Absorption, Gastrointestinal, 39-43 ABT-229, 244F, 245 Abzymes, 533

Home , Abzyme, Amtolmetin guacil, Betamethasone phosphate, Carmofur, Epitiostanol, Estramustine phosphate

Index

Page numbers followed by f or t indicate figures or tables, respectively.

A Absorption, gastrointestinal, 39-43 ABT-229, 244f, 245 Abzymes, 533 Acetaminophen, 13f, 17 It Acetaminophen phosphate, 170t, 180 Acetanilide, 13f Acetorphan, 587 N-(N-Acetyl-L-methionyl)O,O-biscarbonyl dopamine, 346f, 347 Acetylsalicylic acid, 13f S-Acetyl thiorphan, 587 Acid-labile linkers, 509-513 Aclofenac, 663t Active effiux barrier, 578-579 Acyclovir, 22, 65, 66t, 67f, 665t aminomethylbenzoate esters, 239f prodrugs, 145, 146 see also Valacyclovir spacer groups, 391t N-Acyl derivatives, 89t, 98-101 alkylaminocarbonyl, 98-99 alkylcarbonyl, 99-101 alkyloxycarbonyl, 99 O-Acyl groups, 104t, 105-106 alkylcarbonyl derivatives, 104-106 alkyloxycarbonyl, 106 O-~N Acyl migration reaction, 189f, 190 (Acyloxyalkyl)carbamates, 137 O-Acyl peptides, 189f, 190 Adefovir, 54, 55f prodrugs see Adefovir dipivoxil Adefovir dipivoxil, 16f, 54, 55f, 160, 555f Adenosine deaminase, 609-612 ADAPT see Antibody-directed abz)~me prodrug therapy ADEPT see Antibody-directed enzyme prodrug therapy Adhesion receptors, 474-476 Adrenergic agonist prodrugs, 130-132 dipivefrin, 130, 13 If phenylephrine, 131, 132f 704 Index

Ara-CMP, 556 prodrugs, YNK-01, 565f Area under concentration-time curve, 286, 432, 435-436 Asialofetuin, 558 Asialoglycoprotein receptors, 558-560 Asialoorsomucoid, 558 Aspartyl proteases, 424f AT-125, 471f Atenolol, 135 Auristatin E, 516f Avastin, 509 Axo-linked prodrugs, 687-689 6-Azauridine, 43f Azomethine prodrugs, 604-605 AZT see Zidovudine

B Bacampicillin, 50, 5 If Baclofen, 587 Bambec see Bambuterol Bambuterol, 348 Benfotiamine, 63, 63f Benicar, 16f - Benzamidine prodrugs, 57 Benzoic acids, 4-substituted, 387t O-Benzoyl dextran, 386t Benzyl alcohol, 387t Benzyl elimination; 307f, 308f, 309t, 310f, 31 If amphotericin, 305, 306t, 307f daunorubicin, 303, 304t doxorubicin, 303, 305t oligonucleotides, 311, 312f, 313t, 314 proprotein conjugates, 314f, 315t, 316f vancomycin, 307f, 308f, 309t, 310f, 311f Beta-adrenergic agonist prodrugs, 135-139 nadolol, 138-139 tilisolol, 138f timolol, 135, 136t, 137f Betamethasone, 86 Betamethasone phosphate sodium, 220 Bexxar see Tositumonab Bicine/bicin prodrugs, 319f, 320f, 321,322f Bile acid transporters, 560-562 Bimatoprost, 132, 133f Bioactivation, species-dependence, 351 Index 703

Amphotericin, amine PEG prodrugs, 305, 306t, 307f Ampicillin, 49f prodrugs, 50f serum concentrations, 5 If Amprenavir, 16, 17f, 18, 162, 171t, 175 prodrugs see Fosamprenavir Analog approach, 5 Anchimeric assistance, 295 Angiogenesis, 465, 474 and hypoxia, 467 Angiotensin-converting enzyme inhibitors, 58-59, 60f Angiotension II receptor blockers, 60, 61f Aniline mustard, 461 Anionic intermediates, 600-603 phosphates, 601-603 phosphinates, 600-601 phosphonates, 601 Anthracyclines, 45 lf, 452-453 side effects, 452 see also individual drugs Antibody-directed abzyme prodrug therapy (ADAPT), 456 Antibody-directed enzyme prodrug therapy (ADEPT), 7, 11,432, 455, 479, 525-540 London group studies, 527-532 cause of myelosuppression, 530 clearing antibody, 531 fusion proteins, 531-532 pilot scale clinical trials, 529-530 prodrug and drug characteristics, 531 preclinical studies, 533-534 prodrugs, 534 Antibody-drug conjugates, 478-479 Anticancer agents see Cancer chemotherapy Antimetabolites, 451 Antiviral agents brain targeting, 595-596 prodrugs activation, 607-608 polyethylene glycol, 294 Apoptosis, 425f, 426 Aquavan see GPI 15715 1-[3-D-Arabinofuranosylcytosine prodrug, 47 lf, 472 9-[3-D-Arabinosyl-2-fluoroadenine, 227f Ara-C, 559 prodrugs MB07133, 556-558 PEG derivatives, 297, 298t, 299t 704 Index

Bioavailability, 193 Bipartate amides, 297-300 extenders, 299-300 Biphenylylacetic acid, cyclodextrin prodrugs, 69 lf, 692f, 693f Bisantrene, 230f Bispilocarpic acid mono- and diesters, 140f, 141 Blood-brain barrier, 577-579 active efflux, 578 enzymatic, 578 passive permeability, 577-578 prodrug design for CNS delivery, 579 Blood coagulation, 425f, 426 BMS-207147, 245f, 247 BMS-379224, 19f, 235f, 236 Bortezomib, 19, 20f BR96-doxorubicin, 512f, 513 BR96-phenylalanine-lysine-p-aminobenzyl-doxorubicin, 516 Brain, drug delivery, 573-651 chemical (non-enzymatic) activation, 604-606 azomethine prodrugs, 604-605 base catalyzed ring opening of temozolomide, 605-606 gene-directed enzyme prodrug therapy (GDEPT), 11,433, 455, 615, 616f lipophilic esters, 579-594 ester-activated prodrugs, 579-587 optimum lipophilicity for CNS delivery, 590-594 overcoming effiux transport, 587-590 locked-in intermediates of active drugs, 594-603 anionic intermediates, 600-603 redox trapping, 594-600 oxidoreductase-activated prodrugs, 606-608 dihydropyridine oxidation, 606 monoamine oxidase, 607 xanthine oxidase, 607-608 transferase-activated prodrugs, 609-615 adenosine deaminase, 609-612 glutathione/glutathione S-transferase, 613-615 thymidine phosphorylase/cytidine deaminase, 612-613 transporter/receptor-mediated delivery, 617-621 glucose transporter, 620, 62 If large amino acid transporter, 619, 620f receptor-mediated transcytotic pathways, 617f, 618 small molecular transporters, 618-619 Brain tissue esterase activity, 584t, 585 Bristol-Myers Squibb, 25, 236 Budenoside-[3-D-glucuronide, 690, 690f Bumetanide, 562 706 Index

Buparvaquone, 171t Buparvaquone phosphate, 170t Bupranolol, 662t n-Butyric acid prodrugs, 691f Buy ins, 25

C Calcitonin prodrugs, 345t CAM 4451, 185, 187 structure, 186f Camptothecin, 292, 45 lf, 452-453 prodrugs, 248-253 glycinate ester, 249f 20-phosphoryloxymethyl derivative, 249f, 250f Camptothecin PEG derivatives, 250f, 251,293t, 294t clinical trials, 296-297 Camptothecin phosphate, 162 Canadensol, O-acyl prodrugs, 190 Cancer chemotherapy, 450, 451-453 anticancer agents, 451-453 macromolecular prodrugs, 478-479 antibody-drug conjugates, 478 polymeric drug delivery, 478 monoclonal antibody conjugates, 507-524 acid-labile linkers, 509-513 disulfide-linked conjugates, 513-515 peptide-linked conjugates, 515-518 multi-drug resistance, 450 prodrugs, 248-262, 453-454 camptothecin, 248-253 monotherapy, 454, 455f paclitaxel, 253-262 strategic considerations, 479-481 protease-activated prodrugs, 468-474 aminopeptidase-activated, 468-469 cathepsins, 470-471 matrix metalloproteinase-activated, 473-474 plasmin-activated, 471-473 prostate-specific antigens, 469 receptor binding prodrugs, 474-478 adhesion receptors, 474-476 folate receptors, 476 hormone rceptors, 476-477 releasable linkers, 456-459 targeting, 447-506 Index 707

tumor-associated targeted prodrugs, 459-474 [3-glucuronidase-activated prodrugs, 461-463 hypoxia-activated prodrugs, 459, 460f, 461 pH-sensitive prodrugs, 459 tumor-specific prodrug targets, 463-468 cathepsin B, 464 enzyme-receptor interactions, 465-468 matrix metalloproteinases, 465 plasmin and u-PA system, 464-465 two-step therapies, 455-456 see also individual agents Candesartan cilexitil, 60, 61f Cantuzumab mertansine, 513, 514f Capecitabine, 612f see also 5-Fluorouracil Capoten see Captopril Captopril, 58, 60f, 144 Carbenicillin, 69 Carbonic anhydrase inhibitor prodrugs, 142, 143f Carboxylesterases, 579-580 Carboxylic groups, 108, 109t, 110, 11 lt- 112 Carcinoembryonic antigen, 528 Carindacillin, 69 Cascade activation, 425-426 apoptosis, 425f, 426 blood coagulation, 425f, 426 Cascade-release dendrimers, 458f, 459 Catalytic triad, 422f Cathepsin-activated prodrugs, 470-471 Cathepsin B, 464, 515-516 Cathepsins, 458 CC1065, 514-515 Cefcapene pivoxil, 52 Cefditoren pivoxil, 52 Cefetamet pivoxil, 52 Cefotiam hexetil, 52 Cefpodoxime, 52 Cefteram pivoxil, 52 Ceftin see Cefuroxime axetil Cefuroxime, 52, 53f Cefuroxime axetil, 18f, 52, 53f Celecoxib, 247 CEP-5214, 186t, 187 structure, 186f Cephalexin, 144 708 Index

Cephalosporins, 48f, 49, 230f, 231 absorption, 51-52 Cephazolin, 144 Cephradine, 65, 68 Cerebyx see Fosphenytoin CGH 509A, 561/ Chemical delivery systems, 594-600 Chemical (non-enzymatic) activation, 604-606 azomethine prodrugs, 604-605 base catalyzed ring opening,of temozolomide, 605-606 Chlorambucil, 662t Chloramphenicol, 14, 15t, 223, 224f 3-aminomethylbenzoate esters, 224f cycle phosphoric acid ester, 223, 224f prodrugs glycinate, 224f monosuccinate, 223, 224f palmitate, 15f 4-[(2-Chloroethyl)[2(mesyloxy)ethyl]amino]benzoyl-L-glutamic acid, 529-530 4-Chlorokynurenine, 620f oL-Chymotrypsin, 422f Chymotrypsinogen, 420, 42 If Cidofovir, 665t Cinnarizine, 233f plasma concentrations, 234f Circulatory retention, 287-288 Clearance, 26, 193, 434, 435 Clearing antibody, 531 Clindamycin, 226f, 227 prodrugs see Clindamycin phosphate serum concentrations, 226f Clindamycin phosphate, 226f Clindets see Clindamycin phosphate Clinical trials, 23-24 Clinoril see Sulindac Clopidogrel, 20, 2 If Closantel, 660t, 662t Closantel palmitate, 660t Codeine, 13, 14t Colchicine prodrugs, 373 Colonic delivery, 683-699 biological factors, 686-687 controlled release, 372 physiological factors, 685-686 prodrugs, 687-695 amino acid, 689-690 Index 709

azo-linked, 687-689 cyclodextrin, 691-695 glucoside and glucuronide, 690-691 Combretastin-A4-phosphate, 162 Controlled release, 6, 357f macromolecular prodrugs, 379-416 catalytic rate constants, 386t drug attachment to/near polymer backbone, 385-390 enzyme-mediated cleavage of polymer backbone, 395-398 incorporation of spacer group, 390-395 intra-articular injection, 408-409 macromolecule-drug bond, 384f, 385 manipulation of drug release rate, 398-403 oral administration, 403-406 routes of administration, 385t subcutaneous injection, 406-407 oral, 361 parenteral, 361-362 absorption/disposition from oily depots, 366 fluphenazine decanoate depot, 366, 367-369f, 370 IM absorption, 362, 363-365t prodrugs colonic delivery, 372 dissolution controlled depots, 370, 371t modified release formulations, 372 ophthalmic delivery, 372-373 site-directed delivery, 373-374 proenzymes, 417-428 activation, 420-424 activation cascades, 425-426 pancreatic serine proteases, 420-423 proenzyme-like prodrugs, 426-427 small molecules, 357-377 Corneal barrier, 128 COX-2 inhibitors, 247 see also Parecoxib Crohn's disease, 403 CT-2103, 260f, 261 Cyclin-dependent kinases, 300 Cyclization linkers, 456, 457f, 473f Cyclodextrin prodrugs, 691-695 . Cyclooxygenase-2 inhibitors see COX-2 inhibitors Cyclosporine A, 60, 183 prodrugs, 183, 184f, 185 CYP3A4, 551,553 CYP3A, 555 71 o Index

CYP450, 551 Cysteine proteases, 424f Cytarabine see Ara-C Cytidine deaminase, 612-613 Cytochrome see CYP Cytosine deaminase conjugates, 533 Cytovene see Ganciclovir

D Dapsone, 243f amino acid prodrugs, 243f, 244 Daunorubicin, 45 lf, 452-453, 559 prodrugs amine PEG, 303, 304t [3-glucuronidase-activated, 462f [3-glucuronide carbamate, 457-458 trimethyl lock lactonization, 318t, 319t spacer groups, 39 It Desmethyldiazepam, 14t Desmethyl-naproxen, 663t Desmopressin prodrugs, 345t Dexamethasone, 145 spacer groups, 39 it structure, 393f Dexamethasone acetate, 37It Dexamethasone-21-[3-glucoside, 690 Dexamethasone-13-D-glucuronide, 690 Dexamethasone hemisuccinate, 406 Dexamethasone phosphate sodium, 220 Dexamethasone-succinate-dextran, 406 Dexanabinol, 241,242f N-substituted glycine esters, 241,242f plasma concentrations, 242f Dextran, 286 Dialkylamino groups, 108 Dialkylaminomethyl derivatives, 96, 97f, 98 Diazepam, 14t 6,7-Dichloro-3,4-dihydro-3-oxo-2-quinoxalinecarboxylic acid, CNS delivery, 599-600 Diclofenac carboxylic acid ester, 387t polyoxyethylene esters, 109t, 110 regeneration half-life, 388t 2',3'-Dideoxyinosine, 5'-esters, 584t Diethylstilbesterol, 228f Index 711

Diffusivity, 41 Dihydropyridine oxidation, 606 Dihydropyridine-pyridinium redox pair, 595-599 Dihydroxyalkyl groups, 107t, 108 Diketopiperazine, 192 Dilantin see Phenytoin N,N-Dimethylglycinate, 236, 237f Dipivefrin, 127, 130, 13 If Disease-modifying anti-rheumatic drugs, 409 Disodium monofluorophosphate, 162 Dissolution rate, 179-180 Dissolution ratio, 179-180 Disulfide-linked conjugates, 513-515 DM1, 513-514 Docetaxel, O-acyl prodrugs, 190 Dolastatin 10, 516-517 L-Dopa see Levodopa Dopamine, 64f, 65t prodrugs, 344t, 346f, 347 Dose number, 194 high with high permeability, 178-179 high with low permeability, 178 low with high permeability, 177 low with low permeability, 177-178 medium with high permeability, 178 parent drugs and prodrugs, 176-179 in selection of parent drugs, 176 Doxorubicin, 45 lf, 452-453, 516f, 559 prodrugs amine PEG, 303, 305t cathepsin-activated, 470f [3-glucuronidase-activated, 462f hydrazone conjugates, 323, 512f, 513 plasmin-activated, 47 lf, 472 receptor binding, 475f DP-VPA, 670-672 Drugable properties, 5, 8 Drug central volume, 435 Drug concentration and infusion time, 440f, 44 If repeated bolus input, 441f Drug delivery, barriers to, 6, 12t Drug discovery paradigm, 8f Drug latentiation, 5 Drug permeability effects, 439-444 Drug release rate, manipulation of, 398-403 712 Index

Drug targeting index, 431,432 Drug target site volume, 435 Duocarmycins, 451 Dynastat see Parecoxib

E Edrecolomab, 509 Effiux, active, 578 Effiux transporters, 26-27, 39-72 and failed prodrugs, 70-71 overcoming, 587-590 Ehrlich, Paul, 15, 453 Electronic cascade linkers, 456f, 460, 473f 1,4-Elimination linkers, 457 1,6-Elimination linkers, 456f, 457, 461 Enalapril, 18f, 58, 60f, 144, 585 absorption, 68 Enalaprilat, 58, 60f, 68 prodrugs see Enalapril Endopeptidase inhibition, 586-587 Enhanced permeability and retention effect, 292, 455 Enkephalin analogs, 596, 597f leu-Enkephalin prodrugs, 345t Entacapone, 17 lt, 172f, 177-178 dissolution rate, 179 ester prodrugs, 188f Entacapone phosphate, 170t, 172f, 173 Enterokinase, 420 Enzcheck kit, 195 Enzymatic blood-brain barrier, 578 Enzymes, 551 Epitiostanol, 660t Ester-activated prodrugs, 579-587 bioconversion selectivity, 584-587 ester lability design, 582-584 parent drug hydrophilicity/lock-in potential, 580-581 Ester bipartate prodrugs, 289, 290t Ester spacers, 290-294 Estradiol cypionate, 363t Estradiol prodrugs, 344t, 346f see also individual compounds Estradiol valerate, 363t Estramustine, 17 lt, 174f, 179 dissolution rate, 179 Estramustine phosphate, 162, 170t, 174f, 180, 228, 229f Index 713

Estrogen prodrugs, 344t, 347 Estrone sulfate, 347 Ethyl benzoate, 386t 7-Ethylcamptothecin, 252-253 Etoposide, 171t, 229, 230f prodrugs see Etoposide phosphate Etoposide phosphate, 166, 170t, 229, 230f Excretion, 546 Extenders, 299-300 Extracellular matrix, 463, 466

F Facilitated permeability, 63-70 Famciclovir, 44, 45f metabolic pathways, 45f Fenoprofen carboxylic acid ester, 387t regeneration half-life, 388t Fick's law, 40 First pass metabolism, 655 Fluconazole, 19f, 228, 229f Fludara see Fludarabine phosphate Fludarabine, 162, 17 lt, 177, 227f, 228 dissolution rate, 179 Fludarabine phosphate, 162, 170t, 173f, 180 Fludarabine-5'-triphosphate, 227f, 228 Fluorescent dye labeling, 324f, 325 5-Fluorocytosine, 615 Fluorometholone, 145 5-Fluorouracil, 88, 451 characteristics, 91t prodrugs characteristics, 89-90t cyclodextrin, 691f solubility, 97t structure, 116f see also Capecitabine spacer groups, 39 It structure, 116f Fluorouridine, 665t Fluphenazine decanoate, 363t depot preparations, 366, 367-369f, 370 [3-Fluro D-alanine, 20, 22f Folate receptors, 476 Folic acid prodrugs, 476 714 Index

Formaldehyde, 13f, 50 Forscarnet, 665t Fosama see Alendronate sodium Fosamprenavir, 16, 17-18, 17f, 162, 176 structure, 175f Fosamprenavir-Ca, 170t, 176 Fosamprenavir-Na, 170t, 176 Fosfluconazole, 228, 229f solubility, 229 Fosfosal, 162 Fosinopril, 59, 60f, 585 Fosinoprilat, 59, 60f prodrugs see Fosinpril Fosphenytoin, 18, 19f, 162, 165f, 170t, 178, 195, 232 metabolism, 232 Functional groups, 94-112 aliphatic hydroxy, 8, 107t, 108 amide-/imide-like, 94-101 alkylcarbonyloxymethyl, 89, 94-96 dialkylaminomethyl, 89t, 96, 97t-98 N-acyl, 98-101 carboxylic, 108, 109t, 110, 11 lt- 112 dialkylamino, 108 dihydroxyalkyl, 107t, 108 hydroxy, 103-106 O-acyl, 104t, 105-106 thioamide/thioimide, 101-103 alkylcarbonyloxymethyl, 102-103 N-alkyl-N-alkyloxycarbonylaminomethyl, 103 Furosemide, 562 Fusion proteins, 531-532

G GABA, 662t, 663t Gabapentin, 68, 69f Ganciclovir, 67f, 615 CNS delivery, 596 oral bioavailability, 67 Garlic, and thiamine deficiency, 62-63 Gastrointestinal tract transporters, 63-70 GDEPT see Gene-directed enzyme prodrug therapy Gemtuzumab ozogamicin, 479, 509, 510f, 511-512 Genasense, 312, 313t Gene-directed enzyme prodrug therapy (GDEPT), 11,433, 455, 615, 616f Gilead Sciences, 9-10 Index 715

GlaxoSmithKline, 16, 52, 175 Glucocorticoids, 693 Glucose transporter, 620, 62 If Glucoside prodrugs, 690-691 [3-Glucuronidase-activated prodrugs, 461-463 Glucuronide prodrugs, 690-691 Glutaric acid, 237f Glutathione, 613-615 Glutathione S-transferase, 613-615 Glyceride prodrugs, 661-664 Gly-paclitaxel, 290, 291f anti-tumor activity, 292t GPI 15715, 23f, 24, 50, 162, 235f pharmacokinetics, 236

Haldol decanoate see Haloperidol decanoate Half-life, 26 Haloperidol decanoate, 364t Hemisuccinate, 15f Hemisuccinate esters, 221 Hepatitis, 546-547 Hepatocytes, 545 HepDirect prodrugs, 551-558 MB07133, 556, 557f, 558 pradefovir, 554, 555f, 556f Hepsera see Adefovir Herceptin see Trastuzamab High affinity trap, 8 High throughput screening, 7 HIV, in brain tissue, 587-588 Hormone receptors, 476-477 Hu3S 193-N-acetyl calicheamicin immunoconjugate, 512 Hyaluronic acid, 408f, 477 ester prodrugs, 408f Hydrazone conjugates, 510, 512-513 doxorubicin, 323, 512f, 513 Hydrocortisone, 145, 17 lt, 177 3-[(-4-methylpiperazin- 1-yl)methyl]benzoate ester, 239f Hydrocortisone phosphate, 170t, 1.77 Hydrocortisone phosphate sodium, 221 Hydrocortisone succinate sodium, 220 Hydrocortisone 21-sulfate, 221 Hydrocortisone 21-m-sulfobenzoate, 221 716 Index

Hydroxyacetanilide prodrugs, structure, 116f structure, 116f N-Hydroxyalkylated polyglutamines, 382f N-Hydroxyalkylated vinyl polymers, 382f Hydroxydione, 225f bis-Hydroxyethyl glycine prodrugs see Bicine/bicin prodrugs Hydroxy groups, 103-106 3-(Hydroxymethyl)phenytoin, 23 lf, 232 Hydroxyprogesterone caproate, "364t Hydroxypropyl methacrylamide copolymer, 286 Hypercholesterolemia, 547 Hypoxia-activated prodrugs, 459, 460f, 461

Ibrimmomab, 509 Ibuprofen, 663t, 665t carboxylic acid ester, 387t regeneration half-life, 388t Indinavir, 185 Indole prodrugs, 300-302 alsterpaullone, 300, 30 lf, 302t Indomethacin, 660t, 663t alkylcarbonylaminoalkyl esters, 109t, 110 farnesyl ester, 660t polyoxyethylene esters, 109t, 110 Integrins, 466 Intestinal peptide transport system, 65 Intra-articular injection, 408-409 Intramolecular cyclization-elimination reactions, 190, 19 lf, 192f Intramuscular absorption, 362, 363-365t Irinotecan, 251,252f Isopropyl benzoate, 386t Isopropyl myristate, 87 Isotopic labeling, 325-326 Itraconazole, 245f, 247

K K7DA peptide, 618 Ketoconazole, 245f, 247 Ketoprofen, 663t carboxylic acid ester, 387t CNS delivery, 592f.593 Index 717

polyoxyethylene esters, 109t, 110 prodrugs cyclodextrin, 691f plasma concentration-time profiles, 405f regeneration half-life, 388t Km, 435 K'm, 435 KNI-722, 189f, 190 KNI-727, 189f, 190, 191 KNI-729, 189f, 190 Kupffer cells, 544, 549 Kupo

L Labetalol, 135 [3-Lactam antibiotics, 48 Lansoprazole, 21 Large amino acid transporter, 619, 620f Latanoprost, 132, 133f Levodopa, 64f, 65t, 387t, 662t CNS delivery, 599f esters, 585 transport, 619 Levonorgestrel, 107t Lexiva see Fosamprenavir LH-RH analogs, 476-477 Linear peptides, 60-61 cyclic prodrugs, 61, 62f Linkers see Spacers Lipids digestion, 658f solubility, 6 transport, 659 Lipophilic esters, 579-594, 661 ester-activated prodrugs, 579-587 bioconversion selectivity, 584-587 ester lability design, 582-584 parent drug hydrophilicity/lock-in potential, 580-581 optimum lipophilicity for CNS delivery, 590-594 overcoming effiux transport, ~87-590 Lipophilic ethers, 661 Lipophilic prodrugs, 41, 42, 43-64, 196 controlled release, 361-362 masking polar ionizable functional groups, 47-654 masking polar non-ionized functional groups, 43-47 718 Index

ocular, 128-129 Liver blood flow, 193 Liver diseases, 546-548 Liver, structure and function, 544f, 545-546 drug metabolism and excretion, 545-546 Liver-targeted drug delivery, 541-572 asialoglycoprotein receptors, 558-560 bile acid transporters, 560-562 enzymes, 551 HepDirect prodrugs, 551-'558 MB07133, 556, 557f, 558 pradefovir, 554, 555f, 556f nucleoside-based drugs, 547, 548f phospholipid prodrugs, 564-565 receptors, 549 transporters, 549, 550f, 551 viramidine, 562-564 YNK-01, 565 LK-A, 662f Locked-in intermediates, 594-603 anionic intermediates, 600-603 phosphates, 601-603 phosphinates, 600-601 phosphonates, 601 redox trapping, 594-600 dihydropyridine-pyridinium redox pair, 595-599 quaternary thiazolium intermediates, 599 Log P, 41-42f Low-density lipoprotein, 477 Loxapine, 233f, 234 Lumigan see Bimatoprost LY303366, 171t, 178, 194 LY307835, 170t LY307853, 178 LY334740, 68f Lymphatic absorption, 653-682 D P-VPA, 670-672 food and formulation considerations, 672-673 glyceride prodrugs, 661-664 lipid digestion, absorption and lymphatic transport, 657-661 lipophilic esters/ethers, 661 phospholipid prodrugs, 664-666 testosterone undecanoate, 667-670 Index 719

M Macromolecular-Directed Enzyme Prodrug Therapy (PDEPT), 455 Macromolecular prodrugs, 379-416 cancer chemotherapy, 478-479 antibody-drug conjugates, 478 polymeric drug delivery, 478 catalytic rate constants, 386t drug attachment to/near polymer backbone, 385-390 enzyme-mediated cleavage of polymer backbone, 395-398 incorporation of spacer group, 390-395 macromolecule-drug bond, 38@ 385 manipulation of drug release rate, 398-403 routes of administration, 385t intra-articular injection, 408-409 oral, 403-406 subcutaneous, 406-407 Magic bullets, 15, 453 Maleic acid, 237f N-Mannich bases, 96, 97f, 98 Matrix metalloproteinases, 423-424, 465 Matrix metalloproteinase-activated prodrugs, 473-474 Maximum tolerated dose, 462, 513 Maytansine, 513 MB07133, 556, 557f, 558 Medroxyprogesterone acetate, 37 It Melagatran, 57, 58f, 350 ionization schemes, 59f prodrugs see Ximelagatran Melphalan, 451,473, 662t Menahydroquinone-4, 239, 240f Menaquinone-4, 239, 240f Menthol-[3-D-glucuronide, 690 Mepitiostane, 660t 6-Mercaptopurine, 87, 88 alkylcarbonyloxymethyl derivatives, 87 characteristics, 91t prodrugs characteristics, 89t solubility, 97t structure, 116f structure, 116f Metabasis, 10 Metabolic enzymes, and failed prodrugs, 70-71 Metabolism, 545-546 Metallo-proteases, 423, 424f 720 Index

Methanol, 50 Methenamine, 13f, 27 Methotrexate, 451,559 aminopeptidase-activated prodrugs, 468-469 spacer groups, 39 It Methyldopa, 387t prodrugs, 344t L-et-methyldopa, 65t, 66f L-ot-methyldopa-L-phenylalanine, 65t, 66f (R)-ot-Methylhistamine, 604-606 Methylprednisolone spacer groups, 391t structure, 393f sulfonate and amino prodrugs, 222, 223f Methylprednisolone acetate, 221,371t Methylprednisolone 21-diethylaminoacetate, 220 Methylprednisolone phosphate sodium, 220 Methylprednisolone 21-succinate, 221 hydrolysis of, 222f Methylprednisolone succinate sodium, 220 Methylprednisolone suleptanate, 222, 223f Metoprolol, 135 Metronidazole, 236, 237f amino acid esters, 236, 237f aminomethylbenzoate esters, 238f dextran ester prodrugs, 391f, 392t, 393f phosphate esters, 237f spacer groups, 391t MFE-CPG2, 532 Michaelis constant, 164 Michaelis-Menton kinetics, 433, 434 Miconazole, 245f, 247 Microspheres, 409 Milacemide, N-dealkylation, 607 Miproxifene, 168f, 17 It Miproxifene phosphate (TAT-59), 168f, 169-170, 170t, 179, 195 dissolution rate, 179 Mitomycin C, 451,460, 516 dextran conjugates, 39@ 395 prodrugs, 373 spacer groups, 391t MMAE conjugates, 517f, 518 Molecular packaging, 596-597 Molecular weight, 287-288 Monoamine oxidase, 607 Monocarboxylic acid transporters, 68-69 Index 721

Monoclonal antibody conjugates, 507-524 acid-labile linkers, 509-513 disulfide-linked conjugates, 513-515 peptide-linked conjugates, 515-518 Monopril see Fosinopril Morphine, 13, 14t, 88 N-Morpholinomethyl salicylamide, 346f Multidrug resistance, 450 Multidrug resistance 1 gene product P-glycoprotein, 164 Multidrug resistance proteins, 550 Mylotarg see Gemtuzumab ozogamicin

N Nadolol, 135, 138f, 139 Nalbuphine prodrugs, 344t, 346f Nalfinavir, 185 Naltrexone PHPG polymer coupling, 402f prodrugs, 344t Nandrolone decanoate, 364t Naproxen, 663t alkylcarbonylaminoalkyl esters, 109t, 110 carboxylic acid ester, 387t dialkylaminoalkylcarbonyoxyalkyl esters, 112 N3A14HS-copoly(HPG/leu) conjugate, 402f, 407f plasma concentration-time curves, 396f polyoxyethylene esters, 109t, 110 prodrugs, 403, 404f, 404t bioavailability, 404t oral administration, 404f release from, 397t subcutaneous administration, 406, 407f regeneration half-life, 388t spacer groups, 391t New chemical entities, 7, 160 Niclosamide, 662t Nicotinic acid esters, 585 Nipecotic acid prodrugs, 580, 58 lf, 583f Nitrogen mustard, 451 matrix metalloproteinase-acti.vated prodrug, 473-474 N-Nitrosourea prodrugs, 472f Nobex, 10 Non-alcoholic steatohepatitis, 547 Non-steroidal anti-inflammatory drugs see NSAIDs Norethisterone enanthate, 364t 722 Index

Novartis, 172 Noyes-Whitney equation, 163 NSMDs, 109, 663t prodrugs, 408f, 409 NTCP transporters, 560-561 Nucleoside kinase, bypass, 548f Nucleoside monophosphate, 551-553 Nucleoside triphosphate, 547, 553

O OATP transporters, 560 Ocular prodrugs, 127-145 acyclovir, 145, 146 adrenergic agonists, 130-132 aqueous solubility, 129 beta-adrenergic agonists, 135-139 carbonic anhydrase inhibitors, 142, 143f controlled release, 372-373 corneal barrier, 128 criteria for, 129-130 dipivefrin, 127, 130, 13 If drug delivery, 127t lipophilicity, 128-129 nadolol, 135, 138f, 139 phenylephrine, 131, 132f physicochemical properties, 1289 pilocarpine, 139-142 prostaglandins, 1-32, 133f, 134f, 135 steroids, 145 tilisolol, 138f timolol, 135, 136t, 137f Oily depot preparations, 366 Oleandomycin, 47f Oligonucleotides, amine PEG prodrugs, 311, 312f, 313t, 314 Olmesartan medoxomil, 60, 61f Olsalazine, 688f Omeprazole, 21, 22f Oral bioavailability, maximization of, 341-342 obstacles to success, 349-352 sequential metabolism, 350 species-dependence of bioactivation, 351 prodrug approach, 342f, 343-349 calcitonin, 345t desmopressin, 345t dopamine, 344t, 346f, 347 Index 723

estradiol, 344t, 346f estrogens, 344t, 347 leu-enkephalin, 345t methyldopa, 344t nalbuphine, 344t, 346f naltrexone, 344t propranolol, 345t, 348 salicylamide, 344t, 346f terbutaline, 345t tetragastrin, 345t, 349 Oral prodrugs, 39-72 barriers to, 39 controlled release, 361,403-406 dose number, 276 drug transport, 40f famciclovir, 44, 45f gastrointestinal absorption, 39, 40f, 41-43 lymphatic absorption, 653-682 DP-VPA, 670-672 food and formulation considerations, 672-673 glyceride prodrugs, 661-664 lipid digestion, absorption and lymphatic transport, 657-661 lipophilic esters/ethers, 661 phospholipid prodrugs, 664-666 testosterone undecanoate, 667-670 melagatran, 57, 58f, 59f oseltamivir (Tamiflu), 16f, 52, 53f, 54 penciclovir, 44, 45f penicillins, 48, 49f phosphate ester, 161-168 poor aqueous solubility, 160-198 tenofovir disoproxil, 16f, 22-23, 23, 54, 55f valacyclovir, 16f, 23, 46, 65, 66t, 67f, 144 Organic anion transporters, 550 in brain, 589 Organic cation transporters, 69-70, 550 Orion Pharma, 172 Oseltamivir, 16f, 52, 53f bioavailability, 54t Osteoarthritis, 409 OX26 monoclonal antibody, 617-6.18 Oxazepam, 14t, 225f Oxazepam sodium succinate, 225f Oxidoreductase-actived prodrugs, 606-608 dihydropyridine oxidation, 606 monoamine oxidase, 607 724 Index

xanthine oxidase, 607-608 2-Oxoclopidogrel, 20, 2 If Oxyanion hole, 421,422f Oxyphenbutazone, 13, 14t Oxyphenbutazone phosphate, 165

P Paclitaxel, 184-185, 45 lf, 452-453 prodrugs, 253-262, 462-46"3 carboxymethyldextran, 262 cathepsin-activated, 470f disulfide conjugates, 515 malic acid esters, 256, 257f 2'-(N-methylpyridinium acetate), 256, 257f 7-(N-methylpyridinium acetate), 257f O-acyl, 190 PEG derivatives, 259, 260f plasmin-activated, 472-473 poly-(L-glutamic acid) conjugates, 260f, 261 Pamidronate, 68 Pancreatic serine proteases, 420-423 Panorex see Edrecolomab Para-aminobenzyl alcohol spacers, 470 Paracellular transport, 39-72 Parecoxib, 16, 17f, 247, 248f Parenteral dosing, 219 Parenteral prodrugs, 217-281 amino acids dexanabinol, 241,242f metronidazole, 236, 237f rapamycin, 240, 24 If camptothecin, 248-253 controlled release, 361-362 absorption/disposition from oily depots, 366 fluphenazine decanoate depot, 366, 367-369f, 370 IM absorption, 362, 363-365t history, 220-225 increased solubility, 220-248 paclitaxel, 253-262 phosphate, 225-231 clindamycin, 226f, 227 estramustine phosphate, 162, 170t, 174f, 180, 228, 229f fosfluconazole, 228, 229f vidarabine-5'-phosphate, 227f Index 725

phosphonooxymethyl GPI 15715, 23f, 24, 50, 162, 235f loxapine, 233f, 234 phenytoin, 23 If, 232 Parke-Davis, 14-15 Partition coefficient, 41, 56-57 Passive diffusion, 39-72 Passive permeability barrier, 577-578 Patents, 9-12 by barrier overcome, 12t literature, 6-7f percent distribution, 10t therapeutic area, 10-1It PDEPT see Polymer-directed enzyme prodrug therapy Pediapred, 162 PEG see Polyethylene glycol Pegamotecan, 250f, 251,296-297 Penciclovir, 44, 45f blood concentrations, 46f Penicillins, 48, 49f Penicillin G, 48 PepT-1 transporter, 65, 68 Peptides, blood-brain transport, 585 Peptide-linked conjugates, 515-518 Peptide mimetics, 60-61 cyclic prodrugs, 61, 62f Peptide transporters, 63-68 Pfizer, 9, 25 Phenacetin, 13f Phenobarbital, 14t Phenylbutazone, 13, 14t Phenylene diamine mustard, 47 If Phenylephrine, 131, 132f Phenylephrine oxazolidine, 131, 132f Phenylephrine pivalate, 132 Phenytoin, 165f, 17 lt, 178, 23 lf, 662t dissolution rate, 179 prodrugs, 23 If, 232 see also Fosphenytoin Phosphate prodrugs, 230f, 601-603 oral delivery absorption model, 164f challenges, 167-168 dose number, 180 enhanced drug absorption, 165f, 166 entacapone phosphate, 170t, 171t, 172f, 173, 177-178 726 Index

estramustine phosphate, 162, 170t, 174f, 180 failure to enhance drug absorption, 166 fludarabine phosphate, 162, 170t, 173f miproxifene phosphate (TAT-59), 168f, 169-170, 170t, 179 oral delivery, 161-168 screening, 192, 193f, 194-196 solubility, 176 parenteral delivery, 225-231 see also individual drugs Phosphinate prodrugs, 600-60"1 Phosphodiesterases, 565 Phospholipid prodrugs, 564-565, 664-666 Phosphonate prodrugs, 601 Phosphonooxymethyl prodrugs, 231-236 N-Phosphono prodrugs, 230f 9-(2-Phosphonymethoxyethyl)adenine, 554 pH partition hypothesis, 56-57, 167 pH-sensitive prodrugs, 459 PHPG see poly-N5-(3-hydrocypropyl)-L-glutamine Physicochemical properties, 5 modification of, 398-403 Pilocarpic acid diester, 139f, 140 Pilocarpic acid monoester, 139f, 140 Pilocarpine prodrugs, 139-142 soft quaternary salts, 141, 142f Pindolol, 135 Pipothiazine palmitate, 365t Pivalic acid, 49-50 Pivampicillin, 49f Plasmin, 427, 464-465 Plasmin-activated prodrugs, 47 lf, 472-473 Plavix (clopidogrel), 20, 2 If PNU 166945, 26 lf, 262 Polyaspartic acid, 286 Polydispersity, 309 Polyethylene glycol prodrugs, 181-185, 283-338 amines, 302-324 benzyl elimination system, 302-316 bicine/bicin, 319f, 320f, 321,322f trimethyl lock lactonization, 317-319 anti-cancer agents, 183 antiviral agents, 294 bicine/bicin, 319-322 bipartate amides, 297-300 camptothecin, 250f, 251,293t, 294t circulatory retention, 287-288 Index 727

clinical trials, 296-297 ester bipartate, 289, 290t ester spacers, 290-294 excretion and toxicity, 295-296 hydrazone derivatives of doxorubicin, 323 indoles, 300-302 labeling studies, 324-326 fluorescent dye labeling, 324f, 325 isotopic labeling, 325-326 paclitaxel, 290t, 291f, 292t prolinkers, 288-295 targeting, 323 tripartite prodrugs benzyl elimination system, 302-316 trimethyl lock lactonization, 317-319 Polyglutamic acid, 286 Poly(L-glutamic acid)-Gly-camptothecin, 250f, 251 Polymer-directed enzyme prodrug therapy (PDEPT), 455 Polymeric drug delivery, 478 Poly[N-(2-hydroxypropyl)methacrylamide], 399, 400t Poly-N5-(3-hydrocypropyl)-L-glutamine, 401 Polysaccharides, 382 Pradefovir, 554, 555f, 556f Prednisolone, 145, 17 lt, 220f Prednisolone acetate, 145 Prednisolone 21-deithylaminoacetate, 220f Prednisolone-21-[3-glucoside, 690 Prednisolone phosphate, 145, 170t, 180 Prednisolone phosphate sodium, 220f Prednisolone succinate sodium, 220f Prednisolone 21-m-sulfobenzoate sodium, 220f Presystemic metabolism, 26 maximization of oral bioavailability, 341-342 obstacles to success, 349-352 prodrug approach, 342f, 343-349 sequential metabolism, 350 species-dependence of bioactivation, 35 It Prilosec, 21 Primadone, 13, 14t Procainamide, spacer groups, 391t Procif, 19f Prodrugs definition, 5f dose number, 176-179 failed strategies, 70-71 functional groups, 94-112 728 Index

oral prodrugs, 39-72 rationale, 7f, 8f, 9 research history, 13-15 screening tools, 196-197 solubility-enhancing, 160-198 structure and reversibility, 112, 113t, 114t successful programs, 24-26 topical delivery, 86-118 unmet needs, 26-27, 71-72 see also individual prodrugs Prodrug central volume, 435 Prodrug-related volume, 434 Prodrug target site volume, 435 Proenzymes, 417-428, 419f activation, 420-424 activation cascades, 425-426 apoptosis, 425f, 426 blood coagulation, 425f, 426 pancreatic serine proteases, 420-423 proenzyme-like prodrugs, 426, 427f Prolinkers, 288-295 Promedrol see methylprednisolone suleptanate Promoiety, 5f Prontosil, 13f, 688f Propofol, 23f, 24, 235f Propranolol, 135, 164, 660t prodrugs, 345t, 348 propranolol palmitate, 660t Proprotein conjugates, amine PEG products, 314f, 315t, 316f Propylene glycol, 87 Prostaglandins, 132, 133f, 134f, 135 Prostate-specific antigen-activated prodrugs, 469 Proteolytic enzymes, catalytic cycles, 424f Proxetil, 52 Psicofuranine, 43f, 44f L-Pyroglumate-L-dopa-L-proline, 65t, 66f Pyrrolothiazole, 244f Q Quaternary thiazolium intermediates, 599 Quercetin, 186t, 187-188 structure, 186f Quinones, 460 Quinuclidine, 233f Index 729

R Ramipril, 585 Rapamycin-28-N,N-dimethylglycinate, 24 If Rapamycin, 240, 241f ester prodrugs, 240, 24 If Ravuconazole, 235f, 236 RB101, 615f Receptor-mediated transcytotic pathways, 617f, 618 Receptors, 549 Redox trapping, 594-600 dihydropyridine-pyridinium redox pair, 595-599 quaternary thiazolium intermediates, 599 Releasable linkers, 456-459 cascade-release dendrimers, 458f, 459 cyclization linkers, 456, 457f electronic cascade linkers, 456f [3-glucuronidase-activated prodrugs, 461-463 Relenza see Zanamivir Rescula see Unoprostone isopropyl Retinyl palmitate, 660t Rheumatoid arthritis, 409 Rheumatoid disorders, 409 Ribavirin, 559, 562, 563f Ricin, 559 Rituxan see Rituximab Rituximab, 509 Roberts-Sloan equation, 93 Rofecoxib, 247

S Salicylamide prodrugs, 344t, 346f Salicylic acid prodrugs, 689f Saquinavir, 185 SCH 59884, 162 Screening tools, 196-197 Serine protease inhibitors, 464 Serine proteases, 424f Shionogi, 10 Skin see Topical delivery Small molecular transporters, 618-619 SN-38, 251,252f prodrugs see Irinotecan Sodium phenytoin, 19f Sodium salicylate, 13f 730 Index

Somatostatin analog, 477 Space of Disse, 545 Spacers, 195, 390-395 acid-labile linkers, 509-513 amine group, 391t anchimeric assistance, 295 carbonyl group, 39 It carboxylic acid, 391t cyclization linkers, 456, 457f, 473f electronic cascade linkers, 456f, 460, 473f ester, 290-294 hydroxy group, 391t para-aminobenzyl alcohol, 470 releasable linkers, 456-459 succinate, 402f Stachyflin, 166f, 17 It Stachyflin phosphate, 170t Stellate cells, 549 Steroid prodrugs, 145 Stratum corneum, as barrier, 86, 87-88 Styrene-maleic anhydride neocarzinostatin copolymer, 286 Subcutaneous injection, 406-407 Succinate spacers, 402f Succinic acid, 237f Suicide inhibitors, 20, 2 If Sulfanilamide, 13f Sulfasalazine, 688f Sulindac, 181 Sulindac sulfide, 181, 182f Sulindac sulfone, 182f Sulindac sulfoxide, 181, 182f Systemic prodrug clearance, 457-459

T-91825, 230f, 231 TAK-456, 245f, 247 TAK-457, 245f, 247 TAK-599, 230f, 231 Takeda, 10 Talaglumetad, 68f Tallisomycin, 516 Tamiflu see Oseltamivir Targeting cancer, 447-506 theoretical and computational models, 429-445 Index 731

background, 431-435 drug permeability effects, 439-444 model based simulations, 455-457 systemic prodrug clearance, 437-439 Target site drug concentration, 457-459 TAT-59 see Miproxifene phosphate Taxanes, 451 Taxol, 289 Telzir see Fosamprenavir Temozolomide, base catalyzed ring opening, 605f, 606 Tenofovir disoproxil fumarate, 16f, 22-23, 23, 54, 55f oral availability, 57f prodrugs, 55f, 56t Terbutaline prodrugs, 345t Tertiary amine prodrugs, 244f Testosterone, 660t prodrugs cypionate, 365t enanthate, 365t undecanoate, 660f, 667-670 Tetragastrin prodrugs, 345t, 349 Theophylline, 88 characteristics, 91t prodrugs characteristics, 90-91t solubility, 97t structure, 116f structure, 116f Therapeutic advantage, 431,432 Therapeutic index, 431,450 Thiamine, 62, 63f deficiency, 63-64 Thioamide/thioimide groups, 101-103 alkylcarbonyloxymethyl, 102-103 N-alkyl-N-alkyloxycarbonylaminomethyl, 103 Thiorphan, 663t Thymidine phosphorylase, 612-613 Thyrotrophin-releasing hormone, CNS delivery, 597, 598f Tilisolol, 138f Timolol, 135, 136t, 137f prodrugs, 136t, 137f TIMP2, 423-424 Topical prodrugs, 86-118 amide-/imide-like functional groups, 94-101 alkylcarbonyloxymethyl, 89t, 94-96 dialkylaminomethyl, 89, 96, 97f, 98 732 Index

N-acyl, 89t, 98-101 carboxylic groups, 108, 109t, 110, 11 lt-112 controlled release, 406-407 hydroxy groups, 103-106 model development, 89-91t, 92-93 thioamide/thioimide groups, 101-103 alkylcarbonyloxymethyl, 102-103 N-alkyl-N-alkyloxycarbonylaminomethyl, 103 water solubility, 86-87 Tosimmomab, 509 Transcellular passive diffusion, 39-40 Transcellular transport, 39-72 Transferase-activated prodrugs, 609-615 adenosine deaminase, 609-612 glutathione/glutathione S-transferase, 613-615 thymidine phosphorylase/cytidine deaminase, 612-613 Transporters, 39-72, 549, 550f, 551 bile acid, 560-562 efflux, 26-27, 39-72 gastrointestinal tract, 63-70 glucose, 620, 62 If intestinal peptide, 65 large amino acid, 619, 620f monocarboxylic acid, 68-69 NTCR 560-561 OATE 560 organic anion, 550 organic cation, 69-70, 550 PepT-1, 65, 68. peptide, 63-70 small molecular, 618-619 Transporter/receptor-mediated delivery, 617-621 glucose transporter, 620, 62 If large amino acid transporter, 619, 620f receptor-mediated transcytotic pathways, 617f, 618 small molecular transporters, 618-619 Trasmzamab, 509 Travatan see Travoprost Travoprost, 132, 133f Triamcinolone acetonide, 37 It Triamcinolone diacetate, 37 It Triazolium salts, 245f, 247 Trimethyl lock lactonization prodrugs, 317f, 318t, 319t daunorubicin, 318t, 319t Troleandomycin, 47f Trypsin, 420, 421 Index 733

Trypsinogen, 420

U Ulcerative colitis, 403 Unoprostone isopropyl, 132, 133f Urokinase-type plasminogen activator system, 464-465

V Valacyclovir, 16f, 23, 46, 65, 66t, 67f, 144 carrier-mediated transport, 66-67 Valcyte see Valganciclovir Valdecoxib, 16, 17f, 247, 248f Valganciclovir, 16f, 23, 67f D-Valine-acyclovir, 66t Valproate, 663t, 665t Vancomycin amine PEG prodrugs, 307f, 308f, 309t, 310f, 311f pharmacokinetics, 309t Variable domain resurfacing, 513 VDEPT see Virus-directed enzyme prodr-ug therapy Velcade (bortezomib), 19, 20f Verapamil, 562 Vertex Pharmaceutical, 16, 175 Vidarabine-5'-formate, 227f Vidarabine-5'-phosphate, 227f Vidarabine, 227f Vinca alkaloids, 451 Vinyl-type copolymer conjugates, 401f Viramidine, 562, 563f, 564 Viread see Tenofovir disoproxil Virus-directed enzyme prodrug therapy (VDEPT), 433, 455 Vitamin A (retinol), 660t Vitamin B1 see Thiamine Vitamin E, 660t prodrugs, 660t Vitamin K prodrugs, 239, 240f V .... 435 Volume of distribution, 26

W Warner-Lambert, 19 Water solubility, 86-87 734 Index

ocular prodrugs, 129 poor, overcoming, 160-198 Wernicke's disease, 3 Wettability, 401 Woodchuck hepatitis virus, 564 x Xalatan see Latanoprost Xanthine oxidase, 607-608 Xeloda see Capecitabine Xenoport, 10, 71 Ximelagatran, 23[, 24, 57, 58[, 350

YNK-Ol, 565 z Zanamivir, 53 see also Oseltamivir ZD2767~ 531 ZD-6061, 162 Zevalin see Ibritumomab Zidovudine, 660t, 665t AZT-5'-esters, 660t CNS delivery, 588[, 589[, 590-591, 596, 603[ spacer groups, 391t Zinnat see Cefuroxime axetil Zofenopril, 585 Zuclopenthixol decanoate, 365t Index

Page numbers followed by f or t indicate figures or tables, respectively.

A-85783, 327t Absorption, distribution, metabolism and excretion see ADME ABT299, 327t Acetaminophen, 78f bis-(N-Acetoxybenzamidines), 195 Acetylcholinesterase, 349 N-Acetyl-L-cysteine, 107 N-Acetyloxymethyl phenytoin, 153f O-Acetylpropranolol, 35f S-Acetylthionethanol esters, 244 Acivicin, 107 Acyclic prodrugs of cyclic drugs, 171-1 74 Acyclovir bioavailability, 43 plasma concentrations, 674f prodrugs see Valacyclovir N-Acylcarbonylbenzamidines, 199-201 Acyl-CoA, 427, 458 Acyloxyalkoxy systems, 268-273 (Acyloxy)alkyl/[(alkoxycarbonyl)oxy]methyl esters, 15-1 7 Acyloxyalkyl esters amides/imides, 152-159 amines, 113,114,115 Acyloxyalkyl phosphate esters, 251 Acyloxyalkyl phosphonate esters, 237-242 N-Acyloxybenzamidines, 198-199 N-Acyl prodrugs, 105-109 amides/imides, 160-168 peptide-assisted cleavage, 106-107 promoiety-assisted cleavage, 107-109 N,0 Acyl transfer prodrugs, 168-171 Adefovir, 239[, 256t prodrugs, 234, 256t ~ acyloxyalkyl esters, 238, 239f alkoxycarbonyloxyalkyl esters, 237-238 phosphonamidates, 242 see also Adefovir dipivoxil 704 Index

Adefovir dipivoxil, 238, 239[, 350t, 387, 441t, 451-458 clinical spectrum, 457-458 degradation, 388f formulation issues, 456 mechanism and site of bioconversion, 455 rationale, 453-454 resistance, 458 structures and bioconversion pathway, 453f synthesis, 454, 455f toxicity, 456 ADEPT see Antibody-directed enzyme prodrug therapy ADME, 346,416-417 Alatrofloxacin mesylate, 398t Alcohol/phenol prodrugs, 31-81 aliphatic/aromatic esters, 34-46 aliphatic esters, 35-40 a-amino acid and cyclic amino acid esters, 41-46 aromatic esters, 40-41 hemiesters of dicarboxylic acids, 39-40 carbamate esters, 55-58 ethers, 60-63 intramolecular activated, 63-78 release by cyclization-elimination reaction, 66-73 release by electronic cascade, 73-78 oxidation/reduction leading to hydroxylation, 78-81 phosphate esters, 46-52 sulfamate esters, 58-60 Aldehyde oxidase, 533f Aldomet see Methyldopate hydrochloride Aldophosphamide, 367f Alendronate sodium, 241,2421 Alginic acid, 312 Aliphatic/aromatic esters, 34-46 aliphatic esters, 35-40 a-amino acid and cyclic amino acid esters, 41-46 aromatic esters, 40-41 hemiesters of dicarboxylic acids, 39-40 bis-N-Alkoxyamidines, 194-195 anti-Pneumocystis activity, 206t N-Alkoxycarbonylbenzamidines, 199-201 anti-Pneumocystis activity, 215t inhibition of collagen-induced platelet aggregation, 216t, 217t Alkoxycarbonyloxyalkyl phosphonate esters, 237-242 Alkoxycarbonyloxybenzamidines, 198-199 platelet aggregation, 213t, 214t Alkoxycarbonyl?xymethyl phosphate esters, 251 Index 705

Alkyl phosphate esters, 248-250 Alkyl phosphonate esters, 230-237 Allopurinol, 144, 367 prodrugs, 154j: 164, 165f Amide/imide prodrugs, 133-175 acyclic prodrugs of cyclic drugs, 171-1 74 N-acyloxyalkyl prodrugs, 152-159 N-acyl prodrugs, 160-168 N,O acyl transfer prodrugs, 168-171 advantages, 136-137 definitions, 135-136 N-hydroxyalkyl prodrugs, 149-152 imidazolidinone prodrugs, 147-149 N-Mannich bases, 142-146 oxazolidinone prodrugs, 159-160 redox prodrugs, 174-175 sulfenamide prodrugs, 137-142 Amifostine, 329, 330t, 398t, 463-468 clinical profile, 467-468 formulation, 467 mechanism and site of bioreversion, 466-467 rationale, 465-466 structures and bioconversion pathway, 465f synthesis, 466 toxicity, 467 Amine prodrugs, 101-123 N-acyl derivatives, 105-109 peptide-assisted cleavage, 106-107 promoiety-assisted cleavage, 107-109 N-acyloxyalkyl derivatives, 113 azo compounds, 121 basicity, 103-104 carbamates, 109-113 double prodrugs, 110-111 higher order prodrugs, 111-113 enaminones, 120 4-imidazolidinones, 122-123 N-Mannich bases, 117-118 oxazolidines, 121-122 N-oxides, 116-117 quaternary ammonium derivati'les, 113-116 Schiff bases, 119-120 a-Amino acid esters, 41-46 E-Aminocaproic acid, 309 Aminoimidazole carboxamide, 370 Amino-pendent polyacetals, 314j: 315 706 Index

5-Amino salicylic acid, 121 Amiodarone, 115 Ampicillin, 1471 Ampiroxicam, 611 pharmacokinetics, 62t Amprenavir, 491 pharmacokinetics, 50t prodrugs see Fosamprenavir Amtolmetin guacil, 151 Angiotensin-converting enzyme inhibitors, 246-248 Anthracyclines, 1181 Antibody-directed enzyme prodrug therapy (ADEPT), 50-51,55,112,305 AQ4N, 117.h 3711 Aquavan see GPI 15715 Ara-C, 249.h 304, 363-364 Ara-CM~ 2491 alkyl prodrugs, 2491 Arachis oil, 395 Aromatic esters, 34-39, 40-41 Aryl esterase, 607 Aryl esters, 14-15 Aryl phosphate esters, 248-250 Aryl phosphonate esters, 230-237 blood levels, 231-233t Ascorbic acid, 393t Atacand see Candesartan cilexetil Aza-2,5-bis-benzamidofuran derivatives, anti-trypanosomal activity, 207-21 Ot 3'-Azido-2',3'-dideoxyuridine, 61f 3'-Azido-3'-deoxythymidine, 60.h 61 Azo compounds, 121 AZT see Zidovudine

Bambec see Bambuterol Bambuterol, 56, 571 Barbital, 1741 Barbituric acids, 172f, 1731 Benazepril, 9t, 350t prodrugs see Benazepril hydrochloride Benazepril hydrochloride, 389 Benicar see Olmesartan medoxomil Benzaclin see Clindamycin phosphate Benzamidine prodrugs, 189-217 N-acyl- and N-alkoxycarbonylbenzamidines, 199-201 anti-Pneumocystis activity, 203-206t Index 707

anti-trypanosomal activity, 207-21 Ot bioavailability, 212t N-hydroxybenzamidines, 192-199 bis-(N-acetoxybenzamidines), 195 bis-N-alkoxyamidines, 194-195 N-alkoxycarbonyloxybenzamidines and N-acyloxybenzamidines, 198-199 bis-N-hydroxybenzamidines, 193-194 metabolism, 192-193 as protease inhibitors and integrin antagonists, 196-198 oxadiazolidinones, thiadiazolidinones and 5-membered heterocycles, 201-202 pharmacokinetics, 211t platelet aggregation, 213t, 214t 2,5-bis-Benzamidofuran derivatives, anti-Pneumocystis activity, 205t N-(Benzylaminomethyl)benzamide, 145[ Benzyl phosphate esters, 248-250 Benzyl phosphonate esters, 230-237 blood levels, 231-233t Bergman cyclization, 333f, 334f, 335[ Betamethasone acetate celestone soluspan, 398t Betamethasone phosphate sodium, 398t Bimatoprost, 11[ Biphenyl hydrolase-like protein, 42 Bisphosphonates, 241, 242f Blood-brain barrier, 105-106, 357-360 BMS-207147, 325 Boniva see Ibandronate sodium Brain, drug delivery, 105-106, 357-360 6-Bromohexanoic acid, 310 Brovincamine, 8[ Butanilicaine, 352[, 352t n-Butyl esters, 12-13 Butyrylcholinesterase, 349 O-Butyryl timolol, 36[ Bystander effect, 362 c

Calcium carbonate, 393t Calicheamicin, 333[ Camptosar see Irinotecan Camptothecin, 67f, 308, 571 Candesartan, 373[ Candesartan cilexetil, 350t, 373[ Capecitabine, 11 Of, 331, 365[ bioconversion, 480 clinical profile, 480-481 708 Index

design and discovery, 475,476[, 477[, 478f formulation, 480 rationale, 475 structures and bioconversion pathway, 475f tumor selective delivery, 478, 479[, 480f see also 5-Fluorouracil Capoten see Captopril Captopril, 330t, 555 Carbamate ester prodrugs, 55-58 Carbamates, 109-113 Carbamazepine, 145, 146f Carboxyesterases, 349 activity of, 352t sub-cellular localization, 355-356 Carboxylic acid prodrugs, 3-23 ester prodrugs, 5-18 (acyloxy)alkyl/[(alkoxycarbonyl)oxy]methyl esters, 15-17 aryl esters, 14-15 n-butyl esters, 12-13 ethyl esters, 8-11 isopropyl esters, 11-12 methyl esters, 5-8 (oxodioxolyl)methyl esters, 17-18 lactones, 20-21 oxidative activation, 18-20 Carboxymethyl cellulose, 312 Carboxymethyl dextran, 294t, 312 Carboxy-n-pentyl-dextran, 310 Carboxyphosphamide, 367f Carboxysterase, 332f Carfecillin, 14f Carindacillin, 14f Carmofur, 476f Carnitine homeostasis, 429-440 cellular pivaloylcarnitine generation, 430-440 animal models, 430-432 clinical experience in humans, 436-437 human studies, 432-436 special clinical populations, 437-440 humans, 429-430 CB 1954, 363f Cefatamet pivoxil, 16t Cefcapene pivoxil, 16t Cefditoren pivoxil, 433, 434[, 441t, 485-491 clinical profile, 489, 490t, 491f formulation, 489 Index 709

mechanism and site of bioreversion, 488-489 pharmacokinetics, 490t rationale, 487-488 structures and bioconversion pathway, 487[ synthesis, 488[ toxicity, 489 Cefotiam hexetil, 16t Cefpodoxime proxetil, 16t, 687-692 clinical profile, 690, 691[, 692t formulation, 681 mechanism and site of action, 680-681 pharmacokinetics, 692t rationale, 680 structures and bioconversion, 680[ synthesis, 680 toxicity, 681 Cefteram pivoxil, 16t Ceftin see Cefuroxime axetil Cefuroxime axetil, 16t, 495-502 clinical profile, 499-500 formulation, 499 mechanism and site of bioreversion, 499 pharmacokinetics, 500t rationale, 497-498 serum levels, 500[, 50If structures and bioconversion pathway, 497[ synthesis, 498[, 499 toxicity, 499 Celecoxib, 353, 639 Celestone soluspan see Betamethasone CellCept see Mycophenolate mofetil Central nervous system see Brain Cerebyx see Fosphenytoin Chemical stability, 385 Chemotherapy, drug-induced resistance, 368-369 Chloramphenicol, 367 Chloroacetaldehyde, 367f N,N-di-(2-Chloroethyl)-phenylene diamine mustard, 303[ Chlorpromazine, 367 Chlorzoxazone, 153[ Cholesterol esterase, 349 Cholinesterases, 110 Cicaprost, 19[ Cidofovir, 234, 235[, 245[, 246 ether lipid esters, 245[, 246 710 Index

Cilazapril, 9t Cimicoxib, 167[ Cinnarizine, 115 Cleocin phosphate see Clindamycin phosphate Cleocin T see Clindamycin phosphate Clindagel see Clindamycin phosphate Clindamycin, 42, 43[ prodrugs see Clindamycin phosphate Clindamycin phosphate, 42,43[, 3.98t, 507-516 assay, 512, 513[ bioconversion and blood levels, 513, 514[, 515[ formulations, 515-516 parenteral clinical observations, 510 reduced pain on IV/1M injection, 510 physicochemical properties, 512 rational, 510 safety, 515 stability in solution, 513 structure, 509[ synthesis, 512 topical clinical observations, 511-512 reduced GI side effects, 511 use, 509 Clindets see Clindamycin phosphate Clopidogrel, 20[ Cocaine, 8[ Codeine, 373 Coenzyme A, 427 Cortisone, 311,312f Cortisone acetate, 399t Cortone see Cortisone acetate Coumarins, 109 Coumarinic acid-based prodrugs, 273-279 application to peptide mimetics, 278, 279[ coumarin-based prodrugs of opioid peptides, 276-278 cyclic, conformational effect on permeability, 279-280 facile cyclization, 276[ structural effect on release kinetics, 274[, 275t, 276[ CPT-II see Irinotecan Cremophor EL, 406 CS-866 see Olmesartan medoxomil Cyclic amino acid esters, 41-46 Cyclic HPMPC, 234, 235[ aryl ester prodrugs, 236[ Index 711

Cyclization, 385 Cyclization-elimination spacers, 64-65, 66-73 O-Cyclobutanoyl timolol, 36[ Cyclooxygenase, 61 Cyclooxygenase inhibitors see Parecoxib Cyclophosphamide, 366, 367[ CycloSal-pronucleotides, 251[, 252t, 253 Cycloserine, acetylacetone prodrug, 120 Cyclosporin A, 169[, 282 CYP2B6, 366 CYP2C9*2, 372 CYP2C9*3, 372 CYP2C9, 366,371 CYP3A4, 366,371 CYP450 enzyme prodrugs, 370-374 losartan, 371-374 CYP450 reductase, 363 Cysteine, 329, 330t Cytidine deaminase, 332[, 477[ Cytochrome see CYP Cytomegalovirus, 234 Cytosine arabinoside see AraC Cytotoxic drugs, tumor-specific delivery, 360-370 Cytovene see Ganciclovir

Dacarbazine, 371[ DADLE, 269, 270t acyloxyalkoxy cyclic prodrugs, 271-272 properties, 272t coumarin-based prodrugs, 276-278 properties of, 277t properties, 272t synthesis, 271[ Dalalone D.~ see Dexamethasone acetate Dapsone, prodrugs, 107 Daunorubicin, 312 prodrugs, 122,312 DB-67, 404[ Decadron see Dexamethasone phosphate sodium Decadron-LA see Dexamethasone acetate Delapril, 9t Delatestryl see Testosterone enanthate Delta-sleep-inducing peptide, 268, 270t Dendrimers, 76, 77[, 78, 121 712 Index

5'-Deoxy-5-fluorocytidine, 354 Depo-Medrol see Methylprednisolone acetate Depo-Provera see Medroxyprogesterone acetate Desmethyldiazepam, 1741, 175f Dexabinol, 43, 44f prodrugs, 43, 441, 45f Dexamethasone, 307, 367 Dexamethasone acetate, 399t Dexamethasone phosphate sodium, 400t Dextran, 293t, 294t, 305 dicarboxymethyl, 309 modified, 307-308, 308f partially oxidized, 2941, 307-308, 309f Diazepam, 791, 1741, 175f Dicarboxylic acid hemiesters, 39-40 Dicarboxymethyl dextran, 294t, 309 cis-Dichloro(cyclohexane-trans-1-1,2-diamine)platinum, 308 Diclofenac, 306 Dicyclohexylcarbodiimide, 310 Dideoxyinosine, 358, 359f Diethylamine, 145f Diflucan see Fluconazole 5,6-Dihydro-5-fluorouracil, 331 Dihydropyrimidine dehydrogenase, 331,3321 Diketopiperazine, 30If Dimerization, 385 5,5-Dimethyl-2,4-oxazolidinedione, 1741, 175 Dimethylamine, 144f Dipivefrine, 37, 38f Dipropylamine, 145f Directed enzyme prodrug therapy, 368 Disodium citrate, 390 Disulfide prodrugs, 330t Dithioethanol esters, 244 DMP754, 389, 390f L:Dopa see Levodopa Dopa decarboxylase, 358 Dopamine, 358f prodrugs, 1051, 106-107 Double prodrugs, 108, 110-111 Doxorubicin, 107, 361f conjugation, 314f prodrugs, 122 Drug exposure, 414-415 Drug resistance, 368-369 DT-diaphorase, 363 Index 713

Duac see Clindamycin phosphate Dynastat see Parecoxib Dynemicin A, 333[, 334

E3174, 19[ Efflux transporters, 357 Electronic cascade spacers, 65, 73-78, 111[ EMD 76334, 200 Enalapril, 9t, 348[, 350t, 389[, 521-526 clinical profile, 525[, 526 formulation, 524-525 mechanism and site of bioreversion, 524 rationale, 523-524 structure and bioconversion pathway, 523[ synthesis, 524 toxicity, 524 Enalaprilat, 525[ prodrugs see Enalapril Enaminones, 120 Enediyne prodrugs, 333-335 Enhanced permeability and retention effect, 292-296 [leus-]Enkephalin, 269, 270t acyloxyalkoxy cyclic prodrugs, 271, 272t coumarin-based prodrugs, 276, 277t, 278 properties, 272t synthesis, 271[ Enosiprost, 6t Enprostil, 6t Enterocytes, 356[ EO-9, 363[ Epinephrine, 37, 38[ Eptaloprost, 19[ Esmolol, 8[ Esterases, 349-355 Ester prodrugs, 5-18, 349-355 (acyloxy)alkyl/[(alkoxycarbonyl)oxy]methyl esters, 15-17 aryl esters, 14-15 n-butyl esters, 12-13 isopropyl esters, 11-12 (oxodioxolyl)methyl esters, 17-18 Estradiol 17-N,N-dimethylaminobutyrate, 360[ Estradiol, 360[ Ether prodrugs, 60-63 N-Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, 302 714 Index

5-Ethyl-5-methyl-2,4-oxazolidinedione, 174[, 175 5-Ethyl-5-phenylhydantoin, 174f Ethylenediamine, 310 Ethyol see Amifostine Etopophos see Etoposide phosphate Etoposide, 49, 51[, 67f prodrugs, 71,72f see also Etoposide phosphate Etoposide phosphate, 49, 51[, 400t Etoricoxib, 639 Exanta see Ximelagatran Excipients, 393t EXP3174, 371,372f Extended release solutions, 407 Extended release suspensions, 408

Factor Xa inhibitors, 197f Famciclovir, 37[, 353[, 531-537 clinical profile, 535, 536[, 537 mechanism and site of bioconversion, 534, 535f prodrugs, 369 rationale, 533-534 structures and bioconversion pathway, 533f synthesis, 534 toxicity, 535 Fenoprofen, 306 First-pass metabolism, 33,371 Flouruidine, 354 Fluconazole, 42, 43[, 367 Fludarabine phosphate, 40It 5-Fluoro-2'-deoxyuridine-5'-monophosphate, 364 5-Fluorouracil, 110, 364, 365f prodrugs, 155, 156[, 161-164[, 331 see also Capecitabine Fluphenazine enanthate, 38f Fluvastatin, 2lf Formaldehyde, 145, 388f Formamidine-type prodrugs, 119f Formulation of prodrugs, 383-408 oral formulations, 387-396 effect of pH, 389-394 effect ofwater, 387-389 liquid filled capsules, 394-396 oral solutions, 394 Index 715

parenteral formulations, 396-408 lipid-soluble prodrugs, 406-408 solubility enhancement, 397-404 water-soluble prodrugs, 404 see also individual prodrugs Fosama see Alendronate sodium Fosamprenavir, 49f, 541-547 clinical profile, 545, 546t 547 concentration-time profiles, 546[ formulation, 545 mechanism and site of action, 54~ 545 pharmacokinetics, 50t rationale, 543 structures and bioconversion pathway, 543[ synthesis, 544 toxicity, 545 Fosfluconazole, 48[ Fosinopril, 247t 350t, 353t 551-556 clinical profile, 555-556 formulation, 554 mechanism and site of bioreversion, 554 rationale, 553 structures and bioconversion pathway, 553[ synthesis, 554 toxicity, 554 Fosinoprilat, 246, 247[ prodrugs see Fosinopril Fosphenytoin, 51, 137t 157, 158t 370t 401t, 559-565 clinical profile, 563, 564t 565 formulation, 562-563 mechanism and site of bioreversion, 562 rationale, 561 shelf-life, 404-405 structures and bioconversion pathways, 561[ synthesis, 562 toxicity, 562 Fradafiban, 200 Ftorafur, 364, 365[ Functional groups, 265-288 Furamidine, 191t 207t Furtulon, 476[

Ganciclovir bioavailability, 43 716 Index

prodrugs, 42f see also Valganciclovir GCS 35601, 7[ GCS 37808, 7[ GDEPT see Gene-directed enzyme prodrug therapy Gemcitabine, 354 Gemeprost, 6t Gemfibrozil, 300, 301[ Gene-directed enzyme prodrug therapy (GDEPT), 361, 368 Glutethimide, 173f GPI 15715, 51,52f GS-7171, 243t GS-7339, 243t GS-7340, 242, 243t GS-7485, 243t

HAART therapy, 49, 653 Haemophilus influenzae, 499 Haldol decanoate see Haloperidol decanoate Haloalkyl phosphate esters, 248-250 Haloalkyl phosphonate esters, 230-237 blood levels, 231-233t Haloperidol decanoate, 37, 38[, 401t Hammett plot, 283 Helicobacter pylori, 615 Hepatocytes, 356f HepDirect technology, 255, 256[, 256t, 257 Hepsera see Adefovir Hetacillin, 147[ Histamine, 296 HI~ 234, 653-654 HIV protease inhibitors, 170[ Hormone replacement therapy, 58[, 59[ Hyaluronan, 294t, 295t, 311[ Hydantoins, 171, 172 Hydrocortisone, 311, 312f prodrugs, 57, 58f Hydrocortisone acetate, 40It Hydrocortisone phosphate sodium, 402t N-Hydroxyalkyl prodrugs, 149-152 N-Hydroxybenzamidines, 192-199 anti-Pneumocystis activity, 203-205t bis-N-hydroxybenzamidines, 193-194 metabolism, 192-193 Index 717

as protease inhibitors and integrin antagonists, 196-198 bis-N-Hydroxybenzamidines, 193-194 anti-Pneumocystis activity, 203-205t bis-(N-acetoxybenzamidines), 195 bis-N-alkoxyamidines, 194-195 N-alkoxycarbonyloxybenzamidines and N-acyloxybenzamidines, 198-199 2-Hydroxymethylbenzamide prodrugs, 108f N-Hydroxymethylbenzamide prodrugs, 150f Hydroxymethylnitrofurantoin, 151f N7-Hydroxymethyl theophylline, 151f Hydroxynaphtholquinones, 521 N-(2-Hydroxypropyl)methacrylamide (HPMA), 295t, 313f

Ibandronate sodium, 241, 2421 Ibuprofen, 306 Ibuprofen guaiacol ester, 15f Ifosfamide, 366, 367f Imidapril, lOt Imidazolidinone prodrugs amides/imides, 147-149 amines, 122-123 Imide prodrugs see Amide/imide prodrugs Indomethacin farnesil, 395, 396f Inosine monophosphate dehydrogenase, 601 Integrin antagonists, 196-198 Intracellular prodrugs, 234 Intramolecular activated prodrugs, 63-78 release by cyclization-elimination reaction, 66-73 release by electronic cascade, 73-78 N,O-Intramolecular acyl migration-based prodrugs, 281-283 Inulin, 294f, 305 Irinotecan, 350t, 354-355, 355f, 569-576 assay, 574 bioconversion and pharmacokinetics, 574, 575f formulation, 573 physicochemical properties, 572, 573f rationale, 571-572 safety, 575-576 stability, 405, 406f structure and bioconversion, 571f synthesis, 5721 Irinotecan hydrochloride, 56f, 402t N-(Isobutylaminomethyl)benzamide, 145f 718 Index

O-Isobutyryl timolol, 36f Isocarboxazid, 352f, 352t Isocyclosporin A, 282 Isoniazid, 296 Isopropyl esters, 11-12

Ketoprofen, 306 Kinase bypass, 255

Lactones, 20-21 Lamifiban, 197, 198f Latanoprost, 12t, 350t, 581-586 clinical profile, 585-586 formulation, 584f, 585 mechanism and site of bioreversion, 583-584 rationale, 583 structure, 583f synthesis, 583 toxicity, 584 Lefradafiban, 19 If, 192, 200 Lenampicillin, 17f Levodopa, 348f, 358, 359f prodrugs, 106-107 Levomet, 7f Lexiva see Fosamprenavir Linezolid, 139, 140f Linkers see Spacers Lipid-soluble prodrugs, 406-408 extended release solutions, 407 extended release suspensions, 408 Liquid filled capsules, 394-396 Jjong-chain alkyloxyalkyl monoesters, 245f, 246 Losartan, 371-374 Losartan potassium, 19f Lotensin see Benazepril Lotrel see Benazepril Lovastatin, 21f Loxapine, 115 Lumiracoxib, 639 LY354740, 221 LY354740-L-Ala, 221 Index 719

Macromolecular prodrugs, 289-315 enhanced permeability and retention effect, 292-296 linkage importance, 296 poly-amino acids, 296-305 polysaccharides, 305-313 synthetic polymers, 313-315 Malathione, 352[, 352t N-Mannich bases amides/imides, 142-146 amines, 117-118 MCC-478, 236f MDL100173, 329, 330t MDL100240, 330t ME3229, 13f ME3277, 13f Medroxyprogesterone acetate, 402t Melagatran, 196, 698f prodrugs see Ximelagatran ethyl-Melagatran, 698f OH-Melagatran, 698f 5-Membered heterocycles, 201-202 Mephenytoin, 1721 Mephobarbital, 174f Metharbital, 174f Methoin, 174f Methotrexate, 297, 298f 0-2'-Methylcyclopropranoyl timolol, 36f Methyldopate hydrochloride, 403t 3-Methylphenytoin, 1721 Methylprednisolone acetate, 307, 403t Methylprednisolone succinate sodium, 403t 0-1'-Methyl timolol, 36f Metronidazole, 305, 306f Metronidazole hemiglutarate, 39f Metronidazole hemimaleinate, 39f Metronidazole hemisuccinate, 39f Metronidazole p-methoxybenzoate, 41f Metronidazole p-nitrobenzoate, 41f Midodrine, 107 Misoprostil, 6t Mitomycin C, 309, 361f dextran conjugates, 309 Moexiprilat, 391, 591 prodrugs see Moexipril hydrochloride 720 Index

Moexipril hydrochloride, lOt, 389, 589-595 clinical profile, 595, 5961, 597 excipients, 393t formulation, 592, 593[ mechanism and site of bioreversion, 592 pharmacokinetics, 392, 3931, 394[ pH-rate profiles, 392f product distribution profiles, 392f rationale, 591 structures and bioconversion pathway, 591[ synthesis, 592 toxicity, 592 Monopril see Fosinopril Morpholine, 144f N-(Morpholinomethyl)-p-toluenesulphonamide, 145[ Mycophenolate mofetil, 131, 599-603 clinical profile, 603 formulation, 602-603 mechanism and site of bioconversion, 602 rationale, 601-602 structures and bioconversion pathway, 601[ synthesis, 602 toxicity, 602 Mycophenolic acid, 601[

Naproxen, 306-307 O-Neopentanoyl timolol, 36[ Neuraminidase, 627 Neuraminidase inhibitors see Oseltamivir; Zanamivir Niflumic acid, 18[ Nitric oxide synthase, 363 4-Nitrobenzylcarbamate, 334[ Nitrofurantoin, 151[ Nitrogen-containing heteroaromatic rings, prodrugs of, 325-328 p-Nitrophenyl acetate, 352[, 352t 4-Nitrophenyl carbonates, 303[ Nitroxide radical, 362 NM441, 18[ Non-steroidal anti-inflammatory drugs see NSAIDs Norfloxacin, 302, 303[ NSAIDs, 61[ Nucleoside prodrugs, 363-366 Index 721

Oligopeptide transporter, 43 Olmesartan, 607[ prodrugs see Olmesartan medoxomil Olmesartan medoxomil, 17[, 605-610 clinical profile, 608, 609[, 610 formulation, 608 mechanism and site of bioconversion, 607-608 rationale, 607 structures and bioconversion pathway, 607[ synthesis, 607 toxicity, 608 Omeprazole, 613-618 clinical profile, 618 formulation, 617, 618f mechanism and site of bioreversion, 616[, 61 7 rationale, 615-616 structures and bioconversion pathway, 615f synthesis, 616 toxicity, 61 7 Opioid peptides, coumarin-based prodrugs, 276-278 Oral bioavailability, 347-357 barriers to, 357 ester prodrugs, 349-355 Oral formulations, 387-396 effect of pH, 389-394 effect ofwater, 387-389 liquid filled capsules, 394-396 oral solutions, 394 Oral solutions, 394 Orapred see Prednisolone Ornoprostil, 6t Oseltamivir, I1f, 348[, 351t, 623-631 clinical profile, 627, 628[, 629[, 630-631 formulation, 626 mechanism and sites of biotransformation, 626 rationale, 625 structures and bioconversion pathway, 625f synthesis, 625-626 Oseltamivir carboxylate, 625[ Oxadiazolidinones, 201-202 Oxazaphosphorines, 366-367, 370, 371f Oxazepam, 79[ Oxazolidines, 121-122 Oxazolidinone prodrugs, 159-160 722 Index

on peptides, 280-281 Oxidation/reduction reactions, 78-81 N-Oxides, 116-117 Oxindole, 62, 63f prodrugs, 62, 63f 2-0xothiazolidine prodrugs, 330t Oxprenolol, prodrugs, O-pivaloyl oxprenolol, 37, 38f Oxymethyloxycarbonyl spacers, 112f

Paclitaxel, 67[, 68[, 169, 170[, 297 prodrugs, 69[, 74[, 75[, 76f N,O-acyl transfer, 169, 170f PROTAX, 70f solubility, 406, 407f Paclitaxel-N-hydroxysuccinimido-hemisuccinate, 312 Paclitaxel oleate, 407f Paramethadione, 174[, 175 Parecoxib, 167[, 635-642 clinical studies, 639, 640[, 641j: 642 formulation, 639 mechanism and site of bioreversion, 638 pharmacokinetics, 639, 640[, 641[, 642 rationale, 637, 638f structure and bioconversion pathway, 637f synthesis and physico-chemical properties, 638 toxicity, 638 Parenteral formulations, 396-408 lipid-soluble prodrugs, 406-408 solubility enhancement, 397-404 water-soluble prodrugs, 404 Partially oxidized dextrans, 294[, 307-308, 309f Pediapred see Prednisolone Penciclovir, 37f -~ prodrugs see Famciclovir Pentamidine, 191[, 193, 205t, 207t prodrugs, bis-(N-acetoxybenzamidine), 195 Peptides, functional groups, 265-288 cyclic prodrugs, 208-280 conformational effects, 279-280 coumarinic acid-based prodrugs, 273-279 phenylpropionic acid and acyloxyalkoxy systems, 268-273 N,O-intramolecular acyl migration-based prodrugs, 281-283 oxazolidinone groups, 280-281 permeability of, 267 Index 723

Peptide-assisted cleavage, 106-107 Peptide mimetics, 278, 279[ Peptide spacers, 302-303, 304[ Perindopril, 9t Phenacetin, 78[ Phenobarbital, 174[, 175[ Phensuximide, 173[ Phenylbutazone, 79[ Phenylenediamine, 107 Phenylpropionic acid-based systems, 268, 269[, 270-273 Phenytoin, 136[, 153[, 154, 157[, 367, 370[ plasma concentrations, 158[ prodrugs, 136[ N-acyloxyalkyl, 153, 155[, 159 N-acyl, 165[ see also Fosphenytoin Phosphate esters, 46-52 Phosphinates, 246-248 Phosphonamidates, 242-244 Phosphonate, phosphinate and phosphate prodrugs, 223-257 advantages of, 228 assay systems, 229 design of, 226-228 phosphates, 248-257 acyloxyalkyl and alkoxycarbonyloxymethyl esters, 251 alkyl, benzyl, aryl and haloalkyl esters, 248-250 cycloSal-pronucleotides, 251[, 252t, 253 HepDirect technology, 255, 256[, 256t, 257 phosphoramidates, 253[, 254t, 255 phosphinates, 246-248 phosphonates, 229-246 S-acetylthionethanol and dithioethanol esters, 244 acyloxyalkyl and alkoxycarbonyloxyalkyl esters, 237-242 alkyl, benzyl, aryl and haloalkyl esters, 230-237 long-chain alkyloxyalkyl monoesters, 245[, 246 phosphonamidates, 242-244 quinone methides, 245 structure, 225[ Phosphonooxymethyl (POM) prodrugs, 51, 52[, 115[ Phosphoramidates, 242-244, 253[, 254t, 255 antiviral activity, 254t cytotoxicity, 254t Phosphoramide mustard, 367[ Piperidine, 144[, 145[ N-(Piperidinomethyl)trichloroiacetamide, 145[ Piroxicam, 61[ 724 Index

pharmacokinetics, 62t Pivalate prodrugs, 425-442 and carnitine homeostasis, 429-440 cellular pivaloylcarnitine generation, 430-440 humans, 429-430 effect on cellular metabolism, 428-429 fate of pivalate in mammals, 427-428 future of, 440-442 O-Pivaloyloxprenolol, 37, 38f O-Pivaloyl timolol, 36f Pivampicillin, 351t, 431, 441t Pivampicillin hydrochloride, 441t Pivilic acid, 388f Pivmecillinam, 436 Plasminogen activator, 304 Platelet aggregation, 213t, 214t Pneumocystis carinii, 191, 193 2,5-bis-benzamidofuran derivatives, 205t bis-N-hydroxyamidines, 203-205t Poly-amino acids, 296-305 Polyglutamate, 312 Poly-L-aspartic acid, 293t, 299 Poly-L-glutamic acid, 293t, 297, 298f, 299f Poly-L-glutamic acid hydrazide, 298, 299f Poly-L-Iysine, 293t, 297, 298f Poly-(L-Iysine citramide imide), 293t Polymer-directed enzyme prodrug therapy (PDEPT), 315 Poly[N5-(2-hydroxyethyl-DL-aspartamide)], 293t Poly[N5-(2-hydroxyethyl)-L-glutamine], 293t, 303f Polysaccharides, 305-313 Poly-a,(3-aspartic acid, 293t, 296, 297f Poly[a, (3-(N-2-hydroxyethyl-DL-aspartamide)], 293t, 294t, 300 Poly[a, (3-(N-3-hydroxyethyl-DL-aspartamide)], 293t, 300 Posaconazole, 80f Pravastatin, 21f P{ednisolone, 367, 394 Prilocaine, 123 Prilosec see Omeprazole Primidone, 175f Procaine, 296, 297f Promoiety-assisted cleavage, 107-109 Propofol, 44, 46f, 51, 521 prodrugs, 44,45, 46f, 51, 521 Propranolol, prodrugs, O-acetylpropranolol, 35f Prostaglandin El, 297, 300f Prostaglandin F20: analogs see Latanoprost; Travoprost Index 725

Prostate-specific antigen, 107 PROTAX, 70f Protease inhibitors, 196-198 Pyrimidines, tumor-selective prodrugs, 331-333 Pyroglutamyl aminopeptidase, 146 L-Pyroglutamyl benzylamide, 156 Pyrrolidine, 145

Q Quaternary ammonium prodrugs, 115-116 soft, 116 Quinapril, 9t Quinone, 362 Quinonemethide, 245, 362

Ramipril, 9t Rapidisc see Enalapril Rayzon see Parecoxib Redox prodrugs, 174-1 75 Reductive activation, 362-363 Relenza see Zanamivir Repirinast, 14f Restandol see Testosterone Risklbenefit analysis, 422 Risk evaluation, 417-420 analyte selection, 419 analytical method development, 419 exposure assessment, 418-419 histopathological assessment, 417-418 qualitative differences from prodrug, 418 sampling considerations, 419-420 Risk identification, 413-417 ADME considerations, 416-417 exposure to drug substance(s), 414-415 species selection, 415 Ritalin, 8f Rofecoxib, 639 Rolitetracycline, 145f 726 Index

s Safety assessment, 411-423 initial human trials, 421-422 registration, 423 risk/benefit analysis, 422 risk evaluation, 417-420 analyte selection, 419 analytical method development, 419 exposure assessment, 418-419 histopathological assessment, 417-418 qualitative differences from prodrug, 418 sampling considerations, 419-420 risk identification, 413-41 7 ADME considerations, 416-417 exposure to drug substance(s), 414-415 species selection, 415 toxicology study outcomes, 422 Sch 51048, 80[ Schiff bases, 119-120 Sesame oil, 395 Sibrafiban, 191[, 197[ Simvastatin, 21[, 416, 417[ Single-nucleotide polymorphisms, 372 SN-38, 354, 355[ prodrugs see Irinotecan Sodium bicarbonate, 393t Sodium carbonate, 393t Solid-state pH, 386 Solubility enhancement, 397-404 Solu-Medrol see Methylprednisolone succinate sodium Solution pH, 386 Spacers, 227 cephalosporins, 315 cyclization-elimination, 64-65, 66-73 electronic cascade, 65, 73-78, 111[ macromolecular prodrugs, 296 oxymethyloxycarbonyl, 112f peptide, 302-303 Species selection, 415 Spectracefsee Cefditoren pivoxil Spirapril, lOt Stability considerations, 405-406 Staphylococcus aureus, 499 Steroidal estrogen prodrugs, 58[, 59[ Streptococcus pneumoniae, 499 Index 727

Streptococcus pyogenes, 499 Succinic anhydride, 305 Succinimide, 171f Sulfamate esters, 58-60 Sulfamethoxazole, prodrugs, 106[, 107 Sulfatases, 157 Sulfenamide prodrugs, 137-142 Sulfonamide prodrugs, 166f, 167 Sultamicillin, 15f Synthetic polymers, 313-315

Tacrolimus, 310f TAK-456, 326, 327t TAK-467, 327t Talniflumate, 18f Tamiflu see Oseltamivir Tartaric acid, 394 Taxols, 66f Tazarotene, Ilf Tegafur, 476f Temocapril, lOt Temozolomide, 394 Tenofovir, 238, 240t, 241f prodrugs phosphonamidates, 242[, 243t see also Tenofovir disoproxil fumarate Tenofovir disoproxil fumarate, 240,241[, 243t, 387, 388f clinical profile, 653-654 degradation, 388f formulation, 652-653 mechanism and site of bioconversion, 652 rationale, 649-651 structures and bioconversion pathway, 649f synthesis, 651[, 652 toxicity, 652 Testosterone prodrugs, 57, 58f enanthate, 403t undecanoate, 395f Tetracycline, 145f Theophylline, 145, 154 prodrugs, 154 Thiadiazolidinones, 201-202 Thioester prodrugs, 330t Thiol prodrugs, 328-331 728 Index

Thiophosphate prodrugs, 330t Thiotepa, 367 Thymidine kinase, 252 Thymidine phosphorylase, 332f Timolol prodrugs aliphatic esters, 36[ aromatic esters, 40t Tirapazimine, 75, 116[, 117, 361[ Tocopherol nicotinate, 396, 397[ Toxicokinetics, 418-41 9 Tramadol, 373 Trandolapril, lOt Travatan see Travoprost Travoprost, 12t, 351t, 659-665 clinical profile, 663[, 664[, 665 formulation, 663 mechanism and site of bioreversion, 662 rationale, 661-662 structures and bioconversion pathway, 661[ synthesis, 662 toxicity, 663 Trimethadione, 173[, 174[ Trimethyllock, 66, 108, 268 Trofosfamide, 366, 367[ Trovan see Alatrofloxacin mesylate Truvada see Tenofovir disoproxil Tumor-specific delivery, 360-370 directed enzyme prodrug therapy, 368 drug-induced resistance to chemotherapy, 368-369 5-fluorouracil, 478, 479[, 480[ nucleosides, 363-366 oxazaphosphorines, 366-367 prodrugs for improved solubility, 369-370 reductive activation, 362-363 u

UDP-glucuronosyl transferase, 354 Uniteric see Moexiprilat Univasc see Moexipril hydrochloride Unoprostone isopropyl ester, 12t Index 729

Valacyclovir, 42[, 348.1: 351t, 669-674 clinical profile, 673-674 mechanism and site of bioconversion, 672, 673f rationale, 671-672 structures and bioconversion pathway, 671f synthesis, 672 transport, 672 Valcyte see Valganciclovir Valdecoxib, 6371, 639 prodrugs see Parecoxib O-Valeryl timolol, 36f Valganciclovir, 42[, 677-684 clinical profile, 682[, 6831, 683t, 684 formulation, 682 mechanism and site ofbioreversion, 681t rationale, 679-680 structures and bioconversion pathway, 679f synthesis, 680f toxicity, 682 Valproate, 440 Valtrex see Valacyclovir Vantin see Cefpodoxime proxetil Vaseretic see Enalapril Vasotec see Enalapril Veldecoxib, 167f 5-Vinyluracil, 331 Viread see Tenofovir disoproxil Virus-directed enzyme prodrug therapy (VDEPT), 361, 368 w

Water-soluble prodrugs, 404 solubility, 404-405 stability, 405-406 WR-I065, 330t, 466 see also Amifostine WR-2721, 329, 330t x Xalatan see Latanoprost Xanthine oxidase, 363 Xeloda see Capecitabine 730 Index

Ximelagatran, IIf, 196,695-700 clinical profile, 699-700 formulation, 699 mechanism and site of bioconversion, 6981, 699 rationale, 697-698 structures and bioconversion pathway, 697[ synthesis, 698 toxicity, 699 z

Zanamivir, Ill, 628f see also Oseltamivir ZD2767~ 55[ Zidovudine, 250f PHEA conjugate, 301, 302f Zinnat see Cefuroxime axetil Zocor see Simvastatin Zovirax see Valacyclovir hydrochloride Zyvox see Linezolid