), 3: 110 biotransformation pathway predictions: research methods, 3: 102–104 future research issues, 6: 198–199 in vitro drug metabolism/interaction studies, 3: research background, 6: 177–180 111–112 in silico tools, 6: 180–182 drug-metabolizing enzymes, species differences, in vitro tools, 6: 182–188 1: 122–123 expressed enzyme systems, 6: 187–188 flavin-containing monooxygenases: hepatocytes, 6: 185–186 academic drug development, 1: 283 intestinal homogenates, 6: 188 overview, 1: 279–281 liver slices, 6: 186–187 IND-enabling development, 3: 92–93 research background, 6: 182 overview of process, 3: 89–91 tissue-specific microsomes, 6: 182–185 regulatory issues, 3: 91 in vivo animal studies, 6: 188–194 research background, 3: 87–89 radiolabeled compounds, 6: 190–194 safety testing: species selection, 6: 188–189 future research issues, 3: 237–238 unlabeled compounds, 6: 189–190 reactive metabolites, 3: 227–237 in vivo human studies, 6: 194–198 research background, 3: 221–222 first-in-human studies, 6: 194–195 stable metabolites, 3: 222–227 microtracer and accelerator mass stereoselective research, 4: 366 spectrometry studies, 6: 196–198 INDEX 757

radiolabeled studies, 6: 195–196 Niche therapy, pharmacogenetic testing and, 6: clinical pharmacology, 3: 99–115 25–26 decision-making studies, 3: 105–109 Nicotinamide adenine dinucleotide phosphate drug-drug interactions, 3: 113–114 (NADPH): first in human studies, 3: 101–102 biotransformation pathway predictions, in vitro labeling issues, 3: 114–115 studies, 6: 184–185 metabolic disposition studies, 3: 110–111 drug-drug interactions, mechanism-based CYP premarketing phase, NDA, 3: 114 inhibition, in vitro characterization, 6: radiolabeled studies (ADME), 3: 110 102–105 research methods, 3: 102–104 flavin-containing monooxygenases, 1: 276–279 in vitro drug metabolism/interaction studies, 3: drug candidate selection, 1: 285 111–112 thioamides, 1: 289 drug-drug interactions: thiols, 1: 290 clinical evaluation strategies, 6: 121–122 hepatic drug metabolism: clinical pharmacologic evaluation, 6: 115–120 alcoholism, 6: 322–323 probe substrate drug selection, 6: 118–120 mechanisms of, 6: 312 CYP induction studies, 6: 108–115 myeloperoxidase bioactivation, 4: 83–85 endpoints in studies, 6: 111–112 Nicotine metabolism: molecular mechanisms and in vitro assay age-dependent metabolism, CYP2A expression, 4: platforms, 6: 109–111 455–456 quantitative magnitude predictions, 6: AO/XOR-mediated reactions, 1: 321, 326 113–115 CYP1A2 induction, 6: 465 risk assessment from, 6: 112–113 cytochrome P450 enzymes, CYP2A subfamily, 1: 249–250 CYP inhibition studies, 6: 93–101 drug-drug interactions, time- and dose-dependent drug development risk assessment framework, CYP induction, 4: 438–439 6: 92–93 tertiary amine oxidation to N-oxide metabolite, 4: early clinical development, risk assessment in, 357 6: 122–123 UGT isoforms, UGT2B10, 1: 493 inducers, risk assessment with, 6: 126–127 Nifedipine, drug-drug interactions: mechanism-based CYP inactivation, 6: route-dependent CYP induction, 4: 433–434 101–108 time- and dose-dependent CYP induction, 4: 439 CYP turnover half-life, 6: 107–108 NIH Roadmap, flavin-containing monooxygenases, in vitro-in vivo extrapolation studies, 6: academic drug development, 1: 281–283 105–107 NIH shift, cytochrome P450 enzymes: in vitro studies, 6: 102–105 biotransformation reactions, 6: 56–57 object drug determinants, 6: 120–121 catalytic cycle, 1: 193–194 pharmacokinetic properties, risk assessment Nilotinib, drug-drug interactions, NME clinical and, 6: 124–125 pharmacology, 6: 117–120 precipitant NMEs, 6: 93–101 96-well fluorescence, plasma protein binding, drug quantitative reaction metabolism phenotyping, discovery and development, 5: 668 6: 123–124 “N-in-one” dosing, ADME in vivo studies, 3: 60–61 research background, 6: 89–90 Nitrate reduction, XOR-mediated reactions, 1: transporter contributions, 6: 125–126 326–327 hybrid mass spectrometry: Nitric oxide, inflammation, posttranscriptional development stage studies, 5: 180–181 regulation, 4: 650–651 discovery stage studies, 5: 178–180 Nitrite reduction, XOR-mediated reactions, 1: IND-enabling development, 3: 92–93 326–327 overview of process, 3: 89–91 Nitrogen, cytochrome P450 catalytic cycle, regulatory issues, 3: 91 heteroatom oxidations, 1: 193–194 research background, 3: 87–89 15Nitrogen: solubility and dissolution assessment, oral metabolite identification, NMR spectroscopy, 3: absorption: 157–158 BCS/BDDCS classifications, 3: 505–507 nuclear magnetic resonance, passive nuclei, research background, 3: 494–495 5: 338 stereoselective research, 4: 366 Nitro reductases, classification, 1: 380–381 Next generation sequencing (NGS), toxicogenomics, Nitroreduction: 4: 252–253 AO/XOR-mediated reduction, 1: 324–326 758 INDEX

Nitroreduction (Continued) plasma availability and pooling strategy, 4: cytochrome P450 bioactivation, aromatic amines, 210–212 4: 28–29 Nonresonance excitation, quadrupole ion trap mass S-Nitrosoglutathione reductase, pediatric drug spectrometry, ion activation, 5: 169 metabolism, 6: 549–550 Nonsteroidal anti-inflammatory drugs (NSAIDs). See Nonbiological agents, reactive metabolite also specific compounds bioactivation, adduct detection, 5: 642–643 biotransformation, inhibition, 6: 30 Nonclinical studies: chiral inversion, 4: 358–359 cancer therapies, toxicity testing, 3: 25–26 CYP2C9 metabolism, 6: 464–465 early drug development, pharmacology and cytochrome P450 enzymes, biotransformational toxicology, 3: 94–98 polymorphism, 6: 23–24 Noncoding RNAs (ncRNAs), toxicogenomics, 4: 253 diclofenac, bioactivation, 4: 84 Noncompartmental analysis: phase I metabolism, nabumetone, 6: 364–365 ADME studies: phase II-enzyme-catalyzed xenobiotic conjugation: blood data, 2: 602–603 acyl glucuronidation, 4: 114–118 research background, 2: 600 benoxaprofen, 4: 115–117 clinical dose predictions, drug discovery and plasma protein binding, 2: 532–536 development, 2: 589–590 prostaglandin H synthase bioactivation, 4: 79–83 Noncompetitive inhibition: toxicity studies, structure-toxicity relationships, drug-drug interactions, 4: 409–411 6: 385 cytochrome P450 enzymes, 6: 156–158 UGT enzyme bioactivation, toxicity studies, 6: enzyme kinetics, 1: 89 258–260 Noncovalent interactions, nano-electrospray in vitro toxicity screening, hepatic drug ionization mass spectrometry, 5: 71–72 metabolism, 4: 237–239 Nonhybrid mass analyzers, drug metabolism studies, Nonsynonymous cSNPs: 5: 182–189 glutathione transferase superfamily, alpha class FTICR mass analyzers, 5: 188–189 GSTs, GSTA2, 1: 569 LIT (2D trap), 5: 185–186 sulfotransferases, 1: 543–544 quadrupole mass filter, 5: 182 No observable adverse effect level (NOAEL), early time-of-flight mass analyzers, 5: 186–188 drug development, clinical pharmacology, 3: triple quadrupole ion trap, 5: 183–185 101–102 Non-immune-mediated mechanisms: Norepinephrine, phase II metabolism, idiosyncratic adverse drug reactions, 6: 428–432 methyltransferases, 2: 291–293 inflammagen hypothesis, 6: 431–432 Norfluoxetine, cytochrome P450 bioactivation, active metabolic idiosyncrasy, 6: 429 metabolites, 4: 21–23 mitochondrial toxicity, 6: 429–431 idiosyncratic drug-induced reactions, 4: 567–570 Normalized response, nano-electrospray ionization, Nonlinear drug discovery, oral drug development, 3: 5: 60–61 13–14 Novobiocin, pediatric drug metabolism, 6: 551–553 Nonlinear mixed effects modeling: Noyes-Whitney equation, dissolution, 3: 511 allometric scaling pharmacokinetics, 2: 508–509 N-terminal acetylation, peptide and protein elimination kinetics, 2: 629–633 therapeutics, 2: 905 Non-Michaelis-Menten enzyme kinetics, 1: 81–87 Nuclear factor erythroid 2-related factor (Nrf2), drug biphasic kinetics, 1: 83–84 conjugation and transport, 6: 225–226 κ heteroactivation, 1: 86–87 Nuclear factor-kappa B (NF- B) pathway: sigmoidal kinetics, 1: 81–83 aryl hydrocarbon receptor transcription, 1: 215 substrate inhibition, 1: 84–86 enzyme induction, receptor cross talk, 6: 19 Non-nucleophilic metabolism, flavin-containing flavin-containing monooxygenases, academic drug monooxygenases, 1: 298 development, 1: 282–283 Nonnucleoside reverse transcriptase inhibitors idiosyncratic drug-induced liver injury, (NNRTI): inflammatory response, 4: 602–603 distribution mechanisms, in vivo studies, 2: 137 transcriptional regulation, 4: 649–650 pediatric drug metabolism, drug-drug interactions, Nuclear factor-like 2 (NrF2) transcription factor, 6: 566 toxicogenomics, oxidative stress and reactive Nonradioactive metabolite quantitation, metabolites metabolite formation, 4: 265–266 in safety testing guidelines, 4: 210–215 Nuclear localization signals (NLSs): high resolution mass spectrometry methods, 4: aryl hydrocarbon receptor transcription, 1: 212–215 213–215 INDEX 759

constitutive androstane receptor transcription, 1: precision-cut tissue slices, CYP induction studies, 211–213 3: 471–478 pregnane X receptor transcription, 1: 208–211 solute carrier transporter mediation, 2: Nuclear magnetic resonance (NMR): 226–228 biotransformation pathway predictions, in vivo toxicity studies, cancer therapy, 3: 26–27 animal studies, 6: 193–194 toxicogenomics, 4: 251–252 drug discovery and development, 5: 346–353 xenobiotic metabolism, hepatocyte assessment, economics of, 5: 337 induction, 3: 410–419 future research issues, 5: 354–355 Nucleic acids, MALDI-MS analysis, 5: 130–131 glucuronide analysis, 1: 471–472 Nuclei characteristics, nuclear magnetic resonance hyphenated techniques, 5: 341–343 characterization, 5: 338 instrumentation, 5: 343–344 Nucleophile-mediated metabolism: limitations of, 5: 336–337 flavin-containing monooxygenases, 1: 287–298 metabolite identification, 3: 153–164 aliphatic secondary amines, 1: 297 characterization strategies, 3: 162 aliphatic tertiary amines, 1: 296–297 experimental design, 3: 158–162 amines, 1: 292 nuclei, 3: 156–158 cyclic amines, 1: 295 quantitation applications, 3: 166–167 hydrazines, 1: 293 sample preparation, 3: 154–156 hydroxylamines, 1: 293–295 metabolite structure, 1: 33–34 primary amines, 1: 297–298 metabonomics analysis, 4: 282–285, 287 pyrrolidines, 1: 296 polymorphism identification, 4: 293 sulfoxides, 1: 292 multidimensional NMR, 5: 340–341 theioethers, 1: 290–292 nuclei properties, 5: 338 thioamides, 1: 289 research background, 5: 331–332 thiols, 1: 289–290 safety testing, stable metabolites, 3: 224–227 thiones, 1: 287–288 sample preparation, 5: 345 reactive metabolites, cellular macromolecule solvent suppression, 5: 338–339 binding, 3: 186–188 stereochemistry, 5: 354 safety testing, reactive metabolites, 3: 229–237 strengths of, 5: 333–336 Nucleoside reverse transcriptase inhibitors (NRTIs): structure-activity relationships, 5: 332–333 abacavir, 4: 77–79 Nuclear Overhauser enhancement spectroscopy allometric scaling pharmacokinetics, 2: 510 (NOESY): cytochrome P450 polymorphisms, CYP2B6, basic principles, 5: 335–336 1: 252 metabolite identification, 3: 159–162 Nucleotide binding domains (NBDs), ABC multidimensional analysis, 5: 340–341 transporters, 2: 159 Nuclear receptors. See also specific receptors, e.g., Nucleotide-binding leucine-rich repeat-containing Pregnane X receptor (NLR) family, inflammation and infection, ABC transporter transcriptional regulation, 2: 174 drug-disease-drug interactions, 4: 627–628 biotransformation, enzyme induction, 6: 15–16 Nutritional status, hepatic drug metabolism, 6: 319 conjugation and transport, 6: 225–226 Nutrition Labeling and Education Act (NELA), drug conjugation and transport, 6: 226–227 dietary supplements regulation, 2: 806 drug-drug interactions: cytochrome P450 induction, 6: 160 Object drug research, drug-drug interactions: NME-precipitated CYP induction, 6: 109–111 NME as object drug, 6: 120–121 genetically modified animal models, 3: 657–666 physiologically-based pharmacokinetic modeling, aryl hydrocarbon receptor, 3: 665–666 6: 127–128 constitutive androstane receptor, 3: 659–661 Ocular disease, imaging mass spectrometry, 5: farnesoic X-activated receptor, 3: 663–664 244–246 multiple nuclear receptor studies, 3: 664–665 Off-lable drug therapies, pediatric populations, 6: peroxisome-proliferator-activated receptors, 3: 570–571 661–663 Okadaic acid response element (OAREKI), pregnane X receptor, 3: 658–659 cytochrome P450 genes, transcriptional hepatic drug metabolism, CYP induction, 3: regulation, receptor cross talk, CYP2B6, 371–380 1: 217 pharmacodynamics mechanisms, 2: 692 Olanzapine: plant secondary metabolites, human studies, 4: CYP1A2 metabolism, 6: 463, 466–467 491–492 reactive metabolite formation, 6: 394–395 760 INDEX

Olefins, cytochrome P450 enzymes: Oocyte studies, ADME studies, permeability and catalytic cycle, 1: 193–194 transporters, 2: 25 epoxidation, 4: 28–34 Opiate dependency, herb-drug interactions, St. oxidation, phase I metabolism, 2: 259–260 John’s wort, 6: 284 Oligonucleotides, bioanalysis regulations, 5: Opioid drug metabolism: 505–507 cirrhosis and, 6: 331 Oligopeptide transporter (PEPT1): cytochrome P450 enzymes, CYP2D6, 1: 257–258 cardiovascular drugs, 2: 865 stereoselectivity, 4: 350–351 ACE inhibitors, ADME studies, 2: 880 UGT isoform regulation, UGT2B7, 1: 491–492 human distribution, 2: 198 Opportunistic infections, immunomodulated intestinal metabolism, 2: 209–210 therapeutics, 3: 31 nomenclature and general structure, 2: 199–201 Oral absorption: oral absorption, 2: 92–93 ADME studies, bioavailability, 2: 5 substrates and inhibitors, 2: 203–205 bioavailability studies vectorial transport, 2: 557–558 ADME studies, 2: 5 Omeprazole: determinants, 2: 470–480 age-dependent metabolism, CYP2C expression, 4: estimate variability, 2: 459–460 457–458 fundamentals, 2: 82–83 drug-drug interactions: Lipinski’s rule-of-five, 2: 85 ADME studies, 2: 863–864 drug discovery and development: time- and dose-dependent CYP induction, 4: intestinal absorption pathways, 2: 85–89 437–439 intestinal metabolism, 2: 93–94 toxicity, CYP-mediated induction, 4: 443–444 intestinal transporters, 2: 89–93 physicochemical properties, 2: 83–85 pediatric drug metabolism, 6: 565–566 FDA regulations, 2: 97–99 substrate stereoselective metabolism, 4: 353 intestinal absorption assessment, 2: 94–97 OMICS technology, PK-PD assessment, preclinical pharmacokinetic modeling, 6: 586–588 and clinical trials, 2: 780–781 phase I metabolism, oseltmavir, 6: 362 On-chip synthesis, DNA microarrays, 3: 318–320 physiologically-based pharmacokinetic modeling, Oncology, imaging mass spectrometry, 5: 233–244 intestinal modeling, 2: 653–656 brain tumors, 5: 233–234 research overview, 2: 81–82 breast cancer, 5: 234–236 solubility and dissolution assessment: gastrointestinal tract tumors, 5: 240–243 Biopharmaceutical Classification System, 3: intratumor heterogeneity, 5: 243–244 501–504 lung cancer, 5: 236–237 drug discovery and development, 3: 505–507 ovarian cancer, 5: 237 Biopharmaceutical Drug Disposition prostate cancer, 5: 237–240 Classification System, 3: 504–505 One-compartment model: drug discovery and development, 3: 505–507 absorption kinetics, plasma concentration-time definitions, 3: 508–512 data, 2: 610–612 dissolution, 3: 511–512 distribution calculation, 2: 139–140 solids, 3: 510 drug-drug interactions, 2: 623–626 solubility, 3: 508–510 metabolite analysis, 2: 622–623 dissolution measurement, 3: 522–530 pharmacokinetics/toxicokinetics dose calculations, intrinsic dissolution, 3: 528–530 2: 590 powder dissolution, 3: 526–528 One-dimensional nuclear magnetic resonance excipient effects on drug disposition, 3: spectroscopy: 543–544 metabolite identification, 3: 159–160 formulation strategy, impact on, 3: 540–541 nuclei characterization, 5: 338 decision trees, 3: 531–532 solvent suppression, 5: 338–339 high energy solids, 3: 534–535 One-electron transfer, cytochrome P450 catalytic multicomponent solids, 3: 535–537 cycle, heteroatom oxidations, 1: 191–194 cocrystals, 3: 536 One-sided tests, bioequivalence studies, 2: 466 cyclodextrins, 3: 536–537 On-flow techniques, metabolite identification, hydrates, 3: 536 LC-NMR data, 3: 162–164 salts, 3: 535–536 Ontogenic expression: solid solutions and dispersions, 3: 537 carboxylesterases, 1: 438–439 precipitation formulation, 3: 540–541 molybdenum-containing hydrolases, 1: 343–344 solution formulations, 3: 537–540 INDEX 761

cosolvents, 3: 538 small molecule tyrosine kinase inhibitors, 6: cyclodextrins, 3: 538–539 520–523 lipids, 3: 539–540 drug-drug interactions, 3: 9–10 micelles, 3: 539 induction, 3: 10 pH adjustment, 3: 538 metabolic stability, 3: 9 surface area modification, 3: 532–534 permeability, 3: 9 future research issues, 3: 544–545 plasma protein binding, 3: 10 measurement techniques, 3: 513–518 solubility, 3: 8–9 assay components, 3: 513–514 Orbitrap analyzer (LTQ Orbitrap): compound distribution, 3: 514–515 basic principles, 5: 32, 34 compound/solvent mixing, 3: 516 hybrid instrumentation, 5: 195–197 solid-liquid separation, 3: 516–517 selectivity, 5: 65–66 solute-solid analysis, 3: 517 Organic anion transporter polypeptides (OATPs): solvent distribution and selection, 3: 515 antiarrhythmic agents, 2: 878 preclinical formulations, candidate profiling, 3: atorvastatin, 3: 50–51 541–542 biotransformation, 6: 6–7 rate-limiting-steps, 3: 495–501 enzyme induction, 6: 18 research background, 3: 493–495 in blood-brain barrier, 2: 212–213 schematic, 3: 508 blood-brain barrier penetration, in vitro studies, 3: solubility assays, 3: 518–522 575–576 equilibrium solubility protocols, 3: 521–522 cardiovascular drug metabolism: intrinsic solubility protocols, 3: 522 ADME studies, 2: 863–864 kinetic solubility protocols, 3: 518–521 diuretics, 2: 871 in vivo studies, 2: 32–33, 3: 593–598 drug-drug interactions, 2: 863–864, 869–870 animal studies: statin therapies, 2: 869–870 bioavailability, 3: 595–596 transporter effects, 2: 864–865 food-drug interactions, 3: 597–598 cell-based pharmacokinetics, 2: 521 as human models, 3: 596–597 clinical extrapolations, 2: 220–221 human bioavailability studies, 3: 593–595 distribution alterations, 2: 146–147 Oral contraceptives: drug-drug interactions: drug-drug interactions, anticonvulsants, 6: 480 enzyme induction, 6: 110–111 food-drug interactions, grapefruit juice, 6: 295 inhibition, 2: 223–224 herb-drug interactions, St. John’s wort, 6: 283 orally administered drug absorption or sulfotransferases, drug-drug interactions, 1: 547 elimination, 6: 162 Oral drug development: pharmacokinetic parameters, 6: 163 absorption mechanisms: transporters and NME disposition, 6: 125–126 intestinal absorption pathways, 2: 85–89 drug metabolism, 4: 642–645 intestinal metabolism, 2: 93–94 drug-metabolizing enzymes and, 2: 222–223 intestinal transporters, 2: 89–93 genetically modified animal models, 3: 672–674 physicochemical properties, 2: 83–85 genetic polymorphism, 2: 229 ADME studies, 3: 8–10 hepatic drug metabolism, 2: 486, 3: 377–378 chemotherapeutic agents: herb-drug interactions, transporter-based antimetabolites, 6: 519–520 absorption mechanisms, 2: 811 bioavailability, 6: 501–508 intestinal distribution, 2: 209–210 antiacid medications, 6: 506 in kidney, 2: 210–211, 213–214 first-pass metabolism, 6: 501–502 lipopolysaccharide model, 4: 643 food effect, 6: 506–507 in liver, 2: 210–211 intestinal ABCBA1 efflux, 6: 503–506 nuclear receptor mediation, 2: 226 surgery, 6: 508 OAT1-5 subtypes, 2: 206–207 cytotoxic agents, 6: 508, 518–519 drug-drug interactions, 2: 224–225 future research issues, 6: 526 genetically modified animal models, 3: hormonal agents, 6: 523–525 675–676 immune-modulating agents, 6: 525 nuclear receptor mediation, 2: 226–227 mechanism of action and clinical pregnancy drug metabolism and, 2: 942–945 pharmacology, 6: 509–517 in vivo studies, 2: 218–220 mTOR inhibitors, 6: 523 oral absorption, bioavailability studies, 2: 480 plant alkaloids, 6: 520 organ clearance mechanisms, 2: 562–564 research background, 6: 499–501 rate-limiting step, 2: 565–568 762 INDEX

Organic anion transporter polypeptides (OATPs) intrinsic clearance, 2: 569–570 (Continued) rate-limiting step, 2: 564–568 pathophysiology, 2: 202–205 isoform effect, 2: 559–564 pediatric drug metabolism, 6: 560–562 mechanisms, 2: 558–570 pharmacogenetics, 4: 390 physiologically-based pharmacokinetic physiologically-based pharmacokinetic modeling, modeling, 2: 570–574 2: 572–574 physiologically-based pharmacokinetic modeling, pregnancy drug metabolism and, 2: 942–945 2: 649–659 vectorial transport, 2: 552–558 kidney, 2: 656–659 in vitro studies, 2: 215–217 liver, 2: 650–652 in vivo studies, 2: 218–220 small intestine, 2: 653–656 xenobiotic metabolism, hepatocyte assessment: whole-body model, 2: 659–664 hepatobiliary transport, 3: 419–428 sequential metabolism and metabolite induction, 3: 410–419 behavior, 2: 660 Organic cation transporters (OCTs): transporter-enzyme interactions, 2: 660–664 in blood-brain barrier, 2: 213 solute carrier proteins, in vivo studies, 2: 218 cardiovascular drugs, transporter effects, 2: in vitro models, drug metabolism, 1: 49–50 864–865 Organ slices: drug-drug interactions, inhibition, 2: 224 drug metabolism, in vitro models, 1: 48–49 drug-metabolizing enzymes and, 2: 223 liquid scintillation counting assays, animal studies, genetically modified animal models, 3: 674–675 5: 364–366 genetic polymorphism, 2: 229–230 Organ-specific autoimmunity, idiosyncratic adverse intestinal distribution, 2: 209–210 drug reactions, 6: 417 in kidney, 2: 213–214 Organ transplants: in liver, 2: 210–211 biotransformation, reversible inhibitors, 6: 27–29 nuclear receptor mediation, 2: 227 drug-drug interactions, cytochrome P450 OCT1-3 subtypes, 2: 207 induction-mediated effects, 4: 439–441 hepatic drug metabolism, 3: 377–378 liver transplant, in vitro toxicity studies, intestinal in kidney, 2: 213–214 drug metabolism, 4: 229 OCT6 subtype, 2: 207 Orlistat, ADME studies, 3: 51 OCTN1-3 subtypes, 2: 207 Orolaryngeal carcinoma, UGT isoforms, UGT1A10, in kidney, 2: 213–214 1: 486 in liver, 2: 210–211 Orphan nuclear receptors, cytochrome P450 genes, pediatric drug metabolism, 6: 560–562 1: 205–206 pregnancy drug metabolism and, 2: 942–945 Orthogonality: in vivo studies, 2: 219 high throughput quantitative mass spectrometry, Organic solvents: mass analyzer tuning and selection, 5: 555 inductively coupled plasma mass ion mobility mass spectrometry-mass spectrometry spectrometry-liquid chromatography integration, 5: 269–270 integration, 5: 291–292 sample preparation quality control, 5: 520–521 micellar electrokinetic chromatography, 5: Ortho-quinone metabolite, safety testing, 3: 430–431 229–233 sulfotransferase kinetics, 1: 540–541 Oseltamivir, carboxylesterase transport, 1: 444–445 in vitro studies, 1: 77–78 Oseltmavir, phase I metabolism, 6: 362 Organizational factor, Lipinski’s rule-of-five, drug Osmium, inductively coupled plasma mass design and, 3: 48–54 spectrometry, 5: 307–308 Organ perfusion and clearance: Outcome biomarkers, drug discovery and blood flow, drug distribution and, 2: 117 development, 5: 579–580 drug discovery and development, 2: 35–36 Out-licensing procedures, early drug development, drug metabolism, 2: 248–256 decision-making studies, 3: 108–109 extrahepatic metabolism, drug-drug interactions, Ovarian cancer, imaging mass spectrometry, 5: 237 2: 376–380 Overlayer sample preparation, MALDI-MS samples, mass balance studies: 5: 126 animal studies, 2: 425–428 Oxazaphosphorines, cytochrome P450 bioactivation, human studies, dosimetry calculations, 2: 4: 24–25 444–446 Oxazepam: pharmacokinetics: chiral inversion, 4: 358–359 future research issues, 2: 575 phase I metabolism, 6: 357 INDEX 763

Oxcarbazepine, drug-drug interactions, 6: 486 mitochondrial dysfunction, 3: 185 Oxidation: nefazodone case study, 3: 199–200 cytochrome P450 reactions, 1: 190–194 nefazodone case study, 3: 198–199 carbon oxidation, 1: 190 redox cycling and ROS generation, 3: ester/amide cleavage, 6: 59 184–185 heteroatom oxidations, 1: 190–193 toxicity initiation, 3: 179–180 hydroxylation, 6: 57–59 research overview, 3: 177–178 phase I metabolism, 2: 256–265 cytochrome P450 enzymes, 6: 53–54 π-bond substrates, 1: 193–194 drug metabolism, 2: 252–256 drug metabolism and, 1: 3–14 phase I metabolism, pediatric populations, 6: pharmacokinetics, 2: 254–256 539–540 electrochemical liquid chromatography mass phase II metabolism, glutathione-S-transferases, 6: spectrometry, flow injection analysis, 5: 213–214 316–318 toxicogenomics, mechanisms of, 4: 264–266 metabolite stereoselectivity, 4: 356–362 in vitro toxicity studies, 4: 244–245 enantiotopic moiety to chiral metabolite, 4: N-Oxide metabolites: 357–358 cytochrome P450 bioactivation, heteroatom sulfide to chiral sulfoxide, 4: 356–357 oxidation, 6: 59–60 tertiary amine to N-oxide, 4: 357 flavin-containing monooxygenases: Oxidative stress. See Oxidative transformation drug candidate selection, 1: 284–285 Oxidative transformation: hydroxylamines, 1: 293–295 bioactivation: phase I metabolism, conjugation and, 6: 355–356 3: acetaminophen case study, 192–198 reduction reactions, 1: 327–328 cellular consequences, 3: 193–194 tertiary amine oxidation to, 4: 357 circadian rhythm, 3: 197–198 S-Oxide metabolites: drug-induced liver injury: flavin-containing monooxygenases: animal studies, inflammatory response, 3: drug candidate selection, 1: 284–285 196–197 thioamides, 1: 289 inflammation and, 3: 194–196 thioethers, 1: 291–292 hepatotoxicity, 3: 192–193 thiols, 1: 289–290 acyl glucuronide case study, 3: 200–204 thione toxicity, 1: 288 reactive metabolites, 3: 201–203 thiocarbonyl bioactivation, 4: 66–67 toxicity mechanisms, 3: 203–204 adverse drug reactions, 3: 180–181 P13K/AKT pathway, cancer therapies, epidermal cellular defense, 3: 182–183 3: glutathione effects, 3: 183 growth factor receptor, 33–35 reactive oxygen species generation, 3: 182 Paclitaxel, cytochrome P450 polymorphisms, biomarkers, 3: 188–192 CYP2C8, 1: 253–254 mercapturate conjugate in vivo indicators, 3: Pairwise analysis, ADME studies, pharmacokinetics, 190–192 3: 78–80 nevirapine case study, 3: 206 Pajouseh’s rules, central nervous system compounds, in vitro biomarkers and trapping agents, 3: 3: 48–49 189–190 Para-aminohippurate (PAH): drug metabolism and, 3: 178–179 organic anion transporter polypeptides, 2: nefazodone case study, 3: 198–200 206–207 bile salt export pump inhibition, toxicity pediatric drug metabolism, 6: 561–562 studies, 3: 198–199 Paracellular transport: mitochondrial dysfunction, 3: 199–200 oral absorption, 2: 88 reactive metabolite formation and covalent in vivo studies, oral absorption and bioavailability, binding, 3: 198–199 3: 595 nevirapine case study, 3: 204–206 Paracetamol, phase I metabolism, 6: 356–357 reactive metabolites: Parallel absorption model, plasma concentration-time acyl glucuronide case study, 3: 201–203 data, 2: 618 glutathione and thiol status disruption, 3: 185 Parallel artificial membrane permeability assay irreversible binding to macromolecules, 3: (PAMPA): 186–188 ADME studies, permeability/transporters, 2: 24 lipid peroxidation, ROS generation, 3: 185 blood-brain barrier penetration, in vitro studies, 3: mechanisms and consequences, 3: 183–188 572–573 764 INDEX

Parallel artificial membrane permeability assay Patient factors: (PAMPA) (Continued) bioavailability estimations, 2: 459–460 drug discovery and development, translational biotransformation, 6: 32–35 research, 2: 752 children and neonates, 6: 33 intestinal absorption, in vitro studies, 2: 95–96 diet, 6: 35 solubility and dissolution assessment, oral disease states, 6: 34–35 absorption, rate-limiting steps, 3: 497–501 elderly, 6: 32–33 in vitro studies, bioanalysis, 5: 7 gender, 6: 33–34 Parallel-group design, bioequivalence studies, 2: 465 pregnancy, 6: 34 Paraquat (PQ), reductive bioactivation, 4: 90 dose calculations and, 6: 612–613 Parasitic infection, drug-disease-drug interactions: drug discovery and development, biomarkers for, CYP1 subfamily, 4: 630 5: 581–582 CYP2C, 4: 634 extrahepatic drug-metabolizing enzymes, 2: 344, CYP3 subfamily, 4: 636 350 glutathione S-transferases, 4: 639 hepatic drug metabolism, 6: 317–320 uridine diphosphate-glucuronosyltransferases, 4: idiosyncratic adverse drug reactions, 6: 405–417 638 physiologically-based pharmacokinetic modeling, 2: Pardrigde’s rule, ADME, permeability properties, 2: whole body model, 667–670 UGT activity, clinical significance, 6: 264–269 8–10 drug-drug interactions, 6: 266–267 Parenchymal disease, hepatic drug metabolism, 6: genetic polymorphism, 6: 265–266 321–322 glucuronidation inhibition, 6: 267–269 Parent ion, quadrupole devices, 5: 157 Pattern-recognition receptors, drug-disease-drug Parent-metabolite model, compartmental analysis, 2: interactions: 622–624 inflammation, 4: 625–628 Parkinson’s disease: regulatory mechanisms, 4: 629 dual A /A receptor antagonist optimization, 4: 2A 1 research background, 4: 624 174–176 Paul traps, quadrupole ion trap mass spectrometry, glutathione transferase superfamily, omega class 5: 152–153 polymorphisms, 1: 575 Pazopanib, oral chemotherapeutic agents, 6: 522 monoamine oxidase bioactivation, 4: 71–74 Peak capacity, ion mobility mass spectrometry-mass Paroxetine: spectrometry integration, 5: 269–270 CYP2D6 metabolism, 6: 461–462 Peak storage, metabolite identification, LC-NMR hepatotoxicity prevention strategies, 4: 182 data, 3: 162–164 reactive metabolite formation, 6: 392–393 Pediatric populations. See also Fetal development Partial agonists, pharmacodynamics, 2: 694 biotransformation in, 6: 33 Partial-block crossover design, bioequivalence dose calculations for, 6: 612 studies, 2: 465–466 drug clearance and exposure, drug metabolism in Particle size: relation to, 6: 562–563 distribution mechanisms, 2: 112–113 drug-drug interactions, metabolism in relation to, solubility and dissolution assessment, oral 6: 563–566 absorption, dissolution enhancement, 3: drug metabolism: 533–534 future research issues, 6: 571 Partition ratio, enzyme kinetics, irreversible mammary gland distribution barrier, 2: inhibition, 1: 91–94 123–124 Passive diffusion: research background, 6: 537–538 oral absorption, 2: 86–87 research limitations and design parameters, 6: bioavailability studies, 2: 476–480 566–570 in vivo studies, renal clearance, 3: 608–609 early drug development, clinical pharmacology, 3: Passive permeability: 103–105 blood-brain barrier penetration, in vitro studies, 3: hepatic drug metabolism, 6: 317–318 572–573 off-lable drug therapies in, 6: 570–571 intestinal absorption, in vitro studies, 2: 95–96 phase I drug metabolism, 6: 538–551 in vivo studies, distribution mechanisms, 3: alcohol dehydrogenases, 6: 549–550 599–600 cytochrome P450 enzymes, 6: 540–547 Pathogen-associated molecular patterns (PAMPs), CYP1 subfamily, 6: 540–541 drug-disease-drug interactions, research CYP2 subfamily, 6: 541–545 background, 4: 624 CYP3 subfamily, 6: 544–547 INDEX 765

flavin-containing monooxygenases, 6: 548–549 research background, 2: 895–897 hydrolytic enzymes, 6: 550–551 Perazine, CYP2D6 metabolism, 6: 462 monoamine oxidases, 6: 549 Perfusion assays, blood-brain barrier penetration, oxidative drug-metabolizing enzymes, 6: in vitro studies, 3: 572–573 539–540 Perfusion-related kinetics: reductive enzymes, 6: 550 distribution mechanisms, 2: 119–121 phase II drug metabolism: physiologically-based pharmacokinetic modeling, glucuronosyltransferase enzymes, 6: 551–553 6: 584–585 sulfotransferase enzymes, 6: 554 Permeability: physiological parameters of drug metabolism, 6: ADME studies, 2: 7–8 554–562 pharmacokinetics, 3: 73–80 hepatic blood flow, 6: 555–556 in vitro studies, 2: 24–25 liver size relative to body weight, 6: 559 apparent permeability (Papp) calculation, intestinal milligram microsomal protein per gram liver, 6: metabolism models, 3: 343–345 559 blood-brain barrier penetration, in vitro studies, 3: protein binding, 6: 554–556 572–573 uptake and efflux drug transporters, 6: 559–562 drug discovery and development: Pegylation, peptide and protein therapeutics, half-life oral drug properties, 3: 6–9, 15–16 increase, 2: 901–904 translational research, 2: 751–752 Pelicular (fused-core) silica, development of, 5: 533 in vitro studies, 3: 55 Penacetin, cytochrome P450 enzymes, dealkylation intestinal absorption assessment, in vitro studies, reaction, 4: 15–16 2: 94–96 Penetration parameters, blood-brain barrier studies: oral absorption, 2: 86–88 in silico predictions and simulations, 3: 576–577 physiologically-based pharmacokinetic modeling, computational models, 3: 576 6: 584–585 multiparameter optimization, 3: 576 solubility and dissolution assessment, oral PBPK models, 3: 577 absorption, rate-limiting steps, 3: 496–501 in vitro penetration studies, 3: 572–576 unstirred water layer (UWL), dissolution, 3: 512 brain tissue binding, 3: 573–574 in vitro studies, bioanalysis, 5: 6–7 permeability, 3: 572–573 Peroxidases, bioactivation, 4: 79–85 transporters, 3: 574–576 clozapine, 4: 85 in vivo penetration studies, 3: 566–572 myeloperoxidase, 4: 83–85 cerebrospinal fluid surrogate, 3: 567–569 diclofenac, 4: 84 microdialysis, 3: 569–570 ticlopidine, 4: 84–85 PET imaging, 3: 570–572 preclinical neuro pharmacokinetics, 3: 566–567 prostaglandin H synthase, 4: 79–83 D-Penicillamine, autoimmune reactions, 4: 578 acetaminophen (APAP), 4: 80–81 Penicillin, thrombocytopenia reaction, 6: 422 aromatic amines, 4: 81–82 Pentachlorophenol, dechlorination, 1: 10 hydantoins, 4: 83 PEPT1. See Oligopeptide transporter (PEPT1) polyaromatic hydrocarbons, 4: 82–83 Peptidase, peptide and protein therapeutics, Peroxisome proliferator-activated receptor (PPAR): selectivity, 2: 900–901 drug conjugation and transport, 6: 225–226 Peptide mass fingering (PMF), protein identification, genetically modified animal models, 3: 661–663 4: 318–319 metabonomic identification, 4: 298–299 Peptide selection: soluble epoxide hydrolase, 1: 411 MALDI-MS procedures, 5: 127–128 sulfotransferases, induction, 1: 544–545 proteomics, LC/MS targeted studies, 4: 332 toxicity studies, cancer therapy, 3: 26–27 reactive metabolite bioactivation, 5: 630–645 toxicogenomics, oxidative stress and reactive amino acid-related adducts, 5: 635–637 metabolite formation, 4: 265–266 GSH thiol derivatives, 5: 631–635 Perpetrator drugs, metabolic drug interactions, 1: nonbiological agent trapping, 5: 642–645 20–21 Peptide therapeutics: Pfizer clinical candidates, blood-brain barrier catabolic reactions, 2: 901–904 penetration, retroanalysis, 3: 577–583 enzyme clearance mechanisms, 2: 897–901 P-glycoprotein (P-gp): immunoassays, 5: 397 adjuvant therapies, 2: 173 quantitative whole-body autoradiography ADME studies, in vitro studies, 3: 59 assessment, 5: 378–380 adverse drug reactions and drug-drug interactions, renal clearance, 2: 897 2: 171 766 INDEX

P-glycoprotein (P-gp) (Continued) technology-based classification, 2: 698–699 bioavailability studies, enzyme-transporter concentration-response relationship, 2: 704–706 interplay, 2: 483–484 desensitization mechanisms, 2: 692 biotransformation, 6: 7 drug action mechanisms, 2: 686–692 inhibitors, 6: 28–29 drug-drug interactions: blood-brain barrier penetration: anticonvulsants, 6: 475 in vitro studies, 3: 574–576 clinical perspectives, 6: 90–92 in vivo studies, 3: 570–572 cytochrome P450 induction-mediated effects, 4: cancer drug resistance, 2: 167 439–444 cardiovascular drug metabolism: therapeutic efficacy, 4: 439–441 drug-drug interactions, 2: 863–864 toxicity effects, 4: 441–444 transporter effects, 2: 864–865 predictive studies, 6: 154–155 cardiovascular drugs, drug-drug interactions, 2: drug-receptor interactions: 863–864 affinity, 2: 695 distribution mechanisms, 2: 125–126 agonists, 2: 693–694 drug-disease-drug interactions, intestinal antagonists, 2: 695–696 2: metabolism, 4: 640 efficacy and potency, 695 inverse agonists, 2: 694–695 drug-drug interactions: partial agonists, 2: 694 clinical perspectives, 6: 90–92 spare receptors, 2: 694 inhibition and induction, 6: 162–163 drug-target interactions, 2: 768–770 orally administered drug absorption or future research issues, 2: 729–730 elimination, 6: 162 G-protein-coupled receptors, 2: 690–691 drug metabolism, 1: 30 hepatic drug metabolism: food-drug interactions, grapefruit juice, 6: alcoholism, 6: 323 290–293, 290–296 cirrhosis, 6: 330 genetically modified animal models, 3: 666–668 immunoassay applications, 5: 413–415 herb-drug interactions: intracellular and nuclear receptors, 2: 692 absorption mechanisms, 2: 809–811 ion channels, 2: 688–689 St. John’s wort, 6: 282–286, 285 mathematical models, 2: 703–704 intestinal drug metabolism, 4: 644–645 delayed effect models, 2: 707–721 oral absorption mechanisms, 2: 89–90 disease progression models, 2: 724–727 bioavailability studies, 2: 477–480 irreversible effects models, 2: 721–724 organ metabolism/transport, 2: 560–564 reversible effect models, 2: 705–707 pediatric drug metabolism, 6: 560–562 tolerance and rebound models, 2: 727–729 drug-drug interactions, 6: 565–566 non-receptor drug mechanisms, 2: 693 plant secondary metabolites, 4: 490–494 pediatric drug clearance and exposure, 6: 562–563 pregnancy drug metabolism and, 2: 938–945 phase I metabolism: single nucleotide polymorphisms, 2: 176–178 PK-PD interplay, 6: 354–355 small molecule transport, 2: 161–166 prodrugs, 6: 360 substrate binding specificity, 2: 161–165 physiologically-based pharmacokinetic modeling, xenobiotic metabolism, hepatocyte assessment, whole body models, 2: 664–667 inhibition studies, 3: 405–406 research background, 2: 685–686 Pharmacodynamics (PD): solubility and dissolution assessment, oral bioequivalence studies, 2: 468 absorption, research background, 3: 494–495 biomarkers: tachyphylaxis, 2: 692 data quality, 5: 589–593 tools and software for, 2: 729 developmental stages, 2: 701–703 tyrosine kinase/guanylate-cyclase-linked receptors, drug discovery and development, 5: 582 2: 691–692 models, 5: 582–583 Pharmacogenetic drug monitoring (PDM) system, optimization, 5: 584–586 ethnic differences in drug metabolism, 6: 77 fit-for-purpose assays, 5: 585–587 Pharmacogenetics: genomic biomarkers, 2: 699–701 ADME-related genes, 4: 380 activity-based biomarkers, 2: 701 allelic variants-star nomenclature, 4: 380 imaging-based biomarkers, 2: 701 arylamine N-acetyltransferases, 4: 386–387 overview, 2: 697–698 biotransformation: PK/PD models, 5: 583–586 drug development, 6: 21–22, 40–41 proximal and distal biomarkers, 2: 698 drug efficacy, 6: 20–27 INDEX 767

future research issues, 6: 26–27 drug discovery and development, 3: 44–47, polymorphisms, 6: 22–25 71–80 cytochrome P450, 6: 22–24 hepatic metabolism, 2: 26–28 flavin monooxygenases, 6: 24 human PK prediction, 2: 12–13 NADPH oxidoreductase, 6: 22 in vivo studies, 3: 59–61 sulfonotransferases, 6: 25 allometric scaling, 2: 496–509 testing protocols, 6: 25–26 human clearance prediction, 2: 497–501 uridine-diphosphate glucuronosyltransferases, nonlinear mixed effects modeling, 2: 508–509 6: 24–25 in vitro metabolic clearance and, 2: 501–503 cytochrome P450 enzymes, 4: 380–386 volume distribution in humans, 2: 501–508 CYP1 subfamily, 4: 385–386 antibody targeting and, 2: 911–912 CYP2B subfamily, 1: 252–253 bioavailability, 2: 455–456 CYP2 subfamily, 4: 381–384 bioequivalence studies, 2: 467 CYP2A, 4: 383–384 biomarkers: CYP2B, 4: 384 data quality, 5: 589–593 CYP2C, 4: 382–383 drug discovery and development, 5: 582–583 CYP2D, 4: 381–382 fit-for-purpose assays, 5: 585–587 CYP3 subfamily, 4: 384–385 PK/PD models, 5: 583–586 polymorphisms, 1: 240–241 biopharmaceuticals, 2: 895–897 CYP2A subfamily, 1: 249–250 blood-brain barrier penetration, in vivo neuroPK drug-drug interactions, predictive studies, 6: studies, 3: 566–567 169–170 cell models: drug transport proteins, 4: 389–393 absorption and disposition kinetics prediction, ABC transporters, 4: 389–393 2: 515–516, 518–521 organic anion transporting polypeptides, 4: 389 DNA binding, 2: 515–517 flavin-containing monooxygenases, 4: 386 lysosome drug distribution, 2: 510–513 future research issues, 4: 393 mitochondrial sequestration of drug molecules, herb-drug interactions, 4: 501 2: 513–515 idiosyncratic drug-induced reactions, 4: 570 drug discovery and development: research background, 4: 378–379 ADME studies, 3: 44–47 sulfotransferases, 4: 388–389 area under the curve values, 2: 584–585 UDP-glucuronosyltransferases, 4: 387–388 bioavailability, 2: 588 uridine diphosphate-glucuronosyltransferases, 1: clearance mechanisms, 2: 585–587 460–461 clinical dose predictions, 2: 588–592 Pharmacogenomics, carboxylesterases, 1: 440–446 cytochrome P450 enzyme system, 1: 442 compartmental analysis, 2: 590–592 drug-insecticide interactions, 1: 445–446 noncompartmental analysis, 2: 589–590 drug transporter interactions, 1: 443–445 future research issues, 2: 596–597 polymorphisms, 1: 441–442 half-life, 2: 588 uridine diphosphate (UDP)- lead optimization and identification, 2: 746–749 glucuronosyltransferases, 1: 442–443 maximum plasma concentration/time of Pharmacokinetic/pharmacodynamic interplay, phase I maximum concentration, 2: 585 metabolism, 6: 353–355 MIST guidelines, 2: 594–596 drug-drug interactions, protease inhibitors, 6: 368 physiologically-based pharmacokinetic Pharmacokinetics (PK). See also Physiologically- modeling, 2: 591–592 based pharmacokinetic modeling (PBPK) research background, 2: 581–583 absolute bioavailability calculations, 2: 458–460 species differences in disposition, 2: 593–594 active metabolites, cytochrome P450, 4: 26–27 steady state, 2: 587 ADME studies: toxicogenomics and biomarkers, 2: 592–593 data analysis and modeling: volume of distribution, 2: 587 blood data, noncompartmental analysis, 2: drug-drug interactions: 602–603 anticonvulsants, 6: 475 future research issues, 2: 633–634 clinical perspectives, 6: 90–92 plasma studies, 2: 608–633 study design, analysis, and results radioactive dose recovery, 2: 600–602 interpretation, 6: 129–136 renal clearance, 2: 603–606 clinical relevance assessment, 6: 134–136 research background, 2: 599–600 statistical issues, 6: 133–134 urine data, 2: 603–607 cytochrome P450 enzymes: 768 INDEX

Pharmacokinetics (PK). See also Physiologically- research background, 6: 89–90 based pharmacokinetic modeling (PBPK) risk assessment and evaluation: (Continued) CYP induction, 6: 112–113 competitive/noncompetitive inhibition, 6: CYP inhibition, 6: 93–101 156–158 quantitative magnitude predictions, 6: induction, 6: 158–160 98–101 induction-mediated effects, 4: 430–439 surrogate selection, 6: 97–98 clearance-dependent induction, 4: 434–437 in vitro studies, 6: 93–97 route-dependent induction, 4: 433–434 drug development framework, 6: 92–93 theoretical issues, 4: 430–433 early clinical development strategies for, 6: time- and dose-dependent induction, 4: 122–123 437–439 inducers as tool for, 6: 126–127 future research issues, 6: 139–140 NME pharmacokinetics, 6: 124–125 metabolic processes, 1: 20–21 drug metabolism, 1: 14, 31 new molecular entities: accelerator mass spectrometry-based human clinical evaluation strategies, 6: 121–122 ADME studies, 4: 216 clinical pharmacologic evaluation, 6: ADME development modifications, 4: 208–210 115–120 basic principles, 2: 247–256 probe substrate drug selection, 6: 118–120 FDA/ICH guidelines harmonization, 4: CYP induction, 6: 108–115 207–208 endpoints in studies, 6: 111–112 future research issues, 4: 218 molecular mechanisms and in vitro assay human carbon-14 ADME study, 4: 215 platforms, 6: 109–111 implementation strategies, 4: 216–218 quantitative magnitude predictions, 6: industrial ADME research and, 4: 206–207 113–115 nonradioactive metabolite quantitation, 4: risk assessment from, 6: 112–113 210–215 CYP inhibition studies, 6: 93–101 high resolution mass spectrometry methods, inducers, risk assessment with, 6: 126–127 4: 212–215 mechanism-based CYP inactivation, 6: plasma availability and pooling strategy, 4: 101–108 210–212 CYP turnover half-life, 6: 107–108 overview, 4: 205–206 in vitro-in vivo extrapolation studies, 6: research background, 4: 206 105–107 strategic initiatives, 4: 208–210 in vitro studies, 6: 102–105 early drug development: object drug determinants, 6: 121 animal-to-human transition, 3: 94 pharmacokinetic properties, risk assessment labeling issues, 3: 114–115 and, 6: 124–125 enantioselective drugs, 4: 361–362 quantitative reaction metabolism excretion mechanisms: phenotyping, 6: 123–124 future research issues, 2: 575 risk assessment in early clinical development, intrinsic clearance: 6: 122–123 organ clearance and, 2: 569–570 transporter contributions, 6: 125–126 rate-limiting step, 2: 564–568 physiologically-based pharmacokinetic isoform effect, 2: 559–564 modeling and simulation, 6: 127–128 organ clearance mechanisms, 2: 558–570 predictive studies, 4: 423–424, 6: 154–165 physiologically-based pharmacokinetic combined analysis, 6: 163–165 modeling, 2: 570–574 conjugative drug-metabolizing enzymes, half-life, drug clearance, 1: 16–17 6: 161 hepatic drug metabolism, in vivo human studies, cytochrome P450s: 3: 355–358 competitive/noncompetitive inhibition, 6: hyphenated chromatography/mass spectrometry 156–158 analysis, 5: 545–548 induction, 6: 158–160 immunoassay applications, 5: 411–412 OATP transporters, 6: 163–164 immunogenicity, 5: 412 P-glycoprotein inhibition and induction, 6: liquid chromatography-mass spectrometry 162–163 advances, 2: 764–768 transporters, orally administered drugs, 6: mass balance studies: 161–162 animal studies: prescription guidelines using, 6: 136–139 clinical goals and aims, 2: 417 INDEX 769

pharmacokinetic parameters, 2: 431–434 Pharmacological properties: preclinical studies: cytochrome P450 enzymes: case study, 2: 435–438 bioactive metabolites, 4: 10–27 experimental design, 2: 418–430 aromatic/aliphatic hydroxylation, 4: 11–15 biliary excretion, 2: 427–428 consequences, 4: 26–27 blood and plasma matrices, 2: 422 dealkylation reactions, 4: 15–18 carcass and carbon dioxide exhalation, inactive compounds (prodrugs), 4: 23–25 2: 428–430 miscellaneous reactions, 4: 18–23 dose, administration route, and CYP2A subfamily, 1: 249–250 formulation, 2: 420–421 CYP2B subfamily, 1: 251–253 excreta and cage wash, 2: 422–425 CYP2C subfamily, 1: 253–256 matrix selection, 2: 421–430 early drug development, nonclinical studies, 3: species selection, 2: 418–420 94–98 tissues and organs, 2: 425–427 microsomal epoxide hydrolase, 1: 398–402 research issues and methodology, 2: clinical implications, 1: 407 438–440 oral chemotherapeutic agents, 6: 509–517 radiolabeled compounds, use, selection physiologically-based pharmacokinetic modeling, criteria and limitations, 2: 430–431 predictive studies, 2: 664–667 research backgound, 2: 415–416 UGT biotransformation, 6: 260–261 future research issues, 2: 450 Pharmacophores: human studies: phase I metabolism, bioprecursors, 6: 363–367 case study, 2: 448–450 in silico studies, 3: 252–253 dosimetry calculations, 2: 441–446 translational drug discovery, modeling tools, 2: effective dose, 2: 445–446 744 gastrointestinal tracts, 2: 444–445 Pharmacovigilance, clinical trials, drug development, organs and tissues, 2: 445 1: 16 experimental design, 2: 447–448 Pharmocologic synergy, plant secondary metabolites, research background, 2: 440–441 4: 501–502 microdose studies, 5: 600–602 Pharynx, anatomy and function, 2: 47–48 accelerator mass spectrometry, 5: 611–612 Phase 0 trials: microdosing studies, research background, 5: cancer therapies, 3: 38–39 601–602 hybrid mass spectrometry, 5: 180–181 pediatric drug metabolism: microdosing studies, 5: 599–602 clearance and exposure mechanisms, 6: safety testing, stable metabolites, 3: 225–227 562–563 hepatic drug metabolism, 6: 554–558 Phase I drug metabolism, 2: 256–278 research background, 6: 537–538 active metabolites, 6: 357–360 research design and methodology, 6: 566–570 benzodiazepine, 6: 357 phase I metabolism, PK-PD interplay, 6: 354–355 codeine, 6: 358 population-based modeling and simulation: tamoxifen, 6: 359–360 apriori and a posteriori modeling, 6: 582–583 tramadol, 6: 358–359 research background, 6: 581–582 aldehyde oxidase, 2: 267–269 predictive studies: bioactivation and conjugation, 6: 355–356 allometric scaling, 2: 496–509 bioprecursors, 6: 363–367 cell models, 2: 509–521 clopidogrel and prasugrel, 6: 365–367 future research issues, 2: 522–523 nabumetone, 6: 364–365 research background, 2: 495–496 tirapazamine, 6: 367 solubility and dissolution assessment, oral carboxylesterase, 2: 271–274 absorption, research background, 3: 494–495 carrier-linked prodrugs, 6: 354, 360–363 sources of variability in, 6: 585–598 capecitabine, 6: 363 translational drug discovery, 2: 738–741 fosprofol, 6: 361 UGT isoforms, UGT2B7, 1: 491–492 oseltmavir, 6: 362 in vivo studies, bioanalysis, 5: 10–13 valacyclovir, 6: 362–363 Pharmacological interaction (p-i) hypothesis: conjugation mechanisms, 6: 205–206 hepatotoxicity studies, 4: 163–165 cytochrome P450 enzymes, 2: 256–265, 6: 77–79 idiosyncratic adverse drug reactions, 6: 427 drug discovery and development, 6: 354–355 reactive metabolite formation, 6: 433 drug-drug interactions, HIV protease inhibitors, idiosyncratic drug-induced reactions, 4: 568–570 6: 368 770 INDEX

Phase I drug metabolism (Continued) S-acyl-glutathione thioester adducts, early drug development, metabolic disposition carboxylic-acid-containing drugs, 4: studies, 3: 110–111 139–140 epoxide hydrolase, 2: 274–276 bromobenzene, 4: 133–134 flavin monooxygenase, 2: 265–267 ethylene dibromide episulfonium ion future research issues, 6: 368–369 formation, 4: 130–131 hepatic drug metabolism, 6: 312 hexachlorobutadiene-induced nephrotoxicity, 4: elderly, 6: 318–319 136–137 3,4-methylenedioxymethamphetamine-induced intestinal metabolism, Caco-2/TC7 cell line neurotoxicity, 4: 131–133 comparisons, 3: 339 α-naphthylisothiocyanate-induced intrahepatic ketoreductase, 2: 276–278 cholestasis, 4: 137–138 metabolic-bioactivity continuum, 6: 353–355 sevoflurane-induced nephrotoxicity, 4: metabolite identification, liquid chromatography 134–136 mass spectrometry identification, 2: 765–767 metabolic activation pathways, 4: 105–108 monoamine oxidase, 2: 269–271 overview, 4: 103–104 pediatric populations, 6: 538–551 sulfonation, 4: 121–126 alcohol dehydrogenases, 6: 549–550 allylic alcohols, 4: 123–124 cytochrome P450 enzymes, 6: 540–547 arylhydroxylamines and arylhydroxamic CYP1 subfamily, 6: 540–541 acids, 4: 124–126 CYP2 subfamily, 6: 541–545 polycyclic aromatic benzylic alcohols, 4: CYP3 subfamily, 6: 544–547 122–123 flavin-containing monooxygenases, 6: 548–549 xenobiotic metabolism classification, 4: hydrolytic enzymes, 6: 550–551 104–105 monoamine oxidases, 6: 549 glucuronosyltransferase, 2: 278–281 oxidative drug-metabolizing enzymes, 6: glutathione transferase, 2: 281–283 539–540 hepatic drug metabolism: reductive enzymes, 6: 550 alcoholism, 6: 322–323 pharmacokinetic/pharmacodynamic interplay, 6: elderly, 6: 319 353–355 liver transplant, 6: 334 precision-cut tissue slices, induction studies, 3: mechanisms of, 6: 312 471–478 human enzymes, 6: 207–218 soft drug development, 6: 356–357 amino acids, 6: 217–218 in vitro toxicity screening, gastrointestinal tract, 4: glutathione-S-transferases, 6: 213–214 225–232 methyltransferases, 6: 214–216 xenobiotics, hepatocyte assessment, 3: 394–396 N-acetyltransferases, 6: 216–217 Phase II drug metabolism: sulfotransferases, 6: 210–213 acyl-CoA synthetase, 2: 288–290 UGT enzymes, 6: 207–210 biotransformation, UGTs, 6: 10–11 intestinal metabolism, Caco-2/TC7 cell line comparisons, 3: 339–340 conjugation mechanisms, 6: 205–206 mechanisms, 2: 278–293 early drug development, metabolic disposition metabolite identification, liquid chromatography studies, 3: 110–111 mass spectrometry identification, 2: 765–767 enzyme-catalyzed xenobiotic conjugation: methyltransferase, 2: 290–293 N-acetylation, 4: 126–129 N-acetyltransferase, 2: 286–288 4: aromatic amines-benzidine, 128–129 pediatric populations: aromatic hydrazines, 4: 127 glucuronosyltransferase enzymes, 6: 551–553 acyl-S-CoA formation, 4: 140–144 sulfotransferase enzymes, 6: 554 acyl-adenylates, 4: 144 pharmacokinetics, 2: 253–256 S-acyl-coA thioesters, 4: 142–144 precision-cut tissue slices, induction studies, 3: future research issues, 4: 144–145 478–481 glucuronidation, 4: 108–121 sulfotransferase, 2: 283–286 acyl glucuronidation, 4: 109–118 transporter mechanisms, hepatic drug metabolism, benoxaprofen, 4: 115–117 6: 220 diclofenac, 4: 117–118 in vitro toxicity studies: arylhydroxamic acids, 4: 118–121 gastrointestinal tract, 4: 225–232 2-acetylaminofluorene, 4: 119–121 glucuronidation and sulfation, 4: 230–231 glutathione conjugation, 4: 129–140 xenobiotics, hepatocyte assessment, 3: 394–396 INDEX 771

Phase III drug metabolism: constitutive androstane receptor translocation, 1: conjugation mechanisms, 6: 205–206 212–213 failures, translational drug discovery, 2: 738–741 peptide and protein therapeutics, 2: 905 hepatic drug metabolism, 6: 312 Phthalazine, AO/XOR-mediated reactions, 1: Phenacetin, electrochemical liquid chromatography 317–320 mass spectrometry, reactive intermediates, 5: pH values: 319–320 dissolution, 3: 511–512 Phenelzine, herb-drug interactions, 6: 288 distribution mechanisms, 2: 109–112 Phenobarbital (PB): elimination alterations, 2: 143, 146 drug-drug interactions, 6: 486–487 drug metabolism, 2: 248–256 microsomal epoxide hydrolase, 1: 400–402 luminal content analysis, 2: 68–71 Phenothiazines: lysosomal drug distribution, 2: 510–513 ABC transport modulation, 2: 172–173 solubility and dissolution assessment, oral in vitro toxicity screening, reactive metabolites, 4: absorption, adjustments to, 3: 538 241–243 Physiologically-based pharmacokinetic modeling Phenprocoumarin, monoclonal antibody enantiomer (PBPK): specificity, 3: 453–454 applications, 2: 664–672 Phenytoin: disease states and patient factors, 2: 667–670 bioactivation, 4: 83 drug-drug interactions, 2: 670–672 CYP2C9 metabolism, 6: 464–465 pharmacological activity/toxicity predictions, 2: drug-drug interactions, 6: 487–488 664–667 enantiotopic oxidation to chiral metabolite, 4: tissue exposure predictions, 2: 664 357–358 basic principles, 2: 639–647 hepatotoxicity studies, 4: 183–185 blood flow rates and tissue volumes, 2: microsomal epoxide hydrolase, 1: 400–402 640–641 pH levels: enzyme/transporter biochemistry, 2: 646–647 chromatographic quality control, 5: 527 plasma protein binding, 2: 641–642 in vitro studies, incubation conditions, 1: 76–77 tissue partition coefficient, 2: 642–645 3-Phosphoadenosine 5-phosphosulfate (PAPS): biomarkers, drug discovery and development, 5: phase II metabolism: 582–583 enzyme-catalyzed xenobiotic conjugation, 4: blood-brain barrier, in silico studies, 3: 577 121–126 clinical dose predictions, 2: 591–592 sulfotransferases, 2: 283–286, 6: 210–213 distribution mechanisms: sulfotransferases: tissue distribution prediction models, 2: drug-drug interactions, 1: 546–547 142–143 enzyme kinetics, 1: 541 in vivo studies, 2: 138 origins, 1: 529–530 drug-drug interactions, 6: 127–128 phase II metabolism, 2: 283–286 research design and methodology, 6: 566–570 structure and function, 1: 531, 533 flow-limited model, 2: 648 sulfation, 1: 536–537 future research issues, 2: 672–673 assays, 1: 537–538 hepatic drug metabolism: Phospholilpase C, pharmacodynamics mechanisms, CYP inhibition, 3: 370–371 2: 690–691 in vivo human pharmacokinetics, 3: 357–358 Phospholipidosis: membrane-limited model, 2: 647–648 toxicity assays, 2: 775–776 Monte Carlo simulation, 6: 585 toxicogenomics studies, 4: 271–272 organ perfusion and clearance, 2: 570–574 Phospholipids: kidney, 2: 656–659 DNA binding, 2: 515 liver, 2: 650–652 sample preparation, quality control, liquid small intestine, 2: 653–656 chromatograph-mass spectrometry, 5: whole-body model, 2: 659–664 519–520 sequential metabolism and metabolite Phosphor imaging, whole-body autoradiography and, behavior, 2: 660 5: 366–370 transporter-enzyme interactions, 2: 660–664 Phosphorus, cytochrome P450 catalytic cycle, pediatric populations, 6: 554–562 heteroatom oxidations, 1: 193–194 hepatic blood flow, 6: 555–556 13Phosphorus, nuclear magnetic resonance, passive liver size relative to body weight, 6: 559 nuclei, 5: 338 milligram microsomal protein per gram liver, Phosphorylation: 6: 559 772 INDEX

Physiologically-based pharmacokinetic modeling citrus juices, 4: 496–499 (PBPK) (Continued) cruciferous vegetables, 4: 494–496 protein binding, 6: 554–556 future research issues, 4: 533 uptake and efflux drug transporters, 6: 559–562 herb-drug interactions: a posteriori variability estimation, 6: 594–598 content variability, 4: 502–503 predictive studies, 2: 496 DSHEA guidelines and dietary supplements, apriori variability prediction, 6: 583–585 4: 499–500 research background, 2: 637–639, 6: 580–582 enteric CYP3A/ABC content/activity, 4: sequential metabolism model, 2: 649 500–501 whole-body model, 2: 660 pharmacogenetics, 4: 501 in silico studies, 3: 264–268 prediction and interpretation uncertainty, 4: sources of variability, 6: 585–594 500–503 Physiological parameters of drug metabolism: synergistic mechanisms, 4: 501–502 age-dependent patterns, 4: 452–454 plant-animal “warfare,” metabolic defense distribution mechanisms, 2: 113–125 mechanisms, 4: 487–488 blood flow, 2: 117 plant secondary metabolites: capillary permeability, 2: 121–122 CYP polymorphisms, 4: 492–494 drug distribution barriers, 2: 122–125 dietary modulation, 4: 490–492 synthesis vs. human metabolism, 4: 488–494 blood-brain barrier, 2: 124–125 research background, 4: 485–487 mammary gland, 2: 123–124 in vitro studies, advantages and limitations, 4: maternal:fetal barrier, 2: 123 503–504 drug distribution patterns, 2: 116–117 in vivo animal methods, advantages and perfusion and diffusion, 2: 120–121 limitations, 4: 504 plasma protein binding, 2: 118–119 in vivo human studies, advantages and red blood cell partitioning, 2: 119–120 limitations, 4: 504–505 tissue storage, 2: 122 p-I hypothesis. See Pharmacological interaction (p-i) extrahepatic metabolism, 2: 350–354 hypothesis hepatic drug metabolism, 6: 317–320 Pilot studies, drug discovery and development, oral absorption, basic principles, 2: 81–83 exploratory toxicology, 2: 770–777 pediatric populations, 6: 554–562 Pioglitazone: hepatic blood flow, 6: 555–556 cytochrome P450 polymorphisms, CYP2C8, 1: liver size relative to body weight, 6: 559 253–254 milligram microsomal protein per gram liver, metabolite identification, 3: 146–150 6: 559 reactive metabolite formation, 6: 394–395 protein binding, 6: 554–556 Piperine, dietary supplement-drug interaction, 4: uptake and efflux drug transporters, 6: 559–562 522–524 in pregnancy, 2: 934–937 π-bond substrates, cytochrome P450 catalytic cycle, Phytochemical modulators: 1: 193–194 drug conjugation, 6: 226–227 Placental drug metabolism: drug metabolism: drug-metabolizing enzymes, 2: 947–951 adulterants and contamination, 4: 505–506 whole-body autoradiography, 5: 377 dietary supplements, drug interaction, 4: Plant alkaloids, oral chemotherapeutic agents, 6: 520 506–532 Plant-animal warfare. See Animal-plant warfare black cohosh, 4: 506–507 hypothesis Echinacea spp., 4: 507–510 Plant secondary metabolites (PSMs): garlic, 4: 510–513 CYP polymorphisms, 4: 492–494 ginkgo biloba, 4: 513–516 dietary supplement-drug interaction: ginseng, 4: 516–518 Ginkgo biloba, 4: 513–516 goldenseal, 4: 518–520 methylenedioxyphenyl compounds, 4: 518–526 kava kava, 4: 521–522 Schisandra spp., 4: 524–526 methylenedioxyphenyl compounds, 4: drug metabolism, research background, 4: 518–526 485–487 milk thistle, 4: 526–528 food-drug interactions, 4: 494–499 piperine/black pepper, 4: 522–525 citrus juices, 4: 496–499 Schisandra spp., 4: 524–526 cruciferous vegetables, 4: 494–496 St. John’s wort, 4: 529–532 herb-drug interactions: food-drug interactions, 4: 494–499 pharmacogenetics, 4: 501 INDEX 773

phytochemical content variability, 4: 502–503 radiometry vs. LC-MS/MS, 5: 664–665 phytochemical synergy, 4: 501–502 research background, 5: 657–660 phytochemical modulators: solid-phase microextraction, 5: 669 CYP polymorphisms, 4: 492–494 spectroscopic methods, 5: 668 dietary modulation, 4: 490–492 surface plasmon resonance biosensors, 5: 668 kava kava, 4: 521–522 ultracentrifugation, 5: 664 synthesis vs. human metabolism, 4: 488–494 ultrafiltration, 5: 661 plant-animal “warfare,” 4: 487–488 undeterminable protein binding, 5: 670–671 in vitro studies, 4: 503–504 in vitro study comparisons, 5: 662 Plasma amine oxidase, classification, 1: 371–373 early drug development, clinical pharmacology, 3: Plasma analysis: 104–105 absorption kinetics, plasma concentration-time estimation techniques, 2: 536–546 data, 2: 608–618 equilibrium dialysis, 2: 537–540 ADME studies, noncompartmental analysis, 2: high performance affinity chromatography, 2: 602–603 543–544 distribution analysis, plasma concentration-time microdialysis, 2: 544–545 data, 2: 618–622 ultracentrifugation, 2: 542–543 elimination kinetics, plasma concentration-time ultrafiltration, 2: 540–542 data, 2: 626–633 future research issues, 2: 546 compartmental analysis, 2: 626–629 hepatic drug metabolism, metabolic stability, 3: nonlinear elimination, 2: 629–633 354–355 mass balance studies, animal studies, 2: 422 pediatric drug metabolism, 6: 538–539, 554–558 drug concentration vs. time profile, 2: 435–438 pharmacokinetic modeling, 6: 589 metabolite identification, 3: 130 physiologically-based pharmacokinetic modeling, peptide and protein therapeutics, half-life increase, 2: 641–642 2: 901–904 research background, 2: 531–536 xenobiotic metabolism, hepatocyte assessment, Plasminogen activator inhibitor-1 (PAI-1), induction studies, 3: 417–419 idiosyncratic drug-induced reactions, hemostasis Plasma-assisted desorption ionization (PADI), basic and hypoxia, 4: 603–604 principles, 5: 93–98 Platinum compounds, inductively coupled plasma Plasma metabolites: mass spectrometry, 5: 298–303 anticonvulsants, drug-drug interactions, 6: DNA-binding mechanism, 5: 298 478–479, 481–482 interaction studies, 5: 299 hepatic drug metabolism: liquid chromatography integration, 5: 299–301 elderly patients, 6: 318–319 sample preparation and stability analysis, 5: 299 liver disease, 6: 321–322 total platinum measurements, 5: 302 MIST analysis guidelines, 4: 209–210 Pleiotrophic molecules, cancer therapy, 3: 24 nonradioactive metabolite quantitation, 4: Pneumatically assisted electrospray, defined, 5: 210–212 49–50 pediatric drug metabolism, 6: 538–539 PO/IV studies, in vivo pharmacokinetics, 5: 11–12 Plasma pooling techniques: Polar solute molecules: nonradioactive metabolite quanitation, 4: 210–212 drug metabolism, 2: 248–256 pharmacokinetics and toxicokinetics, 2: 596 phase I metabolism, monoamine oxidase, 2: Plasma protein binding: 270–271 ADME studies, 2: 10–11 Polar surface area (PSA): assays, 2: 31–32 ADME studies, pharmacokinetics, 3: 73–80 drug-drug interactions, 2: 18–19 drug discovery and development, 2: 750 in vitro studies, 3: 59 ADME studies, 3: 49 distribution mechanisms, 2: 118–119 Polyamine oxidases, classification, 1: 375 regulatory issues, 2: 760–761 Polyaromatic hydrocarbons (PAHs): in vitro studies, 2: 129, 132–133 bioactivation, 4: 82–83 drug discovery and development: aldo-ketoreductases, 4: 86 basic techniques, 5: 660–661 biotransformation, enzyme induction, 6: 16 capillary electrophoresis, 5: 666–667 cytochrome P450 enzymes, epoxidation, 4: 28, chromatographic techniques, 5: 665–666 30–34 emerging technologies, 5: 665–666 Polyclonal antibodies: equilibrium dialysis, 5: 661, 663–664 human drug metabolism and, 3: 462 oral drug development, 3: 10, 16–17 immunoassays, selection criteria, 5: 398–399 774 INDEX

Polycyclic aromatic benzylic alcohols, sulfonation, drug-protein binding, 2: 535–536 4: 122–123 Poor metabolizers (PMs): Polyethyleneglycol (PEG), peptide and protein cytochrome P450 enzymes, ethnic differences in therapeutics, half-life increase, 2: 901–904 expression, 6: 76–77 Polymerase chain reaction (PCR), DNA microarrays, dietary plant secondary metabolites, CYP 3: 318–320 polymorphisms, 4: 492–494 Polymeric pseudostationary phases, micellar drug-drug interactions: electrokinetic chromatography, 5: 427–429 CYP inhibition, 6: 100 Polymorphic distribution, cytochrome P450 therapeutic efficacy, CYP-mediated effects, 4: enzymes, 1: 166–167 441 Polymorphic regulators, cytochrome P450 genes, time- and dose-dependent CYP induction, 4: transcriptional regulation, 1: 226 438–439 Polymorphonuclear leukocytes, idiosyncratic drug metabolism, 1: 29 drug-induced reactions, 4: 604–605 phase I metabolism, codeine active metabolites, 6: Polymorphs, defined, 3: 510 358 Polypeptide tethering, peptide and protein psychotropic drugs: therapeutics, 2: 907 CYP2C19 metabolism, 6: 464 Polypharmacy. See also Drug-drug interactions CYP2D6 metabolism, 6: 462–463 antiepileptic drugs: Population-based pharmacokinetic modeling: brivaracetam, 6: 492–493 a posteriori variability estimation, 6: 594–598 carbamazepine, 6: 477–478 apriori and a posteriori modeling, 6: 582–583 clobazam, 6: 478, 480, 482–483 apriori variability prediction, 6: 583–585 clonazepam, 6: 483 research background, 6: 581–582 enzyme induction, 6: 476–477, 481–482 sources of variability, 6: 585–594 enzyme inhibition, 6: 477 Positive food effect, oral absorption, bioavailability eslicarbazepine acetate, 6: 483 studies, 2: 473–475 ethosuximide, 6: 484 Positron emission tomography (PET): felbamate, 6: 484 blood-brain barrier penetration, in vivo studies, 3: future research issues, 6: 494 570–572 gabapentin, 6: 484 distribution mechanisms, in vivo studies, 2: 138 ganaxolone, 6: 493 microdose studies, 5: 618–620 hepatic isoenzymes, 6: 475–476 blood-brain barrier tracing, 5: 619 lacosamide, 6: 485 targeted cancer therapy, 5: 619–620 lamotrigine, 6: 485 Postapproval studies, whole-body autoradiography, levetiracetam, 6: 485–486 5: 383 oral contraceptives and, 6: 480 Postextraction spike, bioanalysis guidelines, 5: oxcarbazepine, 6: 486 484–486 pharmacodynamics and pharmacokinetics, 6: Post-marketing studies, cancer therapies, toxicity 475 studies, 3: 30–31 phenobarbital, 6: 486–487 Post-source decay, biomolecules, MALDI-MS phenytoin, 6: 487–488 characterization, 5: 136 plasma concentrations, 6: 478–479 Posttranscriptional regulation, inflammation, 4: pregabalin, 6: 488 650–651 primidone, 6: 488–489 Posttranslational modification (PTM): research background, 6: 473–475 peptide and protein therapeutics, half-life rufinamide, 6: 489 extension, 2: 905–907 seletracetam, 6: 493 proteomics, 4: 312 stiripentol, 6: 489–490 two-dimensional electrophoresis, protein talampanel, 6: 493 detection, 4: 317 tiagabine, 6: 490 Potassium channel blockers, ADME studies, 2: 878 tonabersat, 6: 493 Potency studies: topiramate, 6: 490–491 chemical inhibitors, 3: 460–462 valproic acid, 6: 491–492 herb-drug interactions, 2: 808 valrocemide, 6: 494 pharmacodynamics, 2: 695 vigabatrin, 6: 492 pharmacokinetics, 3: 76–80 zonisamide, 6: 492 Powder dissolution, solubility and dissolution biotransformation and, 6: 6 assessment, oral absorption: drug-drug interaction incidence and, 6: 152–153 measurement protocols, 3: 526–528 INDEX 775

schematic, 3: 522–523 solubility and dissolution assessment, oral Prasugrel: absorption, candidate profiling, 3: 541–542 ADME studies, 2: 873–874 toxicogenomics: cytochrome P450 enzymes, bioactivation, 4: 25 drug discovery and development, 4: 253–254 phase I metabolism, 6: 365–367 gene expression profiling, 4: 252–253 thiol metabolite methylation, 1: 13 hepatic drug metabolism, 4: 266–270 Pravastatin, physiologically-based pharmacokinetic PXR, CAR, and AhR expression, 4: 266–270 modeling, 2: 572–574 overview, 4: 251–252 Precipitation: toxicity mechanisms, 4: 260–266 quality controls, research background, 5: 516–518 cholestasis and hepatotoxicity, 4: 262–264 solubility and dissolution assessment, oral hepatomegaly and hepatocellular absorption, formulation and inhibition of, 3: hypertrophy, 4: 261–262 540–541 oxidative stress and reactive metabolite Precision cut intestinal slices (PCIS), in vitro formation, 4: 264–266 toxicity screening, 4: 233–236 toxicity predictions, 4: 254–260 Precision cut tissue slices (PCTS). See also Tissue carcinogenicity, 4: 257–258, 260 slices hepatotoxicity, 4: 256–257 blood-brain barrier penetration, in vitro studies, in vitro toxicity screening and prediction, 4: tissue binding, 3: 573–752 270–272 drug-metabolizing enzyme induction: translational drug research, human PK-PD animal studies, 3: 472–475, 478–480 evaluation, 2: 778–779 clinical and toxicological perspectives, 3: UGT isoforms, 1: 497–499 469–470 in vivo animal studies, 1: 50–51 in vivo studies: cryopreservation, 3: 481–485 central nervous system penetration, 3: 600–602 extrahepatic slices, 3: 476–478, 481 clearance/elimination, 3: 611 future research issues, 3: 485–486 Precolumn electrochemical cells, electrochemical human studies, 3: 475–476, 480–481 liquid chromatography mass spectrometry, 5: phase I systems, 3: 471–478 316–318 phase II systems, 3: 478–481 reactive intermediates, 5: 319–320 preparation and culture protocols, 3: 470–471 Precursor-dependent indirect response model, research background, 3: 467–469 pharmacodynamics, 2: 727–729 in vitro studies: Precursor ion scanning: biotransformation pathway predictions, 6: high resolution mass spectrometry vs., 5: 43–45 186–187 ion mobility mass spectrometry-mass spectrometry toxicity screening, 4: 235 integration, 5: 275–276 Preclinical studies: metabolite identification, 3: 62–63, 136–146 blood-brain barrier penetration: quadrupole devices, 5: 157 retroanalysis, Pfizer clinical candidates, 3: triple quadrupole/tandem mass spectrometry, 5: 578–579 28–29 in vivo studies, 3: 566–567 Predictive studies: cancer therapy, ADR event prediction, 3: 37–38 ADME studies, human pharmacokinetics, 2: drug discovery, 1: 15 26–28 drug-drug interactions, 6: 153 adverse drug reactions: mass balance studies, animal studies: covalent binding studies, 4: 176–179 case study, 2: 435–438 defined, 4: 160–161 experimental design, 2: 418–430 biotransformation pathways: biliary excretion, 2: 427–428 future research issues, 6: 198–199 blood and plasma matrices, 2: 422 research background, 6: 177–180 carcass and carbon dioxide exhalation, 2: in silico tools, 6: 180–182 428–430 in vitro tools, 6: 182–188 dose, administration route, and formulation, expressed enzyme systems, 6: 187–188 2: 420–421 hepatocytes, 6: 185–186 excreta and cage wash, 2: 422–425 intestinal homogenates, 6: 188 matrix selection, 2: 421–430 liver slices, 6: 186–187 species selection, 2: 418–420 research background, 6: 182 tissues and organs, 2: 425–427 tissue-specific microsomes, 6: 182–185 OMICS technology, 2: 780–781 in vivo animal studies, 6: 188–194 776 INDEX

Predictive studies (Continued) total metabolism, 3: 355 radiolabeled compounds, 6: 190–194 in vivo pharmacokinetics, 3: 355–358 species selection, 6: 188–189 idiosyncratic drug reactions, 4: 582–583 unlabeled compounds, 6: 189–190 pharmacokinetics: in vivo human studies, 6: 194–198 allometric scaling, 2: 496–509 first-in-human studies, 6: 194–195 cell models, 2: 509–521 microtracer and accelerator mass clinical dose, 2: 588–592 spectrometry studies, 6: 196–198 future research issues, 2: 522–523 radiolabeled studies, 6: 195–196 research background, 2: 495–496 clearance mechanisms, glucuronidation, 6: physiologically-based pharmacokinetic modeling: 262–264 tissue exposure predictions, 2: 664 drug distribution, pharmacokinetic modeling, 6: toxicity predictions, 2: 664–667 589–590 in silico studies, metabolic rates, 3: 254–257 drug-drug interactions: toxicity studies: clinically significant interactions, 6: 152–153 clinical dose, 2: 588–592 clinical mechanisms for, 6: 153–155 reactive metabolite trapping and covalent CYP induction, 6: 113–115 binding, 6: 391–393 CYP inhibition, victim drug-specific toxicogenomics, 4: 254–260 quantitative magnitude predictions, 6: carcinogenicity, 4: 257–258, 260 98–100 hepatotoxicity, 4: 256–257 drug-metabolizing enzyme involvement, 6: Prednisone/prednisolone, herb-drug interactions, 155–156 St. John’s wort, 6: 283 genetic polymorphism and pharmacogenetics, 6: Pregabalin, drug-drug interactions, 6: 488 169–170 Pregnancy: high-throughput screening, 6: 165–168 biotransformation during, 6: 34 CYP450, 6: 166–167 cardiovascular drug metabolism and, 2: 934–937 limitations, 6: 168 clinical implications of drug therapy in, 2: 951 in silico assessment, 6: 168 drug metabolism research background, 2: UGTs, 6: 167 933–934 pharmacokinetics-based reactions, 6: 156–165 drug-metabolizing enzymes and, 2: 945–951 combined analysis, 6: 163–165 cytochrome P450s, 2: 945–951 conjugative drug-metabolizing enzymes, 6: in fetus, 2: 948, 951 161 GST, 2: 947–951 cytochrome P450s: in mother, 2: 945–947 competitive/noncompetitive inhibition, 6: in placenta, 2: 947–949 156–158 sulfotransferases, 2: 947–951 induction, 6: 158–160 UGTs, 2: 947–951 OATP transporters, 6: 163–164 hepatic drug metabolism, 2: 935–937, 6: 319–320 P-glycoprotein inhibition and induction, 6: intestinal drug metabolism and, 2: 935–937 162–163 physiological changes and drug disposition, 2: transporters, orally administered drugs, 6: 934–937 161–162 physiologically-based pharmacokinetic modeling, preclinical assessment, 6: 153 2: 667–670 research background, 6: 151–152 renal drug metabolism and, 2: 935–937 hepatic drug metabolism, cytochrome P450 transporter function in, 2: 938–945 enzymes: in fetus, 2: 943–945 induction, 3: 371–379 in human placenta, 2: 938–943 FαN-4 cells, 3: 377–378 Pregnane X receptor (PXR): HepaRG cells, 3: 376–377 ABC transporter transcriptional regulation, 2: 174 human hepatocytes, 3: 375–376 ADME studies, CYP induction, 2: 30–31 reporter gene assay, 3: 372, 374–375 biotransformation: in vivo studies, 3: 378–379 efflux transporters, 6: 7 inhibition, 3: 359–371 enzyme induction, 6: 15–16 reversible inhibition, 3: 359–365 cytochrome P450 enzymes: time-dependent inhibition, 3: 365–367 CYPB26, 1: 251 in vivo inhibition, 3: 367–371 transcriptional gene regulation, 1: 206–211 metabolic stability, 3: 353–355 receptor cross talk: research background, 3: 351–352 CYP1A1/2, 1: 216 INDEX 777

CYP2B6, 1: 217 Principal component analysis (PCA): CYP2C8, 1: 218 electrochemical array with mass spectrometry, CYP2C9, 1: 219 metabolomics, 5: 325–326 CYP3A4, 1: 220–221 imaging mass spectrometry, 5: 231 species-related differences, 1: 222–224 metabonomics, 4: 287–288 dietary supplement-drug interaction: Probe equipment, nuclear magnetic resonance, 5: Ginkgo biloba, 4: 514–516 344–345 St. Johns wort, 4: 530–532 Probenecid, cardiovascular metabolism, 2: 871 drug conjugation and transport, 6: 225–226 Probe substrates, drug-drug interactions: drug-drug interactions: clinical studies with, 6: 118–120 CYP-mediated toxicity induction, 4: 444 multiple enzyme studies, 6: 164–165 cytochrome P450 induction, 6: 160 Procainamide: enzyme induction, 1: 63–65 ADME studies, 2: 875 NME-precipitated CYP induction, 6: 109–111 lupus-like syndrome, 4: 579–580, 6: 417 drug metabolism, 1: 30–31 thrombocytopenia reaction, 6: 422 drug-metabolizing enzymes, species differences, Prochirality, metabolite stereoselectivity, 4: 1: 121–123, 125–126 353–354 hepatic drug metabolism: Prodrugs: CYP induction, 3: 372–378 carrier-linked prodrugs, phase I metabolism, 6: pregnancy, 6: 319–320 354, 360–363 herb-drug interactions, transporter-based capecitabine, 6: 363 absorption mechanisms, 2: 810–811 fosprofol, 6: 361 knockin/knockout mouse model, 3: 659 oseltmavir, 6: 362 knockout mouse model, 3: 658–659 valacyclovir, 6: 362–363 plant secondary metabolites, human studies, 4: cytochrome P450 bioactivation, 4: 23–25 491–492 discovery and development, 3: 18–20 in silico studies, 3: 263–264 oral absorption mechanisms, 2: 89 drug discovery and development, 3: 270–274 oral chemotherapeutic agents, 6: sulfotransferases, induction, 1: 544–545 508–520 toxicogenomics: pharmacological activity, 1: 19 cholestasis and hepatotoxicity, 4: 263–264 reductive bioactivation, antitumor compounds, 4: hepatic drug metabolism analysis, 4: 266–270 91–94 pharmacokinetic parameters, 4: 251–252 Product ion scan: UGT isoforms: ion mobility mass spectrometry-mass spectrometry UGT1A1, 1: 472 integration, 5: 276 UGT2A1, 2, and 3, 1: 487 metabolite identification, 3: 62, 136–146 xenobiotic metabolism, hepatocyte assessment, Product stereoselectivity, drug metabolism, 4: induction, 3: 410–419 352–362 Pregnenolone-16α-carbonitrile (PCN): Progress curve analysis, drug-drug interactions, CYP carboxylesterases, species-specific reactions, 1: mechanism-based inhibition, 6: 103–105 448 Proguanil, hepatic drug metabolism, pregnancy, 6: drug-drug interactions, CYP-mediated toxicity 319–320 induction, 4: 444 Promoter regulation, microsomal epoxide hydrolase, Preincubation-dilution, drug-drug interactions, 1: 405–406 enzyme inhibition, 1: 62–63 Prontosil, development of, 6: 360 Prelog’s rule, ketone reduction to secondary alcohol, Proof of activity experiments, clinical trials, drug 4: 354–355 development, 1: 16 Prey proteins, protein microarrays, 3: 316–317 Proof of concept (POC) studies: Primary amines, flavin-containing monooxygenase clinical trials, drug development, 1: 16 metabolism, 1: 297–298 early drug development: Primary cell lines: decision-making studies, 3: 105–109 solute carrier proteins, in vitro studies, 2: 216–217 regulatory issues, 3: 91 xenobiotic metabolism, hepatocyte assessment: metabonomic analysis, 4: 292–293 hepatobiliary transport, 3: 422–428 translational drug discovery, 2: 738–741 hepatotoxicity assays, 3: 430–432 Propafenone: Primary effect, pharmacodynamics, mathematical ADME studies, 2: 876 modeling, 2: 703–704 drug-drug interactions, therapeutic efficacy, Primidone, drug-drug interactions, 6: 488–489 CYP-mediated effects, 4: 440–441 778 INDEX

Propofol: toxicogenomics: pediatric drug metabolism, 6: 552–553 carcinogenicity prediction, 4: 258–260 phase I metabolism, 6: 361 hepatomegaly and hepatocellular hypertrophy, Proportionality constant, ion mobility mass 4: 261–262 spectrometry, 5: 34–35 Protein-protein interactions, uridine diphosphate Propoxyphene, cytochrome P450 bioactivation, (UDP)-glucuronosyltransferases, 1: 469–470 active metabolites, 4: 21–23 Protein quantification, proteomics analysis, label-free Propranolol: protein quantification, 4: 329–331 ADME studies, 3: 12–13 Protein structure: allometric scaling pharmacokinetics, 2: 503, 505 imaging mass spectrometry, 5: 226–228 cardiovascular metabolism, 2: 877 LC-MS vs. immunoassay analysis, 5: 402–404 hepatotoxicity prevention strategies, 4: 179–181 microdose studies, accelerator mass spectrometry, Proprietary clinical candidates, blood-brain barrier 5: 614 penetration, retroanalysis, Pfizer clinical reactive metabolite bioactivation, 5: 630–645 candidates case studies, 3: 582–583 adduct detection, 5: 637–638 Propylthiouracil, autoimmune reaction to, 4: amino acid adducts, 5: 635–637 578–579 GSH thiol derivatives, 5: 631–635 Prostaglandin E1 (PGE1), pediatric phase I nonbiologic agent trapping, 5: 642–643 metabolism, 6: 550 selenium ADME and toxicity studies, 2: 923–924 Prostaglandin H synthase (PGHS), bioactivation, 4: in silico studies, 3: 253–268 79–83 sulfotransferases, 1: 531, 533 acetaminophen (APAP), 4: 80–81 Protein therapeutics: aromatic amines, 4: 81–82 catabolic reactions, 2: 901–904 hydantoins, 4: 83 enzyme clearance mechanisms, 2: 897–901 polyaromatic hydrocarbons, 4: 82–83 quantitative whole-body autoradiography Prostate cancer, imaging mass spectrometry, 5: assessment, 5: 378–380 237–240 renal clearance, 2: 897 Protease inhibitors: research background, 2: 895–897 distribution mechanisms, in vivo studies, 2: 137 Protein trafficking, carboxylesterases, 1: 427–428 dose calculations, 6: 615 Proteinuria, cancer therapies, toxicity studies, 3: food-drug interactions, grapefruit juice, 6: 295 35–36 phase I metabolism, drug-drug interactions, 6: 368 Proteolysis, peptide and protein therapeutics, 2: Protein binding. See also Plasma protein binding 898–901 drug-drug interactions, in vitro-in vivo Proteomics: correlations, 4: 422 drug discovery and development: estimation techniques, 2: 536–546 bioinformatics, 4: 337 equilibrium dialysis, 2: 537–540 future research issues, 4: 337 hepatic drug metabolism, 6: 312–317 liquid chromatography mass spectrometry-based cirrhosis, 6: 327–328 analysis, 4: 322–336 liver transplant patients, 6: 333 data interpretation, 4: 335 pediatric drug metabolism, 6: 554–555 label-free protein quantification, 4: 325–332 pharmacodynamics mechanisms, 2: 687–692 MRM transition determination, 4: 332–334 pharmacokinetic modeling, 6: 589 peptide selection, 4: 332 in vitro studies, bioanalysis, 5: 8 quantification and data analysis, 4: 334–335 Protein “crash,” proteomics analysis, quantitative applications, 4: 335–336 nano-electrospray ionization mass spectrometry, stable-isotope-labeled protein quantification, 5: 70–71 4: 323–325 Protein identification: targeted analysis techniques, 4: 332–335 MALDI-MS procedures, 5: 127–128 platforms, 4: 312 proteomics analysis: protein microarray, 4: 336–337 label-free protein quantification, 4: 327–331 research background, 4: 311–312 two-dimensional electrophoresis, 4: 316–317, two-dimensional-based protein expression 317–319 analysis, 4: 313–322 Protein microarrays. See also Microarrays electrospray ionization mass spectrometry, 4: ADME studies, lysate array technologies, 3: 318 319–320 cellular signaling, 3: 318 first-dimension isoelectric focusing, 4: 315 functional analysis, 3: 316–317 image analysis, 4: 317 proteomics, 4: 336–337 immunoblotting, 4: 318 INDEX 779

mass spectrometric peptide mass metabolism: fingerprinting, 4: 318–319 CYP1A2, 6: 465–467 protein detection and quantification, 4: CYP2B6, 6: 467–468 316–317 CYP2C9, 6: 464–465 protein identification, 4: 317–318 CYP2C19, 6: 464 sample preparation, 4: 314 CYP2D6, 6: 458, 461–463 second-dimension SDS-PAGE, 4: 315–316 CYP3A4, 6: 467–468 toxicity studies, 4: 322 future research issues, 6: 468 two-dimensional difference gel pathways, table of, 6: 459–460 electrophoresis, 4: 320–321 research background, 6: 457–458 two-dimensional electrophoresis, 4: 313–314 Pteridines, AO/XOR-mediated reactions, 1: 319–320 image analysis, mass spectrometry, 5: 215–218 Pulegone, ring closure to menthofuran, 1: 6–7 nano-electrospray ionization mass spectrometry, 5: Pulled-glass capillaries, nano-electrospray ionization, 70–71 5: 54–56 pharmacodynamics studies, 2: 700–701 Pulmonary system metabolism: Proteosome, biotransformation, enzyme induction, CYP enzymes, 2: 329–331 6: 16 early drug development, pharmacology and Proton-dependent cotransport system, oral toxicity, 3: 95–98 absorption, 2: 92–93 toxicity studies, 2: 356, 366–375 Proton pump inhibitors (PPI): Pulsed q dissociation (PDQ): cytochrome P450 enzymes: nonhybrid analyzers, 5: 186 biotransformational polymorphism, 6: 22–23 quadrupole ion trap mass spectrometry, resonant CYP2C19, 1: 255 excitation, ion activation, 5: 168–169 food-drug interactions, grapefruit juice, 6: 295 Pulse sequences, metabolite identification, NMR herb-drug interactions, St. John’s wort, 6: 286 spectroscopy, 3: 158–162 pediatric drug metabolism, 6: 542 Pure red cell aplasia, drug-induced, 6: 422 drug-drug interactions, 6: 566 Purines, AO/XOR-mediated reactions, 1: 319–322 safety testing, 3: 235–237 Pyrazinone-based antagonists, toxicity studies, Protons, nuclear magnetic resonance: reactive metabolite toxicity elimination and multidimensional analysis, 5: 340–341 minimization, 6: 386–390 passive nuclei, 5: 338 Pyridine substrates, oxidation, AO/XOR-mediated Proximal biomarkers, pharmacodynamics studies, 2: reactions, 1: 315–320 698–699 Pyrimidines, oxidation, AO/XOR-mediated reactions, Pseudo first-order rate constant, CYP time-dependent 1: 315–320 inhibition, hepatic drug metabolism, 3: Pyrrolidines, flavin-containing monooxygenase 365–367 metabolism, 1: 296 Pseudogenes, glutathione transferases, human Pyrrolizidine alkaloids, ADME and toxicity studies, genomics, 1: 563–564 2: 926–927 Pseudopotential well, quadrupole ion trap mass Pyrroloquinolone quinone (PPQ): spectrometry, resonant excitation, ion classification, 1: 367–368 activation, 5: 168–169 plasma amine oxidase, 1: 372–373 Pseudostationary phases, micellar electrokinetic chromatography, 5: 426–432 “Qgut” model of pharmacokinetics, 6: 592 classification, 5: 431–432 QTRAP instrumentation: micellar pseudophases, 5: 426–427 hybrid mass analyzers, 5: 189–192 mixed micelles, 5: 430 metabolite identification, 3: 143–146 organic modifiers, 5: 430–431 Quadrupole ion trap (Q-IT) mass spectrometry: polymeric and nanoparticle phases, 5: 427–430 basic principles, 5: 31–32 Pseudo-two-dimensional nuclear magnetic resonance, future research issues, 5: 172 5: 342–343 ion manipulation, 5: 162–164 Psychogenic stress, idiosyncratic drug-induced linear quadrupole ion traps, 5: 164–166 reactions, 4: 569–570 multiple experiments, extended analysis, 5: 65 Psychostimulants, CYP2D6 metabolism, 6: 463 nonhybrid analyzers, 5: 183–185 Psychotropic drugs. See also specific compounds, origins, 5: 161–162 e.g., Antidepressants research background, 5: 151–153 cytochrome P450 enzymes, dealkylation reaction, simultaneous fraction collection, 5: 69 4: 16–18 tandem mass spectrometry principles, 5: 166–172 lysosomal drug distribution, 2: 512–513 collisional activation, 5: 167 780 INDEX

Quadrupole ion trap (Q-IT) mass spectrometry ADME studies, 2: 765 (Continued) biomarker assays, 5: 587–588 gas-phase reactions, 5: 170–172 application, 5: 587–589 infrared multophoton dissociation, 5: 170 biotransformation pathway predictions, in silico ion activation, 5: 167–170 techniques, 6: 180–182 ion isolation, 5: 166–167 chromatographic assays, regulatory guidelines, 5: nonresonance excitation, 5: 169–170 518 resonance excitation, 5: 167–169 drug-drug interactions: in vivo studies, 5: 12–13 CYP induction, magnitude predictions, 6: Quadrupole mass filter (QMF) analyzer, drug 113–115 metabolism studies, 5: 182–183 CYP inhibition: Quadrupole time-of-flight (Q-TOF) mass NME-specific analysis, 6: 100–101 spectrometry: victim drug-specific magnitude predictions, basic principles, 5: 34 6: 98–100 hybrid instrumentation, 5: 192–195 NME as object drug, 6: 120–121 ion mobility mass spectrometry-mass spectrometry reaction phenotyping, NME metabolism, 6: integration, 5: 276–277 123–124 MALDI-MS techniques, instrumentation, 5: drug metabolism, 1: 34–35 124–125 electrochemical array, complex matrices, 5: 323 metabolite fragmentation, 5: 198–201 high throughput quantitative mass spectrometry: noncovalent interactions, 5: 72 applications, 5: 555–557 reactive metabolite bioactivation, glutathione basic principles, 5: 548, 550 derivatives, 5: 633–635 bioinformatics, 5: 564–565 Qualitative analysis: mass analyzer tuning and selection, 5: 552–555 biomarker assays, 5: 587–589 multicolumn parallel chromatography: mass spectrometry techniques, 5: 75–76 multiple ESI sources, 5: 562–563 nuclear magnetic resonance, 5: 336 single ionization source, 5: 560–562 solubility and dissolution assessment, oral multiplexed systems, 5: 558–559 absorption, 3: 513–515 sample pooling, 5: 551–552 Quality assurance and control: sample preparation, 5: 551–552 bioanalysis guidelines, 5: 471–472 serial higher throughput, 5: 557–558 assay transfers and changes, 5: 501–502 staggered parallel chromatography, 5: 563–564 response calibration, 5: 480–481 staggered parallel dual column reconditioning, sample reanalysis, 5: 494–497 5: 560 chromatographic techniques: imaging mass spectrometry, 5: 229 buffer selection, 5: 527–528 inductively coupled plasma mass spectrometry, 5: performance optimization, 5: 526–527 289–290 pH levels, 5: 527 capillary electrophoresis integration, 5: resolution, 5: 524–526 295–297 selectivity, 5: 526–527 metabolite identification, 3: 164–167 data quality, research background, 5: 516–518 NMR spectroscopy, 3: 166–167 ion-pair reagents, 5: 535 radiometric quanitification, 3: 164–166 proteomics, label-free protein quantification, 4: metabolite interference, 5: 536–537 332 microautoradiography, 5: 384–388 quantitative chromatographic assays, 5: 518 MIST analysis guidelines, plasma availability and metabolite interference, 5: 536–537 pooling strategy, 4: 210–212 sample preparation: nano-ESI spectrometry, 5: 76–77 ion suppression/enhancement, 5: 519–520 nuclear magnetic resonance, 5: 336 micro-solid-phase extraction, 5: 521 drug development, 5: 353 online SPE, 5: 523–524 proteomics: orthogonal approaches, 5: 520–521 multiple reaction monitoring, 4: 334–335 research background, 5: 516–518 proteomics analysis, 4: 329–331 supported liquid extraction, 5: 524 solubility and dissolution assessment, oral turbulent flow chromatography, 5: 521–523 absorption, 3: 513–515 sub-2-μm chromatography, 5: 532 stable-isotope-labeled protein quantification, 4: Quality by Design (QbD) initiative, immunoassays, 323–325 5: 407 Quantitative/qualitative (Quan/Qual) workflow, mass Quantitative analysis: analyzer tuning and selection, 5: 555 INDEX 781

Quantitative structure-activity relationships 4-fluoro-N-methylaniline bioactivation, 4: 69–71 (QSARs): metabolic activation, cytochrome P450 enzymes, ADME studies, 2: 20, 23–24 4: 34–37 biotransformation pathway predictions, in silico Quinone methide, two-electron oxidation, 4: 37–39 techniques, 6: 180–182 Quinone reductase, precision-cut tissue slices, phase in silico prediction studies, metabolic rates, 3: II induction studies, 3: 479–481 254–257 Quinones: in silico studies, drug discovery and development, enzyme-catalyzed reduction reactions, 1: 381–383 3: 269–274 two-electron oxidation, 4: 37 Quantitative structure-metabolism relationship Quinoxaline, AO/XOR-mediated reactions, 1: (QSMR), biotransformation pathway 317–320 predictions, in silico techniques, 6: 180–182 Quantitative whole-body autoradiography (QWBA): Radiation dosimetry predictions, quantitative ADME studies, tissue distribution, 3: 62 whole-body autoradiography and, 5: 381–383 animal studies, 5: 366–383 Radical clock experiments, cytochrome P450 history, strengths and limitations of, 5: 368–370 enzymes: drug discovery and development: aliphatic oxidation, 2: 256–260 ADME studies, 5: 380–381 catalytic cycle, 1: 187–188 melanin binding, 5: 373–375 Radioactivity detector (RAD), drug discovery and postapproval studies, 5: 383 development, hybrid mass spectrometry, 5: radiation dosimetry predictions, 5: 381–383 179–180 therapeutic peptides and proteins, 5: 378–380 Radiofrequency/direct current (RF/DC) ratio. See future research issues, 5: 388–389 also Fundamental radiofrequency mass balance studies: ion trap mass spectrometry, 5: 30–33 animal studies, 2: 418–419, 426–430 single quadrupole mass spectrometry, 5: overview, 2: 416 25–27 phosphor imaging, 5: 366–367 Radioimmunoassays (RIA): tissue distribution studies, 5: 361–364 basic principles, 5: 399 Quasi-equilibrium (QE) model, elimination kinetics, bioanalysis regulations, 5: 505–507 target-mediated drug disposition, 2: 632–633 development of, 5: 397 Quasi-irreversible inactivation, cytochrome P450 Radiolabeled compounds: enzymes, 4: 43–45 ADME studies: Quasi-irreversible inhibition, drug-drug interactions, excreta recovery analysis, 2: 600–602 1: 62–63 metabolite identification, 3: 63–65 Quasi-steady-state (QSS) model, elimination kinetics, biotransformation pathway predictions: target-mediated drug disposition, 2: 632–633 in vivo animal studies, 6: 190–194 Quetiapine, toxicity studies, structure-toxicity in vivo human studies, 6: 195–196 relationships, 6: 384–385 early drug development: QuickQuan software, high throughput quantitative ADME studies, 3: 110 mass spectrometry, mass analyzer tuning and clinical pharmacology, 3: 103–105 selection, 5: 553–555 mass balance studies: Quinazoline substrates, AO/XOR-mediated reactions, animal studies, 2: 420–425 1: 317–320 biliary excretion, 2: 427–428 Quinidine: carcass and carbon dioxide exhalation, 2: ADME studies, 2: 874–875 428–430 drug-drug interactions: case studies, 2: 437–438 cytochrome P450 inhibition, 6: 156–158 excreta and cage wash sample, 2: 421–425 therapeutic efficacy, CYP-mediated effects, 4: low recovery issues, 2: 439–440 440–441 use, selection criteria, and limitations, 2: stereoselective inhibition, 4: 359–361 430–431 Quinine: human studies, dosimetry calculations, 2: stereoselectivity, 4: 350–351 442–446 thrombocytopenia reaction, 6: 422 quantitative whole-body radiography, purity of, 5: Quinoline substrates, AO/XOR-mediated reactions, 370 1: 317–320 tissue distribution studies, whole-body assays, 5: Quinone cofactors, copper-containing amine 363–364 oxidases, 1: 368–369 two-dimensional electrophoresis, proteomics Quinone imines: analysis, 4: 316–317 782 INDEX

Radiometric quantification: Reactive intermediates: metabolite identification, 3: 164–166 electrochemical liquid chromatography mass metabolite structure, 1: 33–34 spectrometry, 5: 318–319 plasma protein binding, drug discovery and metabolite identification, 3: 149–150 development, 5: 664–665 safety testing, 3: 235–237 Raloxifene: Reactive metabolites. See also Chemically reactive glucuronidation, 6: 252–254 metabolites hepatotoxicity prevention, 4: 182–183 ADME studies, intermediate trapping, 2: 28 oral absorption, bioavailability determinants, 2: bioactivation, 4: 48–50 470–480 acyl glucuronides, 3: 201–204 phenolic sulfation, 1: 13 data processing, 5: 647–650 reactive metabolite formation, 6: 393–394 DNA adducts, 5: 639–642 safety testing, 3: 232–237 drug-induced adverse reactions, 5: 627–630 UGT enzyme bioactivation, toxicity prevention, 6: nefazodone case study, 3: 198–200 262 oxidative stress: in vitro toxicity screening, subcellular acyl glucuronide case study, 3: 201–203 fractionation, 4: 233–234 glutathione and thiol status disruption, 3: 185 Randomized crossover study design: irreversible binding to macromolecules, 3: bioequivalence studies, 2: 464–465 186–188 drug-drug interactions, 6: 129–136 lipid peroxidation, ROS generation, 3: 185 Ranitidine: mechanisms and consequences, 3: flavin-containing monooxygenases, 1: 286 183–188 idiosyncratic drug-induced liver injury, 4: mitochondrial dysfunction, 3: 185 610–612 nefazodone case study, 3: 199–200 Rank-order methodology, drug-drug interactions, nefazodone case study, 3: 198–199 NME precipitants, CYP inhibition, 6: redox cycling and ROS generation, 3: 115–120 184–185 Rapid amplification of DNA ends (RACE) technique, toxicity initiation, 3: 179–180 microsomal epoxide hydrolase, 1: 405–406 peptide and protein adduct detection, 5: RapidFire system, high throughput quantitative mass 630–645 spectrometry, 5: 557–558 amino acid-related adducts, 5: 635–637 RAS-RAF-MAPK pathway, cancer therapies, GSH thiol derivatives, 5: 631–635 epidermal growth factor receptor, 3: 33–35 nonbiological agent trapping, 5: 642–645 Rate-limiting steps: semiquantitative determination, 5: 645–647 cytochrome P450 catalytic cycle, 1: 188–190 in vitro studies protocol, 5: 647 oral absorption, solubility and dissolution early research, 4: 3–5 assessment, 3: 495–501 hepatotoxicity prevention, formation minimization, BCS classification, 3: 502–504 4: 165–176 organ clearance mechanisms, 2: 564–568 dual A2A/A1 receptor antagonist optimization, Rat studies: 4: 174–176 cytochrome P450 enzymes: leukotriene receptor agonist optimization, 4: CYP2B enzyme, 1: 133 174 expression and activity, 6: 71–73 SERM optimization, 4: 173–174 multidrug resistance (MDR) 1/2 protein models, taranabant optimization, 4: 172–173 3: 670–671 idiosyncratic adverse drug reactions: sex differences in drug metabolism, hepatic drug drug-induced liver injury, 6: 420–421 metabolism, 1: 105–106 mechanistic hypotheses, 6: 432–433 in vivo studies, oral absorption and bioavailability, risk assessment, 6: 404–405, 433–434 3: 596 skin reactions, 6: 417–419 whole-body autoradiography, melanin binding, 5: idiosyncratic drug-induced reactions, 4: 570–571 372–375 metabolite toxicity, 1: 19–20 Rayleigh limit, electrospray ionization, 5: 49 microdose studies, accelerator mass spectrometry, Reaction phenotyping: 5: 614 drug discovery and development, 1: 59–61 MIST guidelines, 2: 595–596 in vitro studies, 3: 56 phase I metabolism, clopidogrel and prasugrel, 6: drug-drug interactions, NME metabolism, 6: 365–366 123–124 safety testing, 3: 227–237 sulfotransferases, 1: 545–546 toxicity, 1: 19–20 INDEX 783

toxicity studies: molybdenum-containing hydroxylases, 1: daily dose/low systemic exposure, 6: 393–395 310–312 elimination and minimization strategies, 6: sulfotransferase kinetics, 1: 540–541 386–390 in vitro toxicity screening: screening, 6: 379–380 hepatotoxicity, 4: 237–239 trapping, 6: 391–393 reactive metabolite formation, 4: 243 toxicogenomics, mechanisms of, 4: 264–266 xenobiotic metabolism, hepatocyte assessment, in vitro toxicity studies, 4: 240–243 hepatotoxicity assays, 3: 431–432 Reactive oxygen species (ROS): Reduction reactions: bioactivation: AO/XOR-mediated reduction, 1: 324 oxidative stress, 3: 182 chiral reduction of carbon-carbon double bond, 4: redox cycling, 3: 184–185 355–356 biomarkers, drug-induced liver injury, 4: 188–192 dechlorination, 1: 383 drug metabolism, 1: 14 drug metabolism and, 1: 3–14 idiosyncratic drug-induced reactions: enzyme-catalyzed reduction reactions, 1: 381–384 hemostasis and hypoxia, 4: 604 ketone reduction to secondary alcohol, 4: 354–355 inflammatory response, 4: 605 reductive bioactivation, 4: 86, 88–94 tumor necrosis factor-α, 4: 603 antitumor prodrugs, 4: 91–94 mitochondrial superoxide drug reactions, 4: 577 mitomycin C and CB 1954, 4: 92–94 toxicogenomics and, 4: 264–266 tirapazamine, 4: 92 in vitro toxicity screening: NADPH cytochrome P450 reductase, 4: 90–91 hepatotoxicity, 4: 237–239 flutamide, 4: 90–91 mitochondrial membrane permeability, 4: 245 paraquat, 4: 90 oxidative stress, 4: 244–245 NADPH-quinoneoxidoreductase, 4: 88–90 reactive metabolite formation, 4: 243 aristolochic acid, 4: 88–90 Reactivity, MALDI-MS techniques, 5: 125 Reductive enzymes, pediatric phase I metabolism, 6: Rebound model, pharmacodynamics, 2: 727–729 550 Receptor-drug interactions: Reference electrode (RE), electrochemical liquid biotransformation, enzyme induction, 6: 18–19 chromatography mass spectrometry, cytochrome P450 genes, transcriptional regulation, electrochemical flow cells, 5: 314 1: 215–221 Regulatory issues: CYP1A1/2, 1: 216 bioanalysis: CYP2B6, 1: 216–218 assay transfers and changes, 5: 501–502 CYP2C8, 1: 218 carryover, 5: 486 CYP2C9, 1: 218–219 clinical trials, 5: 503–504 CYP3A4, 1: 220–221 contamination, 5: 491–493 drug-drug interactions, cytochrome P450 dilutions, 5: 486–487 induction, 6: 159–160 documentation, 5: 502–503 Receptor tyrosine kinases (RTKs), dried blood spots, 5: 507–508 pharmacodynamics mechanisms, 2: 691–692 future issues, 5: 508 Recombinant expressed enzyme systems, instrument qualification, 5: 503 biotransformation pathway predictions, in vitro large molecules, 5: 504–507 studies, 6: 187–188 matrix effects, 5: 482–484 Recombinant human FMO1 (rFMO1), multiple analyte assays, 5: 497–501 4-fluoro-N-methylaniline bioactivation, 4: drug-drug interactions, 5: 500–501 69–71 metabolites, 5: 498–500 Recombinant proteins, glycosylation, 2: 906 recovery, 5: 484–486 Recovery requirements, bioanalysis guidelines, 5: research background, 5: 469–475 484–486 response calibration, 5: 475–482 Red blood cell partitioning: quality controls, 5: 480–482 distribution mechanisms, 2: 119–120 standards, 5: 479–480 physiologically-based pharmacokinetic modeling, sample reanalysis, 5: 494–497 tissue partition coefficient, 2: 643–645 specificity and selectivity, 5: 490–491 Redox cycling: stability, 5: 487–490 bioactivation and oxidative stress, metabolites and system sustainability and response changes, 5: ROS generation, 3: 184–185 493–494 biomarkers, drug-induced liver injury, 4: 188–192 data quality, research background, 5: 516–518 drug metabolism, 1: 14 dieatry supplements, 2: 796, 807 784 INDEX

Regulatory issues (Continued) micellar electrokinetic chromatography, 5: 424 immunoassays, 5: 407–410 sub-2-μm chromatography, 5: 531–532 microdose studies, 5: 600–602 Resonant ejection, quadrupole ion trap mass new drug development, 3: 91 spectrometry, ion manipulation, 5: 164 quantitative chromatographic assays, 5: 518 Resonant excitation, quadrupole ion trap mass solute carrier transporters, 2: 230–231 spectrometry: stereoselectivity studies, 4: 366 ion activation, 5: 167–169 translational drug research, 2: 757–761 ion manipulation, 5: 164 Relative activity factor (RAF): Resperidone, CYP2D6 metabolism, 6: 463 hepatic drug metabolism, CYP enzymes, total Response calibration, bioanalysis guidelines, 5: metabolism effects, 3: 355 475–482 organ clearance mechanisms, 2: 562–564 multiple analyte assays, 5: 498–500 Relative bioavailability, defined, 2: 457 Restricted access media (RAM), biofluid analysis: Relative induction score (RIS): applications, 5: 454–455 ADME studies, CYP induction, 2: 30–31 research background, 5: 445–447, 452–454 drug-drug interactions, CYP induction, 6: Restricted research methods, microautoradiography, 114–115 5: 384–388 hepatic drug metabolism, CYP induction, 3: Retention factor, micellar electrokinetic 378–380 chromatography: Remote sampling, nano-ESI techniques, 5: 101–102 control and prediction, 5: 425 Renal cysteine conjugate β-lyase-dependent uncharged solutes, 5: 423–424 bioactivation, sevoflurane-induced Retina-specific amine oxidase (RAO), 1: 369–370 nephrotoxicity, 4: 134–136 Retinoic acid drugs, cytochrome P450 Renal metabolism: polymorphisms, CYP2C8, 1: 253–254 age-dependent metabolism, physiological factors, Retinoic acid receptor alpha (RXRα): 4: 453–454 ABC transporter transcriptional regulation, 2: 174 cirrhosis and, 6: 329–330 constitutive androstane receptor transcription, 1: distribution mechanisms: 212–213 elimination alterations, 2: 143, 146 pregnane X receptor transcription, 1: 206–211 molecular size and, 2: 112 Retinoic acid receptor response elements (ROREs), dose calculations based on, 6: 613 cytochrome P450 genes, transcriptional drug-disease-drug interactions, 4: 640–641 regulation, receptor cross talk, CYP2C8, 1: 218 drug transporters, 4: 644 Retinoid X receptor (RXR): elimination pathways, impairment effects, 6: ABC transporter transcriptional regulation, 2: 174 224–225 hepatic drug metabolism, pregnancy, 6: excretion mechanisms, transport proteins, 6: 219, 319–320 221–222 toxicogenomics, hepatic drug metabolism analysis, pediatric drug metabolism, 6: 557–559 4: 266–270 peptide and protein therapeutics, 2: 897 Retroanalysis, Pfizer clinical candidates, blood-brain pharmacokinetic modeling: barrier penetration, 3: 577–583 clearance data, 2: 603–606 central nervous system penetration predictions, 3: excretion mechanisms, 6: 592–593 579–581 physiologically-based pharmacokinetic modeling, physicochemical predictability, in vitro and in vivo 2: 656–659 studies, 3: 581–582 in pregnancy, 2: 937 preclinical and clinical data, 3: 578–579 vectorial transport, 2: 554–558 Reversed-phase liquid chromatography (RPLC): in vivo studies, clearance processes, 3: 608–609 micellar electrokinetic chromatography, 5: 422 Renal transplants, drug-drug interactions, cytochrome quality controls: P450 induction-mediated effects, 4: 439–441 buffer selection, 5: 527–528 Repaglinide: pH levels, 5: 527 organic anion transporter polypeptides and, 2: Reverse mutation assay, exploratory toxicology, 2: 222–223 774 organ metabolism/transport, 2: 560–564 Reversibility, metabolic drug interactions, 1: 21 Reporter gene assay, hepatic drug metabolism, CYP Reversible effect models, pharmacodynamics, 2: induction, 3: 372–378 705–707 Resolution quality: Reversible inhibition: chromatographic techniques, 5: 524–526 biotransformation, azoles, 6: 27–29 temperature elevation and, 5: 533–535 drug-drug interactions, 1: 61–63 INDEX 785

ADME studies: drug-drug interactions: CYP 450 inhibition, 3: 57–58 prescription guidance, 6: 138–139 DMEs, 2: 16–17 steady-state administration studies, 6: 131–136 enzyme kinetics, 1: 88–91 therapeutic efficacy, CYP-mediated effects, 4: hepatic drug metabolism, CYP enzymes, 3: 442 359–365 hepatic drug metabolism, CYP enzyme induction, Rhabdomyolysis: 3: 376–378 biotransformational inhibition, 6: 31 herb-drug interactions, garlic, 6: 287 food-drug interactions, grapefruit juice, 6: 293 pediatric drug metabolism, drug-drug interactions, Rhodium, inductively coupled plasma mass 6: 566 spectrometry, 5: 307–308 phase I metabolism, drug-drug interactions, 6: 368 Ribavirin, activation, 1: 13 RNA molecules, toxicogenomics, 4: 252–253 Rifabutin, in vitro toxicity studies, 4: 229 RNA promoters, microsomal epoxide hydrolase, 1: Rifampicin/Rifampin: 405–406 dietary supplement-drug interaction, black cohosh, RO1 drug candidate, clinical programs, 1: 348 4: 506–507 Room temperature ionic liquid matrices (RTILs), dose calculations, 6: 616 basic principles, 5: 133–134 drug-drug interactions: Rosiglitazone: clearance-dependent CYP induction, 4: cytochrome P450 polymorphisms, CYP2C8, 1: 436–437 253–254 route-dependent CYP induction, 4: 433–434 drug-drug interactions, clearance-dependent CYP therapeutic efficacy, CYP-mediated effects, 4: induction, 4: 436–437 440–442 N-demethylation, 1: 10 time- and dose-dependent CYP induction, 4: reactive metabolite formation, 6: 394–395 438–439 Rotating-frame Overhauser enhancement enzyme induction, 1: 63 spectroscopy (ROESY), multidimensional glucuronidation induction, 6: 268 analysis, 5: 340–341 phase I metabolism, clopidogrel and prasugrel, 6: Route-dependent CYP induction, drug-drug 366 interactions, 4: 433–434 Ring-closing metathesis (RCM), peptide and protein Rowland-Main equation, drug-drug interactions, therapeutics, 2: 904 in vitro-in vivo correlation, 4: 414–425 Ring transformations, cytochrome P450 enzymes: Rufinamide, drug-drug interactions, 6: 489 bioactivation, 4: 28–32 Rules-based techniques, biotransformation pathway catalytic cycle, 1: 195–196 predictions, in silico procedures, 6: 180–182 Risk assessment: Ruthenium compounds, inductively coupled plasma covalent binding data, hepatotoxicity prevention mass spectrometry, 5: 304–306 strategies, 4: 179–185 anticonvulsants, 4: 183–185 S-9 fraction: buspirone, 4: 181–182 biotransformation pathway predictions, in vitro paroxetine, 4: 182 studies, tissue-specific, 6: 182–185 propranolol, 4: 179–181 drug metabolism, 1: 23 raloxifene, 4: 182–183 in vitro models, 1: 46–47 sudoxicam, 4: 183 enzyme kinetics, 3: 293 drug-drug interactions: S-acyl-coA thioesters, phase-II-enzyme-catalyzed CYP induction, 6: 112–113 xenobiotic conjugation, 4: 141–144 CYP inhibition, 6: 93–101 Safety testing. See also Metabolites in Safety Testing quantitative magnitude predictions, 6: accelerator mass spectrometry-based human 98–101 ADME studies, 4: 216 surrogate selection, 6: 97–98 ADME development modifications, 4: 208–210 in vitro studies, 6: 93–97 biotransformation, drug development and, 6: drug development framework, 6: 92–93 37–39 early clinical development strategies for, 6: biotransformation pathway predictions, research 122–123 background, 6: 179–180 inducers as tool for, 6: 126–127 drug discovery and development, 2: 594–596 NME pharmacokinetics, 6: 124–125 drug-drug interactions, 4: 424 research background, 6: 89–90 ADME studies, 2: 19–20 Ritonavir: drug metabolites: ADME studies, 3: 51–52 future research issues, 3: 237–238 786 INDEX

Safety testing. See also Metabolites in Safety Testing infusion mass spectrometry, 5: 54 (Continued) liquid chromatography mass spectrometry, 5: reactive metabolites, 3: 227–237 52–54 stable metabolites, 3: 222–227 liquid scintillation counting assays, 5: 365–366 elimination pathways, 6: 223–225 MALDI-MS techniques, 5: 125–126 FDA/ICH guidelines harmonization, 4: 207–208 metabolite identification, NMR spectroscopy, 3: future research issues, 4: 218 154–156 human carbon-14 ADME study, 4: 215 microdose studies: implementation strategies, 4: 216–218 accelerator mass spectrometry, 5: 609 industrial ADME research and, 4: 206–207 LC-MS/MS, 5: 618 nonradioactive metabolite quantitation, 4: nano-electrospray ionization: 210–215 limited quantities, conservation of, 5: 64 high resolution mass spectrometry methods, 4: live single cells, 5: 78–80 212–215 remote sampling, 5: 101–102 plasma availability and pooling strategy, 4: nuclear magnetic resonance, 5: 345 210–212 quality controls: overview, 4: 205–206 ion suppression/enhancement, 5: 519–520 research background, 3: 221–222 micro-solid-phase extraction, 5: 521 strategic initiatives, 4: 208–210 online SPE, 5: 523–524 translational drug research, regulatory issues, 2: orthogonal approaches, 5: 520–521 758 research background, 5: 516–518 St. John’s wort: supported liquid extraction, 5: 524 dietary supplement-drug interaction, 4: 529–532 turbulent flow chromatography, 5: 521–523 herb-drug interactions, 2: 823–825, 6: 281–286 Sandwich culture: 6: anticancer drugs, 283 MALDI-MS samples, 5: 126 anti-HIV drugs, 6: 283–284 organ clearance mechanisms, 2: 564 cardiovascular drugs, 6: 284–286 in vitro toxicity screening, primary hepatocytes, 4: central nervous system effects, 6: 284 246 fexofenadine, 6: 286 xenobiotic metabolism, hepatocyte assessment, immunosuppressive drugs, 6: 282–283 hepatobiliary transport, 3: 423–428 oral contraceptives, 6: 283 Saquinavir: proton pump inhibitors, 6: 286 drug-drug interactions, therapeutic efficacy, theophylline, 6: 286 CYP-mediated effects, 4: 442 in vivo human studies, 4: 504–505 herb-drug interactions, garlic, 6: 287 Salicylic acid, UGT isoforms, UGT1A6 clearance, 1: Saturated solution, equilibrium solubility, 3: 481 Salts, solubility and dissolution assessment, oral 508–509 absorption: Saw palmetto, herb-drug interactions, 2: 822 dissolution measurements, 3: 525–526 Scalar coupling, nuclear magnetic resonance, 5: multicomponent salt formulation, 3: 535–536 335–336 Sample pooling: Scaling factor, hepatic drug metabolism, in vivo ADME in vivo studies, 3: 61 human pharmacokinetics, 3: 356–358 high throughput quantitative mass spectrometry, Scanning modes, ion mobility mass 5: 551–552 spectrometry-mass spectrometry integration, 5: Sample preparation: 274–276 biofluid analysis, on-line SPE, 5: 447–451 Schisandra spp., dietary supplement-drug high throughput quantitative mass spectrometry: interaction, 4: 524–526 automation and batch processing, 5: 551 Secondary aliphatic amines, flavin-containing basic principles, 5: 548–550 monooxygenase metabolism, 1: 297 sample pooling, 5: 551–552 Second-dimension SDS-PAGE, two-dimensional imaging mass spectrometry: electrophoresis, proteomics analysis, 4: matrix application, 5: 224–226 315–316 matrix selection, 5: 224 Second-generation matrix-assisted laser/desorption preparation protocols, 5: 221–226 ionization mass spectrometry, 5: 131–134 tissue samples, 5: 219–221 carbon nanotubes, 5: 132–133 wash protocols, 5: 221–224 desorption/ionization on silicon, 5: 131–132 inductively coupled plasma mass spectrometry, room temperature ionic liquid matrices, 5: platinum compounds, 5: 299 133–134 INDEX 787

Secretory transporters, distribution mechanisms, Semipreparative electrochemistry, electrochemical 2: 129 liquid chromatography mass spectrometry, 5: Secular frequency, quadrupole ion trap mass 316–317 spectrometry, ion manipulation, 5: 162–164 Semiquantitative determination, reactive metabolite Sedation, biotransformational inhibition, 6: 31 bioactivation, 5: 645–647 Segregated flow modeling, physiologically-based Sensitivity analysis: pharmacokinetic modeling, intestinal modeling, bioanalysis guidelines, response calibration, 5: 2: 653–656 475–482 Seldane. See Terfenadine electrospray ionization, 5: 50–51 Selected ion monitoring (SIM): immunoassays, 5: 404–405 imaging mass spectrometry, 5: 249–250 micellar electrokinetic chromatography, 5: reactive metabolite bioactivation, DNA adducts, 5: 432–434 640–642 microdose studies, LC-MS/MS, 5: 618 single quadrupole mass spectrometry, 5: 26–227 nano-electrospray ionization, 5: 58 Selected reaction monitoring (SRM): in silico studies, drug discovery and development, high throughput quantitative mass spectrometry, 3: 271–274 mass analyzer tuning and selection, 5: Sequential mass spectrometry, carbohydrate 552–555 characterization, 5: 74–75 laser-based ionization methods, 5: 566–567 Sequential metabolism pharmacokinetics, 2: 649 liquid chromatography mass spectrometry, whole body physiologically-based 2: simultaneous fraction collection, 5: 68–69 pharmacokinetic modeling, 660 Serine-threonine kinase (mTOR) inhibitors: nano-electrospray ionization: oral chemotherapeutic agents, 6: 523 dynamic range, 5: 61–63 toxicity studies, 3: 30 ion current stability, 5: 59–60 Serotonin norepinephrine reuptake inhibitor (SNRIs), QTRAP instrumentation, 5: 191–192 cytochrome P450 enzymes, dealkylation stable-isotope-labeled protein quantification, 4: reactions, 4: 15–18 324–325 Serotonin syndrome, herb-drug interactions, St. tandem mass spectrometry, 5: 548 John’s wort, 6: 284 triple quadrupole/tandem mass spectrometry, 5: Serotonin transporters, pregnancy drug metabolism, 160–161 2: 943 Selective estrogen receptor modulator (SERM), Sertraline: hepatotoxicity: CYP2C19 metabolism, 6: 464 covalent binding and, 4: 168 CYP2D6 metabolism, 6: 462 optimization strategies, 4: 173–174 Serum protein fusion, peptide and protein raloxifene, 4: 182–183 therapeutics, 2: 904–905 Selective norepinephrine reuptake inhibitors Sevoflurane, nephrotoxicity, 4: 134–136 (SNRIs), oral chemotherapeutic agents, 6: 524 Sex differences in drug metabolism: Selective serotonin reuptake inhibitors (SSRIs): biotransformation: CYP2D6 metabolism, 6: 461–462 patient factors, 6: 33–34 herb-drug interactions, St. John’s wort, 6: 284 polymorphisms, 6: 22–25 monoamine oxidase bioactivation, 4: 71–74 pregnancy, 6: 34 oral chemotherapeutic agents, 6: 524 conjugation, transport and elimination Selectivity guidelines: mechanisms, 6: 230–231 bioanalysis techniques, 5: 490–491 extrahepatic drug-metabolizing enzymes, 2: 344, chromatographic quality control, 5: 526–527 350 resolution quality, research background, 5: hepatic drug metabolism, 1: 102–112 516–518 future research issues, 1: 112 Selenium, ADME and toxicity studies, 2: 923–925 gonadal hormones, 1: 107–108 Seletracetam, drug-drug interactions, 6: 493 growth hormone, 1: 108–110 Self-emulsifying drug delivery systems (SEDDS), HNFα, 1: 112 solubility and dissolution assessment, oral hormonal determinants, cytochrome P450s, 1: absorption, 3: 539–540 107–110 Self-medication, biotransformation and drug human cytochrome P450s, 1: 106–107 interaction and, 6: 6 molecular determinants, 1: 110–112 Semicarbazide-sensitive amine oxidase (SSAO), 1: rat cytochrome P450s, 1: 105–106 370–371 STAT5b tyrosine phosphorylation, 1: 110–111 bioactivation, 4: 74–75 research overview, 1: 101–102 788 INDEX

SGX523 drug candidate, clinical programs, 1: CYP1A subfamily, 1: 242–243, 247 348–349 CYP2A subfamily, 1: 249–250 Shake flask techniques, equilibrium solubility, CYP2B6, 1: 252 solubility and dissolution assessment, 3: CYP2C9, 6: 464–465 521–522 CYP2D6, 1: 256–258 Short-chain fatty acids, amino acid conjugation, CYP2D subfamily, species differences in drug mitochondrial medium chain acyl-CoA metabolism, 1: 135–137 synthetases, 1: 598–602 CYP2E, 1: 260–261 Sigmoidal autoactivation, translational drug research, glutathione transferase superfamily: 2: 754 alpha class GSTs: Sigmoidal kinetics, 1: 81–83 GSTA2, 1: 569 mechanisms, 3: 300–301 GSTA3, 1: 569 Signal 1 and 2 mechanisms, idiosyncratic adverse mu class GSTs, 1: 570–571 drug reactions, danger hypothesis, 6: 425–426 omega class, 1: 574–575 Signal averaging, nano-electrospray ionization, 5: 64 pi class GSTs, 1: 571–572 Signaling pathways, cancer therapies, toxicity theta class GSTs, 1: 572–573 studies, 3: 32–35 zeta class polymorphisms, 1: 573–574 epidermal growth factor, 3: 32–35 OMICS technology, PK-PD assessment, 2: vascular endothelial growth factor, 3: 35 780–781 Signal recognition particle (SRP), aflatoxin oral chemotherapeutic agents, 6: 502 production and toxicity, 2: 920 pediatric drug metabolism, flavin-containing Signal-to-noise ratio (SNR), nuclear magnetic monooxygenases, 6: 548–549 resonance limitations, 5: 337 pharmacogenetics, 4: 378 Signature profiles, pharmacodynamics, biophase/link ABC transporters, 4: 390–393 models, 2: 708–712 soluble epoxide hydrolase, 1: 410 Silica nanoparticles: sulfotransferases, 1: 543–544 hybrid silica particles, 5: 528–529 UGT enzymes, clinical significance, 6: 266 micellar electrokinetic chromatography, 5: Single oral dose (SD), early drug development, 428–429 clinical pharmacology, 3: 101–105 Silymarin compounds, dietary supplement-drug Single quadrupole mass spectrometry, basic interaction, 4: 526–528 principles, 5: 25–27 Simcyp simulation tool, ADME studies, 2: 763 Single reaction monitoring (SRM), triple Simple/sigmoid Emax models, pharmacodynamics, 2: quadrupole/tandem mass spectrometry, 5: 707 28–29 Simulated gastric fluid (SGF), solubility and Single rising dose (SRD) studies, in vivo dissolution assessment, oral absorption, 3: pharmacokinetics, 5: 11–12 515–516 Single-target signal transduction inhibitors: Single ascending dose (SAD): development of, 3: 28 assay transfers and changes, 5: 501–502 toxicity studies, 3: 35–36 MIST analysis guidelines, 4: 209–210 Sink conditions, oral absorption, solubility and plasma availability and pooling strategy, 4: dissolution assessment, 3: 496–501 210–212 Sirolimus: pharmacodynamics, mathematical modeling, 2: hepatic drug metabolism, liver transplant, 6: 337 703–704 pediatric drug metabolism, 6: 543 Single cell analyses, monoclonal antibodies, Site-directed mutagenesis: microsomal drug metabolism, 3: 454–455 drug metabolism, 2: 256 Single compound pharmacokinetics, in silico studies, phase I metabolism, carboxylesterases, 2: 274 3: 264–266 protein glycosyation, 2: 906–907 Single-dimensional separation, ion mobility mass Skin reactions: spectrometry-mass spectrometry integration, 5: covalent drug-protein adducts, 4: 164–165 270–271 CYP enzymes, 2: 333–334 Single-electron transfer (SET), phase I metabolism: HLA genetic markers for, 4: 190–192 cytochrome P450 oxidation, 2: 261–264 idiosyncratic adverse drug reactions (IADRs), 6: monoamine oxidase, 2: 269–271 417–419 Single nucleotide polymorphisms (SNPs): drug reaction with eosinophilia and system ABC transporters, basic properties, 2: 174–176 symptoms, 6: 419 carboxylesterases, 1: 440–446 hypersensitivity reactions, 6: 419 cytochrome P450 enzymes: maculopapular rash, 6: 419 INDEX 789

Stevens-Johnson syndrome, 6: 419 Soft ionization techniques: toxic epidermal necrolysis, 6: 419 liquid chromatography mass spectrometry, 5: 25 urticaria, 6: 418–419 metabolite identification, 3: 138–146 nevirapine-induced reaction, 4: 580–581 safety testing, reactive metabolites, 3: 228–237 Small bore columns, inductively coupled plasma Soft reactions, reactive metabolites: mass spectrometry-liquid chromatography ADME studies, 2: 28 integration, 5: 293 idiosyncratic adverse drug reactions, 6: 434 Small interfering RNA (siRNA): irreversible binding to cellular macromolecules, 3: ADME studies, DNA microarrays, 3: 322–324 186–188 solute carrier transporters, in vitro studies, 2: 217 Solid-liquid separation, solubility and dissolution xenobiotic metabolism, hepatocyte assessment, assessment, oral absorption, 3: 516–517 hepatobiliary transport, 3: 425–428 Solid-phase extraction (SPE): Small intestinal transit time (SITT): biofluid analysis: dissolution, 3: 511–512 miniaturized SPE cartridges, 5: 451–452 solubility and dissolution assessment, oral on-line SPE, 5: 447–451 absorption: research background, 5: 445–447 excipient effects, 3: 544 restricted access media, 5: 454–455 rate-limiting steps, 3: 498–501 high throughput quantitative mass spectrometry: Small intestinal water volume (SIWV), solubility sample pooling, 5: 552 and dissolution assessment, oral absorption, serial LC-MS/MS, 5: 557–558 rate-limiting steps, 3: 496–501 HPLC-NMR and, 5: 343 Small intestine. See also Intestinal drug metabolism hydrophilic interaction chromatography, 5: anatomy and function, 2: 49–51 530–531 surface area, 2: 60–64 quality controls: Small molecules: research background, 5: 516–518 bioanalysis: sample preparation: electrochemical array with mass spectrometry, ion suppression/enhancement, 5: 519–520 metabolomics, 5: 323–326 micro-solid-phase extraction, 5: 521 MALDI-MS characterization, 5: 140 on-line SPE, 5: 523–524 nano-ESI spectrometry, 5: 76–77 orthogonality, 5: 520–521 transporters: Solid-phase microextraction (SPME), plasma protein ABC transporters, 2: 161–166 binding, drug discovery and development, 5: substrate binding specificity, 2: 161–165 669 biopharmaceuticals and, 2: 896 Solids: drug metabolism, 2: 248–256 defined, 3: 510 Small molecule tyrosine kinase inhibitors, oral MALDI-MS techniques, 5: 126 chemotherapeutic agents, 6: 520–523 solubility and dissolution assessment, oral Smoking: absorption, 3: 517–518 CYP1A2 induction, 6: 465 high energy solids, 3: 534–535 drug-metabolizing enzymes, toxicity studies, 2: multicomponent solid solutions and dispersions, 374–375 3: 537 SN-38 irinotecan metabolite: Solubility: CYP2B6 inhibition, 6: 31 ADME studies: UGT biotransformation, 6: 11 optimization, 2: 7–10 Snapshot pharmacokinetics, in vivo studies, 5: 11 in silico studies, 3: 66–69 Sodium dodecylsulfate micelles, micellar in vitro studies, 2: 24 electrokinetic chromatography, 5: 425 drug discovery and development, 2: 749 pseudophases, 5: 426–427 oral drugs, 3: 8–9, 15–16 Sodium-taurocholate cotransporting polypeptide MALDI-MS techniques, 5: 125 (NTCP): oral absorption, 2: 83–84 drug-drug interactions, inhibition, 2: 224–225 bioavailability determinants, 2: 472 in humans, 2: 205 Biopharmaceutical Classification System, 3: in liver, 2: 210–211 501–504 nomenclature and structure, 2: 201 drug discovery and development, 3: 505–507 nuclear receptor mediation, 2: 227–228 Biopharmaceutical Drug Disposition pediatric drug metabolism, 6: 560–562 Classification System, 3: 504–505 vectorial transport, 2: 552–558 drug discovery and development, 3: 505–507 Soft drugs, phase I metabolism, 6: 356–357 definitions, 3: 508–512 790 INDEX

Solubility (Continued) ionizable solutes, 5: 424 dissolution, 3: 511–512 uncharged solutes, 5: 422–424 solids, 3: 510 solubility and dissolution assessment, oral solubility, 3: 508–510 absorption, 3: 517–518 dissolution measurement, 3: 522–530 Solute carrier (SLC) family. See also Organic anion intrinsic dissolution, 3: 528–530 transporter polypeptides (OATPs); Organic powder dissolution, 3: 526–528 cation transporter (OCT) drug discovery and development, 3: 8–9 in blood-brain barrier, 2: 212–213 excipient effects on drug disposition, 3: cardiovascular drug metabolism, 2: 543–544 864–865 formulation strategy, impact on, 3: 540–541 clinical perspectives, 2: 220–221 decision trees, 3: 531–532 dietary supplement-drug interaction: high energy solids, 3: 534–535 black cohosh, 4: 507 multicomponent solids, 3: 535–537 Echinacea spp., 4: 509–510 cocrystals, 3: 536 garlic, 4: 512–513 cyclodextrins, 3: 536–537 milk thistle, 4: 527–528 hydrates, 3: 536 distribution mechanisms, 2: 125–126, 129–131, salts, 3: 535–536 202–208 solid solutions and dispersions, 3: 537 drug-drug interactions, orally administered drug precipitation formulation, 3: 540–541 absorption or elimination, 6: 161–162 4: solution formulations, 3: 537–540 drug metabolism, 641–645 drug-metabolizing enzymes and, 2: 221–225 cosolvents, 3: 538 future research issues, 2: 231–232 cyclodextrins, 3: 538–539 genetic polymorphisms, 2: 228–230 lipids, 3: 539–540 herb-drug interactions, 4: 501 micelles, 3: 539 human distribution, substrates and inhibitors, 2: pH adjustment, 3: 538 203–205 surface area modification, 3: 532–534 inhibition studies, 2: 223 future research issues, 3: 544–545 in kidney, 2: 210–211, 213–214 measurement techniques, 3: 513–518 in liver, 2: 210–211 assay components, 3: 513–514 nomenclature and structure, 2: 198–201 compound distribution, 3: 514–515 nuclear receptor mediation, 2: 226–228 compound/solvent mixing, 3: 516 oral absorption: 3: solid-liquid separation, 516–517 drug-drug interactions, 6: 161–162 solute-solid analysis, 3: 517 mechanisms of, 2: 92–93 solvent distribution and selection, 3: 515 organ functions, 2: 208–214 preclinical formulations, candidate profiling, 3: pathophysiology, 2: 202–208 541–542 plant secondary metabolites, 4: 489–494 rate-limiting-steps, 3: 495–501 pregnancy drug metabolism and, 2: 941–945 research background, 3: 493–495 regulatory guidelines for, 2: 230–231 schematic, 3: 508 research background, 2: 195–198 solubility assays, 3: 518–522 SLC22 superfamily, 2: 206–208 equilibrium solubility protocols, 3: 521–522 intestinal distribution, 2: 209–210 intrinsic solubility protocols, 3: 522 SLCO superfamily, 2: 202–205 kinetic solubility protocols, 3: 518–521 subfamilies, 2: 197 physiologically-based pharmacokinetic modeling, vectorial transport, 2: 550–558 whole body model, 2: 660–664 in vitro models, 2: 215–217 Soluble epoxide hydrolase (sEH), 1: 407–412 in vivo models, 2: 217–220 biological functions, 1: 408–410 Solution formulation, solubility and dissolution expression regulation, 1: 411 assessment, oral absorption, 3: 537–538 genetically modified animal models, 3: 642–644 Solvates, defined, 3: 510 genetic polymorphisms, 1: 410 Solvent effects: phase I metabolism, 2: 274–276 enzyme kinetics, 3: 298 summary/pharmacological implications, 1: solubility and dissolution assessment, oral 411–412 absorption, 3: 515–516 Soluble target assays, basic principles, 5: 406 cosolvents, 3: 538 Solute analysis: Solvent protonation, metabolite identification, NMR micellar electrokinetic chromatography: spectroscopy, 3: 154–156 INDEX 791

Sorafenib: Speed of analysis, ion mobility mass oral chemotherapeutic agents, 6: 522 spectrometry-mass spectrometry integration, 5: toxicity studies, 3: 36 270–271 preclinical ADR event prediction, 3: 37–38 Sphingolipids, MALDI-MS analysis, 5: 130 Space of Disse: Spike recovery, immunoassays, 5: 407 cirrhosis and, 6: 326–327 Splice variants, cytochrome P450 genes, liver anatomy, 6: 310–312 transcriptional regulation, 1: 224–226 Spare receptors, pharmacodynamics, 2: 694 Spray-based ionization techniques. See also Sparteine, cytochrome P450 enzyme expression and, Electrospray ionization mass spectrometry 6: 67 (ESI-MS) Spatial resolution: overview, 5: 90–93 imaging mass spectrometry, 5: 226 summary, 5: 104–105 ion mobility mass spectrometry-mass spectrometry Src kinase inhibitors, flavin-containing integration, 5: 277–280 monooxygenases, drug candidate selection, 1: Species differences in drug metabolism: 284–285 biotransformation pathway predictions, in vivo Stability guidelines, bioanalysis research, 5: animal studies, 6: 188–194 487–490 carboxylesterases, 1: 446–447 Stable-isotope labeling: conjugation, transport, and elimination, 6: bioavailability estimations, 2: 460–462 227–230 inductively coupled plasma mass spectrometry, cytochrome P450 enzymes, 1: 127–141 platinum compounds, 5: 298–303 CYP1A, 1: 128–129 metabolite identification, 3: 152–515 CYP1B, 1: 129 microdose studies, drug discovery and development, 5: 606–610 CYP2A, 1: 129–131 nuclear magnetic resonance, drug development, 5: CYP2B, 1: 131–133 352–353 CYP2C, 1: 133–135 proteomics analysis, 4: 323–325 CYP2D, 1: 135–137 sample preparation quality control, 5: 520 CYP2E, 1: 137–138 Stably transfected cell lines, solute carrier proteins, CYP3A, 1: 137, 139–141 in vitro studies, 2: 215–216 dog enzymes, 6: 73–74 Staggered parallel dual columns: drug discovery and development, 6: 61–76 chromatographic applications, 5: 562–564 human enzymes, 6: 61–69 high throughput quantitative mass spectrometry, monkey enzymes, 6: 74–76 column reconditioning, 5: 560–561 mouse enzymes, 6: 69–71 ™ StarDrop , biotransformation pathway prediction, 6: overview, 1: 127–128 180–182 rat enzymes, 6: 71–73 STAR nomenclature, pharmacogenetics, 4: 380 transcriptional regulation, 1: 222–224 STAT5b gene, sex-dependent hepatic drug cytosolic glutathione transferases, classification, 1: metabolism, 1: 110–112 562–563 Static prediction model, CYP enzyme inhibition, drug discovery and development, 2: 593–594 hepatic drug metabolism, 3: 367–370 flavin-containing monooxygenases, 1: 146–147 Statin therapy. See also specific compounds future research issues, 1: 148 ADME studies, 2: 866–870 glucuronosyltransferases, 1: 141–143 CYP enzyme interactions, 2: 866–869 induction mechanisms, 1: 123, 125–126, 129–130 transporter effects, 2: 869–870 mass balance studies, 2: 418–420 distribution alterations, 2: 146–147 molybdenum-containing hydroxylases, 1: drug-drug interaction, gemfibrozil, 2: 336–338, 340–344 870–871 overview, 1: 121–124 food-drug interactions, grapefruit juice, 6: 293 sulfotransferases, 1: 143–146 hepatic drug metabolism, in vivo human Specificity guidelines, bioanalysis techniques, 5: pharmacokinetics, 3: 357–358 490–491 herb-drug interactions, St. John’s wort, 6: 285 Spectral counting, label-free protein quantification, organic anion transporter polypeptides and, 2: proteomics analysis, 4: 325–332 222–223 Spectrometer components, nuclear magnetic physiologically-based pharmacokinetic modeling, resonance, 5: 344 2: 572–574 Spectroscopic analysis, cytochrome P450 enzymes, UGT isoforms, UGT1A3, 1: 477 1: 168–169 vectorial transport, 2: 552–558 792 INDEX

Statistical methods: UGT isoform regulation, UGT2B4, 1: 488 ADME studies, in silico studies, 2: 23–24, 3: Steroid X receptor (SXR), drug-drug interactions, 65–69 enzyme induction, 1: 63–65 bioequivalence studies, 2: 465–466 Stevens-Johnson syndrome, idiosyncratic adverse drug-drug interaction studies, 6: 133–136 drug reactions, 6: 419 metabonomics analysis, 4: 287–288 Stiripentol, drug-drug interactions, 6: 489–490 a posteriori population modeling, 6: 595–598 Stokes-Einstein equation, dissolution, 3: 512 proteomics, label-free protein quantification, 4: Stomach, anatomy and function, 2: 48–49 331–332 Stop-flow analysis, metabolite identification, Steady state parameters: LC-NMR data, 3: 162–164 allometric scaling pharmacokinetics, volume of Stored Waveform Inverse Fourier Transform distribution, 2: 503, 505–508 (SWIFT), quadrupole ion trap mass distribution mechanisms, 2: 5 spectrometry, ion isolation, 5: 166–167 drug-drug interactions, 6: 131–136 Stringent selection criteria, drug discovery and pharmacokinetic/toxicokinetic profiles, volume of development, 3: 44–47 distribution, 2: 587 Structure-activity relationships (SARs): Stereochemistry: ADME studies, 2: 5 metabolite structure, 1: 34 in silico studies, 3: 66–69 nuclear magnetic resonance, 5: 354 anticancer drugs, cardiotoxicity screening, 3: 28 Stereoisomers, chiral columns, 5: 529–530 nuclear magnetic resonance and, 5: 332–333 Stereoselectivity: safety testing, stable metabolites, 3: 226–227 drug development and regulation, 4: 366 in silico prediction studies, 3: 254–257 drug metabolism, 4: 351–362 xenobiotic metabolism, hepatocyte assessment, chiral inversion, 4: 358–359 metabolite identification, 3: 404–405 drug-metabolizing enzyme inhibition, 4: Structure-toxicity relationships, human drug 359–361 metabolism, 6: 380–386 enantiomer-second drug interactions, 4: 361 Sub-2-μm chromatography, evolution of, 5: 531–532 enantioselective pharmacokinetics, 4: 361–362 Subcellular localization: metabolites, 4: 353–358 drug metabolism, 1: 23 chiral reduction, carbon-carbon double bond, in vitro models, 1: 46–47 4: 355–356 hepatoxicity prevention, 4: 167–172 enantiotopic moiety to chiral metabolite microdose studies, accelerator mass spectrometry, oxidation, 4: 357–358 5: 614 ketone reduction, secondary alcohol in vitro model, toxicity screening, 4: 233–235 formation, 4: 354–355 in vivo model: sulfide to chiral sulfoxide oxidation, 4: basic principles, 1: 46–47 356–357 drug metabolism, 1: 23 tertiary amine to N-oxide oxidation, 4: 357 drug-metabolizing enzymes, 1: 52–56 methyltransferases, 2: 293 Suberoylanilide hydroxamic acid (SAHA), oral substrates, 4: 352–353 chemotherapeutic agents, 6: 523 UGT enzymes, 2: 280–281 Suboxicam, hepatotoxicity risk assessment, 4: 183 oxidation, AO/XOR-mediated reactions, 1: Subset compounds, high throughput quantitative 317–320 mass spectrometry, 5: 552 research background, 4: 345–351 Substrate depletion method, xenobiotic metabolism, toxicity studies, 4: 362–366 hepatocyte assessment, in vitro studies, detoxification pathways, 4: 365 metabolic stability, 3: 396–402 enantiomer pharmacology, 4: 363–364 Substrate reactions: metabolic activation, adverse effects, 4: ABC protein transport, 2: 161–165 365–366 carboxylesterases, 1: 432–434 Sterile inflammation: cytochrome P450 catalytic cycle, 1: 184–186 drug-disease-drug interactions: drug-drug interactions: CYP1 subfamily, 4: 630–631 CYP inhibition, 6: 97–101 CYP3 subfamily, 4: 636 inhibition mechanisms, 4: 407–413 CYP4 subfamily, 4: 637 probe substrate selection, clinical studies, 6: drug transporters, 4: 643 118–120 Steroid synthesis: enzyme kinetics, 1: 84–86 liver transplantation, 6: 334–335 depletion methods, 3: 297–298 microsomal epoxide hydrolase, 1: 396–397 inhibition, 3: 302–304 INDEX 793

microsomal epoxide hydrolase, 1: 397–402 in vitro toxicity studies, 4: 230–231 mitochondrial acyl-coA:glycine N-acyltransferase, Sulfide, oxidation to chiral sulfoxide, 4: 356–357 1: 603 Sulfonamide, hypersensitivity reaction, 4: 573 mitochondrial medium chain acyl-CoA Sulforaphane, food-drug interactions, cruciferous synthetases: vegetables, 4: 495–496 structure-activity relationships, 1: 600–602 Sulfotransferases/sulfonyltransferases (SULTs): xenobiotics, 1: 599–600 age-dependent drug metabolism, 4: 469–470 phase II metabolism, methyltransferases, 2: bioavailability studies, intestinal metabolism, 2: 292–293 484 stereoselective metabolism, 4: 352–353 biotransformation, 6: 11 sulfotransferases, endogenous substrates, 1: induction and, 6: 17–18 541–542 pathway predictions, in vitro studies, 6: translational research, CYP enzyme inhibition, 2: 185–186 754 polymorphisms, 6: 25 transporters, in silico studies, 3: 262 clinical perspectives: uridine diphosphate drug-drug interactions, 1: 546–548 (UDP)-glucuronosyltransferases: induction, 1: 544–545 specificty, 6: 245–251 polymorphisms, 1: 543–544 UGT1A1, 1: 473–474 reaction phenotyping, 1: 545–546 UGT1A3, 1: 476 drug-disease-drug interactions, 4: 638 UGT1A4, 1: 477–478 extrahepatic metabolism, 2: 338–339 UGT1A6, 1: 479–480 food-drug interactions, cruciferous vegetable UGT1A7, 1: 481–482 induction, 4: 494–496 UGT1A8, 1: 483 future research issues, 1: 548 UGT1A9, 1: 484 genetically modified animal models, 3: 656–657 UGT1A10, 1: 486 human compounds, 1: 529–536 UGT2B4, 1: 487–488 classification and nomenclature, 1: 530–532 UGT2B7, 1: 489–490 fetal development, 1: 535–536 UGT2B10, 1: 492 protein structure and function, 1: 531, 533 UGT2B15, 1: 494 tissue distribution, 1: 533–535 UGT2B17, 1: 495–496 intestinal metabolism, Caco-2/TC7 cell line Succinylcholine, pharmacogenetics, 4: 378 comparisons, 3: 339–340 Sucrase-isomaltase (SI) expression, intestinal pediatric drug metabolism, 6: 554 metabolism models, passage study protocols, 3: pharmacogenetics, 4: 388–389 343 phase II metabolism, 2: 283–286, 6: 210–213 Sulfadiazine, N-acetylation, 1: 12 enzyme-catalyzed xenobiotic conjugation, 4: Sulfamethoxazole, cytochrome P450 bioactivation, 121–126 metabolic activation, 4: 28–29 allylic alcohols, 4: 123–124 Sulfation/sulfonation: arylhydroxylamines and arylhydroxamic biotransformation, inhibition, 6: 30 acids, 4: 124–126 drug-disease-drug interactions, 4: 638 polycyclic aromatic benzylic alcohols, 4: metabolic pathways, 4: 105–108 122–123 phase II metabolism: plant secondary metabolites, 4: 488–494 enzyme-catalyzed xenobiotic conjugation, 4: pregnancy drug metabolism, 2: 947–951 121–126 reactive metabolite bioactivation, adverse drug allylic alcohols, 4: 123–124 reactions, 5: 628–630 arylhydroxylamines and arylhydroxamic species differences in metabolism, 1: 143–146 acids, 4: 124–126 sulfation reaction, 1: 536–543 polycyclic aromatic benzylic alcohols, 4: assays, 1: 537–538 122–123 bioactivation, 1: 542–543 sulfotransferases, 2: 283–286 catalytic mechanism, 1: 536–537 sulfotransferases, 1: 536–543 endogenous substrates, 1: 541–542 assays, 1: 537–538 enzyme kinetics, 1: 536–541 bioactivation, 1: 542–543 Sulfoxides: catalytic mechanism, 1: 536–537 chiral molecules, sulfide oxidation to, 4: 356–357 endogenous substrates, 1: 541–542 flavin-containing monooxygenase metabolism, enzyme kinetics, 1: 536–541 1: 292 tissue distribution, 1: 533–535 reduction reactions, 1: 327–328 794 INDEX

Sulfur, cytochrome P450 catalytic cycle, heteroatom Systemic average inhibitor plasma concentration oxidations, 1: 193–194 ([I]avg), drug-drug interactions, in vitro-in vivo Sulfurylation, drug-disease-drug interactions, 4: 638 correlation, 4: 415–425 Sulindac: idiosyncratic drug-induced liver injury, 4: Tachyphylaxis, pharmacodynamics mechanisms, 2: 606–612 693 phase I metabolism, oxidation, 2: 265–267 Tacrolimus: renal metabolism, 2: 355–356 drug-drug interactions, therapeutic efficacy, Sulindac-sulfide: CYP-mediated effects, 4: 440–441 flavin-containing monooxygenases, 1: 286–287 hepatic metabolism, liver transplantation, 6: reduction, 1: 11 334–336 Sumatriptan, monoamine oxidase bioactivation, 4: herb-drug interactions, St. John’s wort, 6: 71–74 282–283 Sunitinib: pediatric drug metabolism, 6: 552–553 cytochrome P450 enzymes, dealkylation reaction, drug-drug interactions, 6: 565–566 4: 16–18 Tadalafil, toxicity studies, reactive metabolite oral chemotherapeutic agents, 6: 522 formation, 6: 394–395 toxicity studies, 3: 36 Tagging SNPs (tSNPs), ABC transporters, 2: preclinical ADR event prediction, 3: 37–38 174–176 Supercritical fluid chromatography (SFC): Talampanel, drug-drug interactions, 6: 493 chiral columns, 5: 529–530 Tamoxifen: metabolite identification, 3: 131–133 CYP2D6, ADME studies, 2: 844–846 Superoxide dismutase: cytochrome P450 enzymes: biomarkers, drug-induced liver injury, 4: 188–192 active metabolic actions, 4: 20–23 mitochondrial superoxide drug reactions, 4: 577 CYP2D6, 1: 258 Supersaturated solutions, defined, 3: 510 CYP3A4, bioactive metabolites, 4: 11–15 Supported liquid extraction (SLE), sample quality CYP3D6, bioactive metabolites, 4: 12–15 control, 5: 524 flavin-containing monooxygenases, 1: 286–287 Suppression mechanisms, carboxylesterases, 1: 440 oral chemotherapeutic agents, 6: 523–524 Surface area measurements: pharmacogenetics testing, 6: 26 intestinal metabolism, 2: 60–67 phase I metabolism, 6: 359–360 oral absorption, solubility and dissolution sulfonation, 4: 123–124 assessment, 3: 496–501 Tamsulosin, bioequivalence studies, 2: 465–466 solubility and dissolution assessment, oral Tandem-in-space experiments, triple absorption, 3: 525 quadrupole/tandem mass spectrometry, 5: modification, dissolution enhancement and, 3: 158–161 532–533 Tandem-in-time experiments, quadrupole ion trap Surface plasmon resonance (SPR): mass spectrometry, 5: 166–172 immunoassays, 5: 401–402 Tandem mass spectrometry (MS/MS): plasma protein binding, 2: 546 compound tuning, automation, 5: 67 drug discovery and development, 5: 668 drug metabolism studies, 5: 181–205 Surgery procedures, oral chemotherapeutic agents, 6: ion mobility mass spectrometry-mass spectrometry 508 integration, 5: 274–280 Surrogate biomarkers, drug discovery and high mass accuracy and resolution, metabolite development, 5: 579–580 identification, 5: 277–280 Suspension hepatocytes, xenobiotic metabolism, high performance modes, 5: 276–277 hepatocyte assessment: scanning modes, 5: 274–276 cryopreserved suspensions, 3: 397–401 metabolite identification, 2: 767–768 hepatobiliary transport, 3: 422–428 multiple experiments, extended analysis, 5: 64–65 Symbiosys system: nano-electrospray ionization, 5: 58 biofluid analysis, on-line SPE, 5: 448–451 quadrupole ion trap mass spectrometry, 5: on-line SPE, sample quality control, 5: 523–524 166–172 Synthetic drug development: collisional activation, 5: 167 phytochemical modulators, plant secondary gas-phase reactions, 5: 170–172 metabolites, 4: 488–494 infrared multophoton dissociation, 5: 170 stereoselectivity, 4: 351 ion activation, 5: 167–170 SYPRO Ruby protein gel stain, two-dimensional ion isolation, 5: 166–167 electrophoresis, protein detection, 4: 316–317 nonresonance excitation, 5: 169–170 INDEX 795

resonance excitation, 5: 167–169 Terfenadine: qualitative analysis, 5: 75–76 biotransformation, 6: 36 quantitative analysis, 5: 76–77 cytochrome P450 enzymes, bioactive metabolites, research background, 5: 548 4: 13–15 selectivity, 5: 65–66 intestinal metabolism, 2: 354–356 simultaneous fraction collection, 5: 69 safety testing, stable metabolites, 3: 226–227 triple quadrupole/tandem mass spectrometry, 5: Ternary SN2 infinite displacement, sulfotransferase, 158–161 1: 538–539 efficiency parameters, 5: 159 Tertiary aliphatic amines, flavin-containing operating modes, 5: 159–161 monooxygenase metabolism, 1: 296–297 Tangier’s disease, ABC transporter mutations, 2: Testosterone 6β-hydroxylation, species differences in 179–180 drug metabolism, CYP3A enzyme, 1: 140–141 Taranabant, hepatotoxicity: Tetrachlorodibenzo-p-dioxin (TCDD): covalent binding and, 4: 168 drug-drug interactions, time- and dose-dependent optimization strategies, 4: 172–173 CYP induction, 4: 437–439 Tardive dyskinesia, CYP1A2 metabolism, 6: 467 molybdenum-containing hydrolase inducers and Targeted imaging mass spectrometry (TAMSIM), regulators, 1: 342–344 techniques, 5: 232–233 Tetrahydropyridines, monoamine oxidase Targeted therapies: bioactivation, 4: 71–72 cancer therapies: 2,3,5,6-Tetramethylbenzoquinone, enzyme-catalyzed front-loading challenges, 3: 32 reduction reactions, 1: 382–383 molecular targets, 3: 28–29 Tetrazolium salts, xenobiotic metabolism, hepatocyte research background, 3: 24–25 assessment, hepatotoxicity assays, 3: drug discovery and development, 3: 6 429–432 biomarkers, 5: 579–580 TFK analogs, carboxylesterases, 1: 436–438 toxicity studies, 3: 29–30 Thalidomide: Target-mechanism-based model (TMBM), toxicity CYP3A4/5, ADME studies, 2: 846–847 testing, 3: 25–26 oral chemotherapeutic agents, 6: 525 Target-mediated drug disposition: toxicity studies, enantiomer antipode toxicity, 4: microdose studies, cancer targeting, 5: 619–620 363–364 pharmacodynamics, immunoassays, 5: 413–415 Theophylline: Target-mediated drug disposition (TMDD): CYP1A expression, knock-in and antibody targeting and, 2: 911–912 knock-in/knock-out mouse models, 3: elimination kinetics, 2: 629–633 632–633 Tariquidar, ABC transport modulation, 2: 173 drug-drug interactions, probe substrates, 6: Taylor approximation, absorption kinetics, 118–120 Loo-Riegelman (L-R) method, 2: 613–614 hepatic drug metabolism: Taylor cone, electrospray ionization, 5: 49 nutritional status, 6: 319 TC7 cell line, intestinal metabolism, Caco-2 pregnancy, 6: 319–320 comparisons: Theorell-Chance reaction mechanism, phase II cellular model, 3: 338–339 metabolism, UGT enzymes, 2: 279–281 phase I enzymes, 3: 339 Theoretical plate number, resolution quality, phase II enzymes, 3: 339–340 chromatographic techniques, 5: 524–526 transporters, 3: 340–341 Therapeutic efficacy: T-cell receptors: biotransformation, 6: 4–5 halothane hepatotoxicity, 4: 573–574 pharmacogenetics, 6: 20–27 hepatotoxicity studies, 4: 163–165 drug-drug interactions, cytochrome P450 Tegafur, CYP2A6, ADME studies, 2: induction-mediated effects, 4: 439–441 842–843 Therapeutic equivalence evaluations, bioequivalence Telmisartan, ADME studies, 2: 881, 3: 51–52 studies, 2: 463–470 Temozolomide, oral chemotherapeutic agents, 6: Thiazide diuretics, cardiovascular metabolism, 2: 871 508–518 Thiazole rings: Temperature parameters, in vitro studies, incubation cytochrome P450 bioactivation, 4: 31–32 conditions, 1: 76–77 toxicity studies, reactive metabolite toxicity Template effect, flavin-containing monooxygenases, elimination and minimization, 6: 386–390 hydroxylamines, 1: 294–295 Thiazolidinediones (TZDs), Temsirolimus, drug-drug interactions, NME clinical peroxisome-proliferator-activated receptor, pharmacology, 6: 116–120 mouse model, 3: 662–663 796 INDEX

Thin layer chromatography (TLC): Ticlopidine: metabolite identification, 3: 131–133 bioactivation, 4: 84–85 sulfotransferase, sulfation assays, 1: 538 cardiovascular metabolism, 2: 873 Thioamides, flavin-containing monooxygenase cytochrome P450 enzymes, bioactivation, 4: metabolism, 1: 289 24–25 Thiocarbonyl compounds, bioactivation, 4: 65–67 Ticrynafen, hepatotoxicity, 4: 575–576 Thioesters, phase-II-enzyme-catalyzed xenobiotic Time-delayed fragmentation (TDF), QTRAP conjugation, S-acyl-coA thioesters, 4: 141–144 instrumentation, 5: 191 Thioethers, flavin-containing monooxygenases, 1: Time-dependent induction, drug-drug interactions, 290–292 CYP enzymes, 4: 437–439 Thiols: Time-dependent inhibition (TDI): flavin-containing monooxygenases, 1: 289–290 biotransformation pathway predictions, in vitro oxidative stress and disruption of, 3: 185 studies, 6: 184–185 reactive metabolite bioactivation, glutathione cytochrome P450 enzymes, 2: 755 derivatives, 5: 631–635 drug-drug interactions, 3: 58 xenobiotic metabolism, hepatocyte assessment, xenobiotic metabolism, hepatocyte assessment, hepatotoxicity assays, 3: 431–432 3: 406–409 Thiones, flavin-containing monooxygenase drug-drug interactions, 1: 62–63 metabolism, 1: 287–288 hepatic drug metabolism, CYP enzymes, 3: Thiophene compounds, cytochrome P450 365–370 bioactivation, 4: 32–34 metabolic drug interaction, 1: 21 covalent modification, 4: 47–48 metabolite identification, 3: 64–65 Thiopurine-S-methyltransferase (TMPT): safety testing, reactive metabolites, 3: 229–237 ADME studies, 2: 848 in silico studies, 3: 67–69 biotransformation: in vitro toxicity studies, cytochrome P450 reaction history, 6: 21 phenotyping, 4: 240 polymorphisms, 6: 25 Time-dependent transduction, pharmacodynamics, 2: extrahepatic metabolism, 2: 339–340 718–721 pharmacogenetics, 6: 26–27 Time-lag focusing, Q-TOF instrumentation, 5: phase II metabolism, 6: 214–216 193–195 Thioridazine: Time-of-flight mass spectrometry (TOF-MS): CYP1A2 metabolism, 6: 467 ion trap mass spectrometry vs., 5: 30–33 CYP2D6 metabolism, 6: 463 MALDI-MS techniques, mass analyzer cytochrome P450 enzymes, active metabolites, 4: instrumentation, 5: 123–125 20–23 mass analyzer tuning and selection, 5: 555 in vitro toxicity screening, reactive metabolites, 4: metabolite identification, 2: 768 241–243 nonhybrid analyzers, 5: 186–188 Thiotepa (TT), drug-drug interactions, quadrupole time-of-flight mass spectrometry, 5: 34 compartmental analysis, 2: 624–626 selectivity, 5: 65–66 Third-generation compounds, ABC transport Time of maximum concentration (Tmax): modulation, 2: 173 ADME studies, noncompartmental analysis, 2: Third-tier assays, bioanalysis guidelines, 5: 499–500 602–603 Three-compartment models, plasma pharmacokinetics/toxicokinetics profiles, 2: 585 concentration-time data, 2: 626–629 Time-proportional plasma pool, MIST analysis Three-dimensional liver models, in vitro toxicity guidelines, 4: 211–212 screening, 4: 246–247 Tirapazamine: Thrombin, idiosyncratic drug-induced reactions, phase I metabolism, bioreactive prodrug hemostasis and hypoxia, 4: 604 development, 6: 367 Thrombin inhibitors, predictive toxicity studies, 6: reductive bioactivation, 4: 92 391–393 Tirilazad, chiral reduction, carbon-carbon double Thrombocytopenia, drug-induced, 6: 422 bond, 4: 355–356 Thromboxane A2 receptor antagonist, oxidation, 1: Tissue distribution: 10 ADME studies, 3: 61–62 Thymidine phosphorylase, tegafur, ADME studies, research background, 5: 362–364 2: 843 blood-brain barrier penetration, in vitro studies, Thyroid hormones, sulfotransferase, fetal tissue binding, 3: 573–752 development, 1: 535–536 carboxylesterases, 1: 438 Tiagabine, drug-drug interactions, 6: 490 human-animal comparisons, 1: 446 INDEX 797

drug-metabolizing enzymes, 2: 316–343 idiosyncratic adverse drug reactions, danger CYP enzymes, 2: 328–334, 371 hypothesis, 6: 425–426 epoxide hydrolases, 2: 340–341 sterile inflammation, 4: 643 flavin-containing monooxygenases, 2: 340–341 viral infection, 4: 643 monoamine oxidases, 2: 341–342 Tolmetin, conjugation, 1: 12 transferases, 2: 334–340 Tonabersat, drug-drug interactions, 6: 493 mass balance studies: Topiramate, drug-drug interactions, 6: 490–491 animal studies, 2: 425–428 Topoquinone (TPQ) residue: human studies, dosimetry calculations, 2: classification, 1: 368 444–446 plasma amine oxidase, 1: 372–373 metabolite identification, 3: 130 Torcetrapib, metabolic profiling and identification, 2: pharmacokinetic modeling, 6: 588–590 35 tissue composition, 6: 589 Torsades des pointes: volume and blood perfusion, 6: 588–589 biotransformational inhibition, 6: 30–31 physiologically-based pharmacokinetic modeling, hERG binding assay, 2: 775 2: 640–641 translational research and biomarkers, 2: exposure prediction, 2: 664 777–781 rate-limiting step, intrinsic clearance, 2: 564–568 Torsemide, cardiovascular metabolism, 2: 871 storage mechanisms, 2: 122 Total clearance (CLtotal): sulfotransferases, 1: 533–535 ADME studies, recent advances, 2: 761–763 UGT enzymes, 6: 251–252 drug metabolism, 4: 430–433 vectorial transport, 2: 550–558 intrinsic vs. organ clearance, 2: 569–570 in vitro ADME studies, 3: 59 Total drug-related exposure, safety testing, stable metabolites, 3: 224–227 whole-body autoradiographic techniques: Total ion chromatogram (TIC): research background, 5: 361–362 electrochemical liquid chromatography mass tissue retention assessment, 5: 378 spectrometry, 5: 316–317 xenobiotic metabolism, hepatocyte assessment, metabolite identification, 3: 139–146 induction, 3: 410–419 derivatization reactions, mass spectrometry, 5: Tissue microarrays (TMAs), proteomics analysis, 4: 36–38 336–337 high resolution mass spectrometry, 5: 41–45 Tissue partition coefficient, physiologically-based Total radioactivity (TRA) values, ADME studies: pharmacokinetic modeling, 2: 642–645 blood data, 2: 602–603 Tissue slices. See also Precision cut tissue slices excreta analysis, 2: 600–602 (PCTS) research background, 2: 600 drug metabolism, in vitro models, 1: 48–49 Toxic epidermal necrolysis (TEN): imaging mass spectrometry, sample preparation, covalent drug-protein adducts, 4: 164–165 5: 219–221 idiosyncratic adverse drug reactions, 6: 419 liquid extraction surface analysis, 5: 77–78 Toxicity studies: Tissue stretch, imaging mass spectrometry, 5: 233 ADME studies: Titanium, inductively coupled plasma mass metabolite prediction, 2: 14–15 spectrometry, 5: 307 natural toxins: Titanium trichloride, metabolite identification, 3: aflatoxins, 2: 918–920 148–150 α-aminitin, 2: 925–926 Tizanidine, drug-drug interactions, prescription aristolochic acid, 2: 920–922 guidance, 6: 136–137 arsenic, 2: 922–923 Tolcapone, two-electron oxidation, 4: 36–37 germander, 2: 927 Tolerance mechanisms: Ibotenic acid and muscimol, 2: 925–926 idiosyncratic drug-induced reactions, 4: 568–570 pyrrolidizine alkaloids, 2: 926–927 pharmacodynamics, 2: 693 research background, 2: 917–918 mathematical models, 2: 727–729 selenium, 2: 923–925 toxicity testing, 2: 773 allyl alcohol, 4: 75–76 Toll-like receptors (TLRs): aristolochic acid, 4: 88–90 drug-disease-drug interactions: aryl piperazines, 4: 66, 68–69 inflammation, 4: 625–628 bioactivation: regulatory mechanisms, 4: 629 acyl glucuronides, 3: 203–204 drug-induced liver injury, inflammatory response, reactive metabolites, 3: 179–180 4: 601–605 biotransformation, 6: 4–5 798 INDEX

Toxicity studies (Continued) flutamide, reductive bioactivation, 4: 90–91 cancer therapy: human drug metabolism: cardiotoxicity screening, 3: 27–28 covalent binding, 6: 391–393 clinical trials or post marketing studies, 3: future research issues, 6: 396 30–31 medicinal chemistry management, 6: 386–390 cytotoxics, 3: 24 MIST guidelines, 2: 595–596 drug discovery and development, 3: 25–28 prediction studies, 6: 391–393 exploratory and phase 0 trials, 3: 38–39 reactive metabolites: future research issues, 3: 39–40 daily dose/low systemic exposure, 6: hepatic toxicity screening, 3: 27 393–395 immunomodulatory drugs, 3: 31 screening, 6: 379–380 molecular targets, 3: 28–29 trapping, 6: 391–393 adverse event prediction, 3: 37–38 research background, 6: 377–379 multikinase inhibitors, 3: 35–36 structure-toxicity relationships, 6: 380–386 nonclinical studies, 3: 25–26 toxicophore prohibition, drug design, 6: research background, 3: 23–24 390–391 signaling pathways, 3: 32–35 metabolism role in, 4: 3–6 epidermal growth factor, 3: 32–35 metabolites, 1: 19–20 vascular endothelial factor, 3: 35 metabonomics, 4: 293–299 targeted therapies: biomarker identification, 4: 296–299 4: adverse event prediction, 3: 37–38 toxicity mechanisms, 299 toxicity screening, 4: 294–296 biomarkers, 3: 29–30 mitochondrial toxicity, 6: 429–431 molecular challenges, 3: 32 myeloperoxidase bioactivation, 4: 83–85 research background, 3: 24–25 phase-II-enzyme-catalyzed xenobiotic conjugation, cytochrome P450 bioactivation: glucuronidation, 4: 108–121 active metabolites, 4: 21–23 physiologically-based pharmacokinetic modeling, thiazole rings, 4: 31–32 prediction studies, 2: 664–667 determinants, 4: 4 proteomics, two-dimensional electrophoresis diclofenac, 4: 84, 118 applications, 4: 322 drug discovery and development: stereoselectivity, 4: 362–366 area under the curve values, 2: 584–585 detoxification pathways, 4: 365 bioavailability, 2: 588 enantiomer pharmacology, 4: 363–364 2: clearance mechanisms, 585–587 metabolic activation, adverse effects, 4: clinical dose predictions, 2: 588–592 365–366 compartmental analysis, 2: 590–592 thiocarbonyl compounds, 4: 66–67 noncompartmental analysis, 2: 589–590 thiones, flavin-containing monooxygenase exploratory toxicology, 2: 770–777 metabolism, 1: 288 future research issues, 2: 596–597 ticlopidine, 4: 84–85 half-life, 2: 588 tirapazamine, 4: 92 maximum plasma concentration/time of toxicogenomics: maximum concentration, 2: 585 carcinogenicity, 4: 257–260 MIST guidelines, 2: 594–596 hepatotoxicity, 4: 256–257 research background, 2: 583–584 prediction, 4: 254–260 species differences in disposition, 2: 593–594 toxicity mechanisms, 4: 260–266 steady state, 2: 587 cholestasis and hepatotoxicity, 4: 262–264 toxicogenomics and biomarkers, 2: 592–593 hepatomegaly and hepatocellular volume of distribution, 2: 587 hypertrophy, 4: 261–262 drug-drug interactions: oxidative stress and reactive metabolite ADME studies, 2: 19 formation, 4: 264–266 CYP-mediated induction, 4: 442–444 UGT enzyme bioactivation, 6: 254–260 drug-metabolizing enzyme induction, 3: 469–470 toxicity prevention, 6: 261–262 drug substructures, 4: 5 in vitro early drug screening: early drug development, nonclinical studies, 3: covalent binding, 4: 243–244 94–98 CYP inhibition and potential drug-drug extrahepatic metabolism, drug-metabolizing interactions, 4: 238–240 enzymes, 2: 356, 366–375 gastrointestinal tract: felbamate, 4: 76–77 metabolic mechanisms, 4: 232–233 INDEX 799

phase I/II metabolism, 4: 225–232 xenobiotics, 2: 550 precision cut tissue slices, 4: 233–235 Transcriptional gene activation: subcellular fractions, 4: 233 drug-drug interactions, enzyme induction, 1: hepatic metabolism and toxicity, 4: 235–238 63–65 future research models, 4: 246–247 glutathione transferases, alternative splicing, 1: mitochondrial membrane permeability, 4: 245 565 overview, 4: 223–225 microsomal epoxide hydrolase, 1: 405 oxidative stress, 4: 244–245 soluble epoxide hydrolase, 1: 411 primary hepatocytes, sandwich culture, 4: 246 Transcriptional regulation: reactive metabolite formation, 4: 240–243 ABC transporters, 2: 173–174 Toxic molecules, reactive metabolites, 3: 235–237 cytochrome P450 genes: Toxicogenomics: aryl hydrocarbon receptor, 1: 213–215 biomarkers, drug-induced liver injury, 4: 187–192 constitutive androstane receptor, 1: 211–213 DNA microarrays, 3: 324–328 future research issues, 1: 227 drug discovery and development, 2: 592–593 genetic polymorphisms, 1: 226 exploratory toxicology, 2: 773 methodology, 1: 222 preclinical phase: pregnane X receptor, 1: 206–211 drug discovery and development, 4: 253–254 receptor cross talk, 1: 215–221 gene expression profiling, 4: 252–253 CYP1A1/2, 1: 216 hepatic drug metabolism, 4: 266–270 CYP2B6, 1: 216–218 PXR, CAR, and AhR expression, 4: 266–270 CYP2C8, 1: 218 overview, 4: 251–252 CYP2C9, 1: 218–219 toxicity mechanisms, 4: 260–266 CYP3A4, 1: 220–221 cholestasis and hepatotoxicity, 4: 262–264 research background, 1: 205–206 hepatomegaly and hepatocellular species specificity, 1: 222–224 hypertrophy, 4: 261–262 splice variants, 1: 224–226 oxidative stress and reactive metabolite drug conjugation and transport, 6: 225–226 formation, 4: 264–266 inflammation, 4: 649–651 toxicity predictions, 4: 254–260 UGT isoforms: carcinogenicity, 4: 257–258, 260 UGT1A1, 1: 471–472 hepatotoxicity, 4: 256–257 UGT1A3, 1: 475–476 in vitro toxicity screening and prediction, 4: UGT1A4, 1: 477 270–272 UGT1A6, 1: 479 Toxicokinetics (TK): UGT1A7, 1: 481 early drug development, 3: 95–98 UGT1A8, 1: 482–483 in vivo pharmacokinetics, 5: 11–12 UGT1A9, 1: 483–484 Toxicophores: UGT1A10, 1: 485–486 drug design and incorporation of, restrictions, 6: UGT2B4, 1: 487 390–391 UGT2B7, 1: 488–489 idiosyncratic drug reactions, 4: 583 UGT2B10, 1: 492 reactive metabolite toxicity elimination and UGT2B15, 1: 493–494 minimization, 6: 386–390 UGT2B17, 1: 495 safety testing, reactive metabolites, 3: 228–237 Transcription factors: Tracer identification, imaging mass spectrometry, 5: biotransformation, receptor cross talk, 6: 246–248 18–19 Traffic Light Multiparameter Optimization tool, 3: in vivo models, chimeric mouse model, 1: 70–71 54–56 Tramadol: Transducers, pharmacodynamics mechanisms, 2: 687 pediatric drug metabolism, 6: 543–544 Transepithelial electrical resistance (TEER): phase I metabolism, 6: 358–359 intestinal metabolism models: Transacylation: cell line experiments, 3: 341–342 phase-II-enzyme-catalyzed xenobiotic conjugation, passage study protocols, 3: 343–345 acyl glucuronidation, 4: 114–118 oral absorption and, 2: 88 UGT enzyme bioactivation, toxicity studies, 6: Transesterification, carboxylesterases, hydrolytic 255–260 metabolism, 1: 425–426 Transcellular transport: Transferase enzymes. See also specific enzymes, in vivo studies, oral absorption and bioavailability, e.g., Glutathione S-transferasees 3: 594 extrahepatic metabolism, 2: 334–340 800 INDEX

Transgenic mice. See also Genetically modified blood-brain barrier penetration, in vitro studies, 3: animal (GEMA) models 574–576 solute carrier proteins, in vivo studies, 2: 218–219 carboxylesterase interactions, 1: 443–445 UGT expression, 3: 656 cardiovascular drug metabolism, 2: 864–865 in vivo drug metabolism studies, 1: 52–56 statin therapies, 2: 869–870 Transiently transfected cell lines, solute carrier cytokines, 4: 645–649 proteins, in vitro studies, 2: 216 distribution mechanisms, 2: 125–129 TRANSIL™ membrane and protein beads, plasma ABC transporters, 2: 126–128 protein binding, drug discovery and barrier membrane expression, 2: 129 development, 5: 669–670 clinical distribution alterations, 2: 146–147 Transitional analog inhibitors: SLC transporters, 2: 126, 129–131 carboxylesterases, 1: 436–438 subtypes, 2: 125–126 phase I metabolism, carboxylesterases, 2: in vitro studies, 2: 133–134 273–274 drug conjugation and transport, 6: 226–227 Transit times, intestinal metabolism, 2: 64–67 drug-disease-drug interactions: Translational drug discovery, 2: 742–781 biomarkers, 4: 630 ADME studies, 2: 761–768 sterile inflammation, 4: 631–632 biomarkers, 2: 777–781 drug-drug interactions: pharmacodynamics technology/methodology, 5: NME disposition and, 6: 125–126 593 orally administered drug absorption or PK/PD models, 5: 583 elimination, 6: 161–162 computational modeling and simulation, 2: drug excretion, 6: 218–222 743–746 bile vs. urine routes, 6: 218–219 drug-target interactions and pharmacodynamics, 2: biliary excretion, 6: 219–220 768–770 drug interactions and clinical relevance, 6: 222 exploratory toxicology, 2: 770–777 hepatic drug metabolism, 6: 220 future research issues, 2: 781–782 renal excretion, 6: 219, 221–222 lead identification, optimization and selection, 2: drug metabolism, 4: 641–645 746–757 enzyme-transporter interplay, bioavailability lead optimization and identification, 2: 742–743, studies, 2: 483–484 746–757 genetically modified animal models: permeability and drug transport, 2: 751–753 bile salt export pump, 3: 676–677 pharmacokinetics and ADME studies, 2: breast cancer resistant protein, 3: 668–669 746–749 disposition studies, 3: 666–677 physico-chemical properties, 2: 749–751 multidrug resistance protein, 3: 669–672 pharmacophore modeling, 2: 744 organic anion transporters, 3: 675–676 regulatory issues, 2: 757–761 organic anion transporting polypeptides, 3: research background, 2: 737–741 672–674 Translocation: organic cation transporters, 3: 674–675 aryl hydrocarbon receptor transcription, 1: P-glycoproteins, 3: 666–668 214–215 summary, 3: 625–626 constitutive androstane receptor, 1: 212–213 hepatic drug metabolism, in vivo human pregnane X receptor, cytochrome P450, pharmacokinetics, 3: 357–358 transcriptional regulation, 1: 208–211 herb-drug interactions, absorption mechanisms, 2: Transmembrane domains (TMDs), ABC transporters, 809–811 2: 159 inflammation and infection: Transmission mode desorption electrospray drug-disease-drug interactions, 4: 627–628 ionization (TM-DESI), basic principles, 5: chronic diseases, 4: 629–630 92–93 cytokine regulation, 4: 629 Transporters. See also specific transporters, e.g., posttranscriptional regulation, 4: 650–651 ABC transporters research background, 4: 621–622 ADME studies: transcriptional regulation, 4: 649–650 clearance mechanisms, 2: 762–763 International Transporter Consortium drug-metabolizing enzyme interaction, 2: 18 recommendations, 2: 98–99 in vitro studies, 2: 24–25, 3: 59 intestinal drug metabolism, 4: 644–645 biotransformation, 6: 6–7 Caco-2/TC7 cell line comparisons, 3: 341–342 enzyme induction, 6: 18 oral absorption mechanisms, 2: 89–93 “phase 3” activation, 6: 12–13 bioavailability studies, 2: 476–480 INDEX 801

efflux transporters, 2: 89–92 pediatric drug metabolism, flavin-containing uptake transporters, 2: 92–93 monooxygenases, 6: 548–549 oral chemotherapeutic agents, intestinal ABCB1 Trimipramine, CYP2D6 metabolism, 6: 458, efflux, 6: 503–506 461–463 organ clearance mechanisms, 2: 562–564 “Triple-play” mass spectrometry, proteomics pediatric drug metabolism, 6: 559–562 analysis, label-free protein quantification, 4: pharmacogenetics, 4: 389–393 327–329 organic anion transporting polypeptides, 4: 390 Triple quadrupole-MALDI (MALDI-QQQ), pharmacokinetic modeling, 6: 589 laser-based ionization methods, 5: 566–567 phase I metabolism, valacyclovir, 6: 362–363 Triple quadrupole/tandem mass specrometry: phenotyping: basic principles, 5: 26, 28–29 drug metabolism, 1: 30 drug metabolism studies, quadrupole mass filter in vivo models, chimeric mouse model, 1: analyzer, 5: 182–183 54–56 future research issues, 5: 172 physiologically-based pharmacokinetic modeling: mass analyzer tuning and selection, 5: 553 enzyme-transporter biochemistry, 2: 646–647 metabolite identification, 2: 767–768 renal metabolism, 2: 656–659 multiple experiments, extended analysis, 5: 65 whole body model, 2: 660–664 operating theory, 5: 153–157 pregnancy and influence of, 2: 938–945 origin, 5: 158 in fetus, 2: 943–945 quantitative analysis, 5: 76–77 in placenta, 2: 938–943 research background, 5: 151–153 in silico studies, 3: 262 tandem mass spectrometry principles, 5: 158–161 species differences, conjugation and, 6: 227–230 efficiency parameters, 5: 159 UGT enzyme bioactivation, toxicity studies, 6: operating modes, 5: 159–161 258–260 in vivo studies, 5: 12–13 in vitro toxicity studies, intestinal drug Tritium: metabolism, 4: 231–233 metabolite identification, NMR spectroscopy, 3: xenobiotic metabolism, hepatocyte assessment: 158 FDA draft guidance concerning, 3: 434 nuclear magnetic resonance, passive nuclei, 5: 338 hepatobiliary transport, 3: 419–428 TriVersa NanoMate Robot: Transposable elements (TEs), microsomal epoxide chip-based nano-electrospray ionization, 5: 56–58 hydrolase, 1: 406–407 liquid extraction surface analysis, 5: 77–78 Transverse heterogeneity, intestinal metabolism, 3: simultaneous fraction collection, 5: 69 337 Trizaic microfabricated chip, nano-electrospray Trapping agents: ionization, 5: 55–56 bioactivation and oxidative stress, in vitro Troglitazone: biomarkers, 3: 189–190 idiosyncratic adverse drug reactions: reactive metabolite bioactivation, in vitro studies, metabolic idiosyncrasy, 6: 429 5: 647 mitochondrial toxicity, 6: 430–431 Traveling wave ion mobility spectrometry, basic idiosyncratic drug-induced liver injury, metabolic principles, 5: 264–265 polymorphism hypothesis, 4: 597–598 Trazodone, nuclear magnetic resonance analysis, 5: mitochondrial superoxide drug reactions, 4: 577 346–350 organic anion transporter polypeptides and, 2: Triazolam: 222–223 phase I metabolism, active metabolites, 6: 357 phase II metabolism, sulfotransferases, 6: in vitro toxicity studies, 4: 227–228 210–213 Tricyclic antidepressants (TCAs): reactive metabolite formation, 6: 394–395 CYP2D6 metabolism, 6: 458, 461–463 safety testing, stable metabolites, 3: 225–226 cytochrome P450 enzymes, dealkylation reaction, sulfotransferases, drug-drug interactions, 1: 547 4: 18–20 Trovafloxacin: Trifluoroacetyl (TFA) chloride, halothane human drug metabolism, structure-toxicity hepatotoxicity, 4: 573–574 relationships, 6: 380–381 Trifluoromethyl ketones (TFKs), phase I metabolism, idiosyncratic drug-induced liver injury, 4: carboxylesterases, 2: 273–274 610–612 Trimethylamine (TMA), flavin-containing Tryptophan fluorescence quenching (TFQ), plasma monooxygenases, 1: 287 protein binding, 2: 545–546 Trimethylaminuria: TS-1 prodrug, oral chemotherapeutic agent, 6: FMO polymorphisms, 6: 24 519–520 802 INDEX

Tumor necrosis factor converting enzyme (TACE), nonhybrid analyzers, 5: 185–186 idiosyncratic drug-induced reactions, tumor Two-dimensional micellar electrokinetic necrosis factor-α, 4: 602–603 chromatography, basic principles, 5: 437–439 Tumor necrosis factor-α: Two-dimensional nuclear magnetic resonance: drug metabolizing enzymes and drug transporters, basic principles, 5: 340–341 4: 645–649 metabolite identification, 3: 161–162 idiosyncratic drug-induced liver injury, nuclei characterization, 5: 338 inflammatory response, 4: 602–603 solvent suppression, 5: 338–339 idiosyncratic drug-induced reactions, sulindac, 4: Two-electron oxidation, cytochrome P450 enzymes, 608–610 4: 34–42 TUNEL assays, xenobiotic metabolism, hepatocyte iminium ions, 4: 40–42 assessment, hepatotoxicity assays, 3: 431–432 imino methide, 4: 39–40 Turbo ion spray (TIS), ion current stability, 5: 59–60 quinone imines, 4: 34–37 Turbulent-flow chromatography: quinone methide, 4: 37–39 biofluid analysis, 5: 457–462 quinones, 4: 37 sample preparation quality control, extraction Two-In-One (TWIN™) technology, emergence of, 5: quality, 5: 521–523 529 sample quality controls, research background, 5: Type I errors, bioequivalence studies, 2: 466 516–518 Type II errors, bioequivalence studies, 2: 466 Turnover half-life, drug-drug interactions, Tyrosine kinase inhibitors (TKIs), small molecule mechanism-based inhibition, risk assessment, 6: oral chemotherapeutic agents, 6: 520–523 107–108 Tyrosine kinases, pharmacodynamics mechanisms, 2: T-wave ion mobility mass spectrometry, basic 691–692 principles, 5: 35 Two-compartment model: UDP-α-D-glucuronic acid, distribution calculation, 2: 140–142 phase-II-enzyme-catalyzed xenobiotic plasma concentration-time data, 2: 619–620 conjugation, glucuronidation, 4: 108–121 drug-drug interactions, 2: 624–626 Ultracentrifugation, plasma protein binding: elimination kinetics, target-mediated drug ADME studies, 2: 31 disposition, 2: 629–633 drug discovery and development, 5: 664 metabolite analysis, 2: 622–623 estimation techniques, 2: 542–543 pharmacodynamics, biophase/link models, 2: Ultrafiltration, plasma protein binding: 711–712 ADME studies, 2: 31 pharmacokinetics/toxicokinetics dose calculations, drug discovery and development, 5: 661 2: 591 estimation techniques, 2: 540–542 Two-dimensional-based protein expression analysis, Ultra performance liquid chromatography (UPLC): proteomics applications, 4: 313–322 chiral columns, 5: 529–530 electrospray ionization mass spectrometry, 4: drug-drug interactions, inhibition mechanisms, 4: 319–320 407–413 first-dimension isoelectric focusing, 4: 315 high throughput technology, 5: 555–557 image analysis, 4: 317 qualitative analysis, 5: 75–76 immunoblotting, 4: 318 quantitative analysis, 5: 76–77 mass spectrometric peptide mass fingerprinting, 4: sample introduction, 5: 53 318–319 simultaneous fraction collection, 5: 68–69 protein detection and quantification, 4: 316–317 solubility and dissolution assessment, oral protein identification, 4: 317–318 absorption, dissolution measurement, 3: sample preparation, 4: 314 529–530 second-dimension SDS-PAGE, 4: 315–316 Ultrarapid metabolizers (UMs): toxicity studies, 4: 322 cytochrome P450 enzymes, ethnic differences in two-dimensional difference gel electrophoresis, 4: expression, 6: 76–77 320–321 drug metabolism, 1: 29 two-dimensional electrophoresis, 4: 313–315 psychotropic drugs, CYP2D6 metabolism, 6: 458, Two-dimensional difference gel electrophoresis 461–463 (2D-DIGE), proteomics, 4: 320–321 Ultraviolet-visible (UV-vis) spectroscopy, metabolite Two-dimensional electrophoresis, proteomics identification, 3: 133–134 applications, 4: 313–315 Unbound fraction (fu): Two-dimensional ion trap: ADME studies, pharmacokinetics, 3: 75–80 ion trap mass spectrometry, 5: 30–33 allometric scaling pharmacokinetics, 2: 507–508 INDEX 803

blood-brain barrier penetration: xenobiotic metabolism, hepatocyte assessment, central nervous system penetration, hepatobiliary transport, 3: 419–428 retroanalysis, Pfizer clinical candidates, 3: Uracil-ftorafur (UFT), oral chemotherapeutic agent, 580–581 6: 519–520 in vitro studies, tissue binding, 3: 573–574 Uridine diphosphate glucuronic acid (UDPGA): in vivo studies, 3: 565–569 biotransformation pathway predictions, in vitro enzyme kinetics, in vitro/in vivo correlation, 3: studies, 6: 185–186 306–307 drug-drug interactions, 6: 156 plasma protein binding, 2: 532–536 phase II metabolism, 2: 278–281, 6: 207–210 xenobiotic metabolism, hepatocyte assessment, in Uridine diphosphate (UDP)-glucuronosyltransferases vitro studies, metabolic stability, 3: 399–402 (UGTs): Unbound volume of brain (Vu,brain), blood-brain age-dependent drug metabolism, 4: 471–472 barrier penetration, in vivo studies, 3: 565–569 bioactivation, 6: 10–11 Unbuffered solubility, defined, 3: 509 acyl glucuronides, 3: 200–204 Uncharged solutes, micellar electrokinetic children and neonates, 6: 33 chromatography, 5: 422–424 clinical perspectives, 6: 254–262 Uncompetitive inhibition: induction and, 6: 17 drug-drug interactions, 4: 411–413 inhibition, 6: 30 enzyme kinetics, 1: 90 polymorphisms, 6: 24–25 substrate inhibition, 1: 84–86 bioavailability studies, intestinal metabolism, 2: Unfolded protein response, idiosyncratic adverse 482–483 drug reactions, 6: 428 biotransformation pathway predictions: United Network for Organ Sharing (UNOS), 6: 325 research background, 6: 179–180 in vitro studies, 6: 185 Unlabeled compounds, biotransformation pathway carboxylesterases pharmacogenomics, 1: 442–443 predictions, in vivo animal studies, 6: 189–190 cardiovascular drug metabolism: Unpredictable adverse reactions, defined, 4: gemfibrozil, 2: 870–871 160–161 β-adrenergic blockade, 2: 876–877 Unsaturated solutions, defined, 3: 510 clinical perspectives: α,β-Unsaturated aldehydes, Enzyme-catalyzed absorption mechanisms, 6: 252–254 reduction reactions, 1: 384 bioactivation mechanisms, 6: 254–262 Unscheduled DNA synthesis (UDS), xenobiotic classification, 6: 244–245 metabolism, hepatocyte assessment, clearance mechanisms, glucuronidation, 6: hepatotoxicity assays, 3: 431–432 262–264 Unstirred water layer (UWL), oral absorption: drug-drug interactions, 6: 269–270 dissolution, 3: 512 patient factors, 6: 264–269 rate-limiting steps, 3: 499–501 drug-drug interactions, 6: 266–267 UPA+/+/SCID mice, chimeric-humanized liver genetic polymorphism, 6: 265–266 models, 3: 628–629 glucuronidation inhibition, 6: 267–269 Upper limit of quantitation (ULOQ), bioanalysis research background, 6: 243–244 guidelines: substrate specificity, 6: 245–251 carryover regulations, 5: 486 tissue distribution, 6: 251–252 response calibration, 5: 475–481 dietary supplement-drug interaction, milk thistle, Uptake-limited clearance, organ clearance 4: 527–528 mechanisms, 2: 565–568 drug-disease-drug interactions, 4: 638–639 Uptake transporters: drug-drug interactions: bioavailability studies, hepatic extraction and anticonvulsants, 6: 476 uptake, 2: 484–486 conjugative inhibition, 6: 161 blood-brain barrier penetration, in vitro studies, 3: genetic polymorphisms and pharmacogenetics, 575–576 6: 169–170 cardiovascular drug metabolism, 2: 864–865 high-throughput screening assays, 6: 167 distribution mechanisms, 2: 146–147 intestinal metabolism, 4: 418–420 drug metabolism, 1: 30 non-P450 metabolism, 4: 423 oral absorption, 2: 92–93 predictive studies, 6: 155–156 bioavailability studies, 2: 477–480 reaction phenotyping, 6: 124 organ clearance, rate-limiting step, 2: 566–568 therapeutic efficacy, 4: 441 pediatric drug metabolism, 6: 559–562 enzyme kinetics, in vitro studies, 3: 289–290 SLC transporters, 2: 210–211 extrahepatic metabolism, 2: 334–336 804 INDEX

Uridine diphosphate (UDP)-glucuronosyltransferases substrates, 1: 476 (UGTs): (Continued) UGT1A4, 1: 477–478 food-drug interactions, cruciferous vegetable UGT1A5, 1: 479 induction, 4: 494–496 UGT1A6, 1: 479–481 genetically modified animal studies, 3: 652–656 2-acetylaminofluorene glucuronidation, 4: genetic polymorphism, dose calculations, 6: 119–121 617–618 pharmacogenetics, 4: 388 glucuronide analysis, 1: 471–472 UGT1A7, 1: 481–482 hepatic drug metabolism: UGT1A8, 1: 482–483 alcoholism, 6: 322–323 UGT1A9, 1: 483–485, 2: 256 Gilbert’s syndrome, 6: 324–325 UGT1A10, 1: 485–486 mechanisms, 6: 312 UGT2A, biotransformation, 6: 10–11 intestinal metabolism, Caco-2/TC7 cell line UGT2A1, 2, and 3, 1: 487 comparisons, 3: 339–340 UGT2B, biotransformation, 6: 10–11 irinotecan, ADME studies, 2: 847–848 UGT2B1: pediatric drug metabolism, 6: 551–553 2-acetylaminofluorene glucuronidation, 4: pharmacogenetics, 1: 460–467, 4: 387–388 119–121 phase II metabolism, 6: 207–218 diclofenac glucuronidation, 4: 117–118 enzyme-catalyzed xenobiotic conjugation, 4: UGT2B2, 2-acetylaminofluorene 108–121 glucuronidation, 4: 119–121 acyl glucuronidation, 4: 109–118 UGT2B4, 1: 487–488 4: benoxaprofen, 115–117 UGT2B7, 1: 488–492 diclofenac, 4: 117–118 active site characterization, 1: 489–491 arylhydroxamic acids, 4: 118–121 clinical relevance, 1: 481–482 2-acetylaminofluorene, 4: 119–121 diclofenac glucuronidation, 4: 117–118 mechanisms of, 2: 278–281 gene expression, regulation and plant secondary metabolites, 4: 488–494 polymorphisms, 1: 488–489 precision-cut tissue slices, phase II induction inhibition, 1: 489 studies, 3: 479–481 pharmacogenetics, 4: 388 preclinical species, 1: 497–499 substrates, 1: 489 pregnancy drug metabolism, 2: 947–951 UGT2B10, 1: 492–493 reactive metabolite bioactivation, adverse drug UGT2B11, 1: 493 reactions, 5: 628–630 UGT2B15, 1: 493–495 research background, 1: 457–460 4: in silico studies, problems, 3: 251–252 pharmacogenetics, 388 species differences, drug-metabolizing enzymes, UGT2B17, 1: 495–496 1: 141–143 UGT2B28, 1: 496 stereoselectivity, substrate metabolism, 4: 353 UGT3A1 and 2, 1: 497 UGT isoforms, 1: 472–497 UGT8A1, 1: 497 pharmacogenetics, 1: 460–461, 4: 387–388 in vitro tools, 1: 461, 468–481 substrate specificity, 6: 245–251 albumin effect, 1: 468–469 β UGT1A, biotransformation, 6: 10–11, 24–25 -glucuronidase, 1: 470–471 UGT1A1, 1: 472–475 protein-protein interaction, 1: 469–470 active site characterization, 1: 474–475 in vivo studies, clearance processes, 3: 607 clinical relevance, 1: 475–476 xenobiotic metabolism, hepatocyte assessment, genetic expression, regulation, and induction, 3: 410–419 polymorphisms, 1: 472–473 Urinary excretion: hepatic drug metabolism, 6: 324–325 distribution mechanisms, elimination alterations, inhibition, 1: 474 2: 143, 146 pharmacogenetics, 4: 387–388 drug elimination, 6: 222–223 substrates, 1: 473–474 drug metabolism, 6: 218–219 UGT1A3, 1: 475–477 urinary metabolism, 2: 331 active site characterization, 1: 476 mass balance studies, animal studies, 2: 422–425 biotransformation, 6: 10–11 metabolite identification, 3: 128–129 clinical relevance, 1: 477 pharmacokinetic analysis, 2: 603–607 genetic expression, regulation, and renal clearance, 2: 603–606 polymorphisms, 1: 475–476 Urticaria, idiosyncratic adverse drug reactions, 6: inhibition, 1: 476 418–419 INDEX 805

User acceptance testing (UAT), bioanalysis identification, 2: 201 guidelines, 5: 472 in vitro studies, 2: 217 Ussing chamber, in vitro toxicity screening, Vicriviroc: intestinal metabolism, 4: 232–233 oxidation, 1: 10 ring contraction of, 1: 6–7 Valacyclovir, phase I metabolism, 6: 362–363 Vigabatrin, drug-drug interactions, 6: 492 Valerian, herb-drug interactions, 2: 825 Viral infection: Valproic acid: drug-disease-drug interactions: dehydrogenation, 1: 11 CYP1 subfamily, 4: 630 drug-drug interactions, 6: 491–492 CYP2C, 4: 633–634 mitochondrial medium chain acyl-CoA CYP2E1, 4: 635 synthetases, structure-activity relationships, CYP3 subfamily, 4: 636 1: 602 glutathione S-transferases, 4: 639 Valrocemide, drug-drug interactions, 6: 494 drug transporters, 4: 643 Valsartan, ADME studies, 2: 881 Viral reactivation, idiosyncratic adverse drug Valves of Kerckring, anatomy and function, 2: 50 reactions, 6: 427 Vanadium, inductively coupled plasma mass reactive metabolite formation, 6: 433 spectrometry, 5: 307–308 Vitamin D quantification, biofluid analysis, Van Deemter equation: turbulent-flow chromatography, 5: 460–462 resolution quality, chromatographic techniques, 5: Vitamin K epoxide reductase (VKOR), ADME 525–526 studies, 2: 872 sub-2-μm chromatography, 5: 531–532 Vitamin K epoxide reductase complex subunit 1 Van’t Hoff equation, high temperature liquid (VKORC1), pharmacogenetics testing, 6: 26 chromatography, 5: 533–535 Vmax. See Maximal velocity (Vmax) Vascular adhesion protein-1 (VAP-1), Volatility, MALDI-MS techniques, 5: 125 semicarbazide-sensitive amine oxidase, 1: 371 Volcano plot, DNA microarrays, toxicogenomics Vascular endothelial growth factor (VEGF), cancer 327– 328 therapies, signaling pathways, 3: 35 Voltage-gated channels, pharmacodynamics Vascularity, gastrointestinal absorption, 2: 54–59 mechanisms, 2: 689 blood flow, 2: 54–55 Volume of distribution: lymphatic flow, 2: 55–56 ADME studies, pharmacokinetics, 3: 78–80 segregation routes, 2: 56–59 allometric scaling pharmacokinetics, human Vaughan-Williams classification, antiarrhythmics, studies, 2: 503, 505–508 ADME studies, 2: 874–875 distribution mechanisms: Vectorial transport, excretion mechanisms: body water distribution, 2: 114–116 hepatic transport, 2: 553–554 calculation of, 2: 139–140 renal transport, 2: 554–558 drug-protein binding, 2: 533–536 xenobiotics, 2: 550–558 enzyme kinetics, autoactivation (sigmoidal) Velocity equations, enzyme kinetics, 1: 94–96 kinetics, 3: 299–300 Venlafaxine: hepatic drug metabolism, cirrhosis, 6: 327–328 CYP2D6 metabolism, 6: 462 pharmacokinetic/toxicokinetic profiles, 2: 587 cytochrome P450 enzymes, dealkylation reaction, Voriconazole: 4: 15–16 pediatric drug clearance and exposure, 6: Verapamil: 562–563, 568–570 ABC transport modulation, 2: 172–173 phase I metabolism, FMO oxidation, 2: 265–267 blood-brain barrier penetration, in vivo studies, 3: Vorinostat, oral chemotherapeutic agents, 6: 523 570–572 cardiovascular metabolism, 2: 879 Wagner-Nelson (W-N) method, absorption kinetics, drug-drug interactions: plasma concentration-time data, 2: 610–612 clearance-dependent CYP induction, 4: Warfarin: 436–437 ADME studies, 2: 871–872 route-dependent CYP induction, 4: 433–434 age-dependent metabolism, CYP2C expression, 4: enantioselective pharmacokinetics, 4: 361–362 457–458 Very low density lipoprotein (VLDL), CYP2C9 metabolism, 6: 464–465 carboxylesterases, 1: 426 dose calculations, 6: 616 Vesicular drug accumulation, ABC transporters, 2: drug-drug interactions, therapeutic efficacy, 166 CYP-mediated effects, 4: 440–441 Vesicular transporters: enantiomer stereoselectivity, 4: 361 806 INDEX

Warfarin (Continued) World Health Organization (WHO) exposure herb-drug interactions: categories, mass balance human studies, dose garlic, 6: 287 calculations, 2: 441–446 ginseng, 6: 288 St. John’s wort, 6: 284–285 Xanthine oxidase (XO), phase I metabolism, 2: pediatric metabolism, 6: 547 267–269 phase I metabolism, ketone reduction, 2: 276–278 Xanthine oxidoreductase (XOR): reduction, 1: 11 activity variation, 1: 338–344 in vitro toxicity studies, 4: 228–229 classification, 1: 308–310 Wash protocols, imaging mass spectrometry, tissue ethnic variations, 1: 344 sample preparation, 5: 221–224 genetics, 1: 312–315 Water-cosolvent mixtures, solubility and dissolution human studies, 1: 335–336 inhibitors, 1: 333–335 assessment, oral absorption, 3: 524–525 ontogenic expression, 1: 343–344 Water distribution, drug distribution and, 2: 114–116 overview, 1: 305–306 Water-soluble materials, gastrointestinal absorption, redox state changes, 1: 310–311 2: 56–59 regulators and inducers, 1: 342–344 Weight: species differences, 1: 336–338 allometric scaling pharmacokinetics, 2: 496–509 structure and function, 1: 306–312 cancer therapies, targeted therapies, 3: 25 xenobiotic biotransformation, 1: 315–331 dose calculations based on, 6: 613 aldehyde oxidation, 1: 320–321 Well-stirred model, pediatric drug metabolism: aromatic N-heterocycle oxidation, 1: 315–320 protein binding, 6: 554–555 heterocycle reduction, 1: 329–331 research design, 6: 568–570 N-hydroxy reduction, 1: 328–329 Western blotting, protein identification, 4: 318 iminium ion oxidation, 1: 321–324 Whole body autoradiography/whole body nitrate/nitrite reduction, 1: 326–327 autoradioluminography (WBAL): nitroreduction, 1: 324–326 animal studies, overview, 5: 366–383 N- and sulfoxide reduction, 1: 327–328 distribution mechanisms: reduction, 1: 324 drug discovery and development, 2: 34–35 Xanthinuria, molybdenum-containing hydroxylases, in vivo studies, 2: 135–136 1: 314–315 drug discovery and development, 5: 370–383 Xenobiotic metabolizing enzymes (XMEs): ADME studies, 5: 380–381 dietary supplement-drug interaction: brain and cerebrospincal fluid penetration, 5: garlic, 4: 512–513 371–372 Ginkgo biloba, 4: 515–516 enzyme induction/inhibition, 5: 375–376 ginseng, 4: 516–518 fetal penetration, 5: 377 milk thistle, 4: 526–528 formulation selection, 5: 377 piperine/black pepper, 4: 523–524 melanin binding, 5: 373–375 St. Johns wort, 4: 529–532 metabolism/covalent binding, 5: 377 Schisandra spp., 4: 524–526 food-drug interactions, cruciferous vegetables, 4: tissue retention, 5: 378 494–496 tumor penetration, 5: 376–377, 380 herb-drug interactions: drug-drug interactions, 5: 372 pharmacogenetics, 4: 501 history, strengths and limitations of, 5: 368–370 phytochemical content variability, 4: 502–503 tissue distribution studies, 5: 361–364 plant-animal “warfare,” 4: 487–488 Whole body physiologically-based pharmacokinetic plant secondary metabolites: modeling, 2: 659–664 food-drug interactions, cruciferous vegetables, disease states and patient factors, 2: 667–670 4: 494–496 sequential metabolism and metabolite behavior, 2: human studies, 4: 490–492 660 research background, 4: 485–487 transporter-enzyme interaction, 2: 660–664 in vivo human studies, 4: 504–505 Withdrawn drugs, hepatotoxicity prediction, 4: Xenobiotic responsive enhancer module (XREM) 159–160, 177–179 response element: Working electrode (WE), electrochemical liquid cytochrome P450 enzymes, CYP2E, 1: 259–260 chromatography mass spectrometry: cytochrome P450 genes, transcriptional regulation, array techniques, 5: 321–322 receptor cross talk: electrochemical flow cells, 5: 314 CYP2B6, 1: 217 INDEX 807

CYP3A4, 1: 220 hepatic couplets, 3: 421–422 Xenobiotics. See also specific compounds and primary culture, 3: 423–425 Drug-metabolizing enzymes primary hepatocytes, 3: 422–423 carboxylic acid metabolism, amino acid small interfering RNA, 3: 425–427 conjugation: suspension hepatocytes, 3: 423 mechanisms for, 1: 596–597 transporter-mediated drug-drug interaction, 3: mitochondrial acyl-coA:glycine 419–421 N-acyltransferase, 1: 602–605 in vitro/in vivo correlation, 3: 427–428 inhibitors, 1: 605 hepatotoxicity studies, 3: 428–433 structure-activity relationships, 1: 603 future toxicity models, 3: 432–433 in vivo conjugation, 1: 603–605 in vitro assays, primary hepatocytes, 3: xenobiotic substrates, 1: 603 430–432 mitochondrial medium chain acyl-CoA metabolic profiling, 3: 403–404 synthetases, 1: 597–602 metabolic stability, drug candidate, 3: 396–402 inhibitors, 1: 602 fresh/cryopreserved suspensions, 3: 397–401 structure-activity relationships, 1: 600–602 in vitro-in vivo correlations, 3: 401–402 substrates, 1: 599–600 metabolite identification, 3: 404–405 overview, 1: 595–596 research background, 3: 393–396 cytochrome P450 enzymes: intestinal absorption, 2: 53–54 anatomic sites, 1: 22–23 metabolism classification, phase I and II reactions, CYP1 subfamily, 1: 241–242 4: 104–105 CYP2B6 subfamily, 1: 251 metabonomics analysis, 4: 291–292 polymorphisms, overview, 1: 239–240 microsomal epoxide hydrolase, 1: 395–407 species specificity: substrates and inhibitors, 1: 397–398 CYP3A enzyme, 1: 137, 139–141 molybdenum-containing hydroxylase transcriptional gene regulation, 1: 222–224 biotransformation, 1: 315–331 structure, 1: 163–165 aldehyde oxidation, 1: 320–321 transcriptional gene regulation: aromatic N-heterocycle oxidation, 1: 315–320 aryl hydrocarbon receptor, 1: 213–215 heterocycle reduction, 1: 329–331 constitutive androstane receptor, 1: 211–213 N-hydroxy reduction, 1: 328–329 future research issues, 1: 227 iminium ion oxidation, 1: 321–324 genetic polymorphisms, 1: 226 nitrate/nitrite reduction, 1: 326–327 methodology, 1: 222 nitroreduction, 1: 324–326 pregnane X receptor, 1: 206–211 N- and sulfoxide reduction, 1: 327–328 receptor cross talk, 1: 215–221 reduction, 1: 324 CYP1A1/2, 1: 216 non-P450 bioactivation, summary, 4: 95 CYP2B6, 1: 216–218 phase II metabolism: CYP2C8, 1: 218 enzyme-catalyzed conjugation: CYP2C9, 1: 218–219 N-acetylation, 4: 126–129 CYP3A4, 1: 220–221 aromatic amines-benzidine, 4: 128–129 research background, 1: 205–206 aromatic hydrazines, 4: 127 species specificity, 1: 222–224 acyl-S-CoA formation, 4: 140–144 splice variants, 1: 224–226 acyl-adenylates, 4: 144 drug-drug interactions, toxicity, CYP-mediated S-acyl-coA thioesters, 4: 142–144 induction, 4: 442–444 future research issues, 4: 144–145 drug-metabolizing enzymes, 1: 4–5 glucuronidation, 4: 108–121 species differences, 1: 121–123, 125–126 acyl glucuronidation, 4: 109–118 extrahepatic metabolism, 2: 354–356 benoxaprofen, 4: 115–117 hepatocyte assessment of hepatic metabolism: diclofenac, 4: 117–118 CYP induction, 3: 409–419 arylhydroxamic acids, 4: 118–121 endpoint measurement, 3: 413–417 2-acetylaminofluorene, 4: 119–121 in vitro-in vivo correlations, 3: 417–419 glutathione conjugation, 4: 129–140 CYP inhibition studies, 3: 405–409 S-acyl-glutathione thioester adducts, FDA draft guidance, 3: 433–434 carboxylic-acid-containing drugs, 4: drug-metabolizing enzymes, 3: 433–434 139–140 transporters, 3: 434 bromobenzene, 4: 133–134 hepatobiliary transport, 3: 419–428 ethylene dibromide episulfonium ion cryopreserved hepatocytes, 3: 425 formation, 4: 130–131 808 INDEX

Xenobiotics. See also specific compounds and Ximelagatran: Drug-metabolizing enzymes (Continued) drug-induced liver injury, 6: 420–421 hexachlorobutadiene-induced predictive toxicity studies, thrombin inhibitors, 6: nephrotoxicity, 4: 136–137 391–393 3,4-methylenedioxymethamphetamine-induced neurotoxicity, 4: 131–133 YTE site-directed mutagenesis, antibody recycling, α-naphthylisothiocyanate-induced neonatal Fc receptor, 2: 910–911 intrahepatic cholestasis, 4: 137–138 sevoflurane-induced nephrotoxicity, 4: Zaleplon, clinical programs, 1: 348 134–136 Zidovudine: metabolic activation pathways, 4: 105–108 glucuronidation induction, 6: 268 overview, 4: 103–104 glucuronidation inhibition, 6: 267 sulfonation, 4: 121–126 phase II metabolism, 6: 207–210 allylic alcohols, 4: 123–124 Ziegler enzymes. See Flavin-containing arylhydroxylamines and arylhydroxamic monooxygenases (FMOs) acids, 4: 124–126 Zinc, inductively coupled plasma mass spectrometry, polycyclic aromatic benzylic alcohols, 4: 5: 307–308 122–123 Ziprasidone, cytochrome P450 enzymes: xenobiotic metabolism classification, 4: dealkylation, 6: 58–59 104–105 oxidation, 6: 59–60 glucuronosyltransferases, 6: 207–210 Zolpidem: precision-cut tissue slices, induction studies, phase drug-drug interactions, therapeutic efficacy, I enzyme systems, 3: 471–478 CYP-mediated effects, 4: 442 prostaglandin H synthase bioactivation, 4: 79–83 toxicity studies, structure-toxicity relationships, 6: solute carrier transport, 2: 198–201 383–384 sulfotransferases, 1: 529–536 Zomepirac acyl glucuronide, UGT enzyme classification and nomenclature, 1: 530–532 bioactivation, 6: 256–260 clinical perspectives: Zonipride, aldehyde oxidase variation, 1: 341–344 drug-drug interactions, 1: 546–548 Zonisamide: induction, 1: 544–545 drug-drug interactions, 6: 492 polymorphisms, 1: 543–544 reduction, 1: 12 reaction phenotyping, 1: 545–546 fetal development, 1: 535–536 protein structure and function, 1: 531, 533 tissue distribution, 1: 533–535 vectorial transport, 2: 550–558 hepatic transport, 2: 553–554 renal transport, 2: 554–558