j377 Index a – terminal 117ff. abacavir 369f. allele association ABT, see 1-aminobenzotriazole – HLA 370 acetaminophen 71, 273ff. allopurinol 373 – metabolic activation 73 2-allylisopropylacetamide (AIA) 117f. – metabolism 72 alpidem 304f., 336, 349 acetaminophen-like metabolite 276 amanitin 204 N-acetyl-p-benzoquinone imine (NAPQI) Ames assay 29 5, 73 AMG 458 139ff. N-acetylcysteine 275 a-amidoacetonitrile 324 N-acetyltransferase (NAT) 16, 283 amine 49 N-acetyltransferase-2 (NAT-2) 79, 283 – aromatic, see aromatic amine acute liver failure (ALF) 363 – carcinogenicity of aromatic and acylating agent 320 heteroaromatic amine 13 afatinib 319 – drug–drug interaction 51 affinity label 313 amineptine 196, 342ff. aflatoxin 214 2-amino-3,8-dimethylimidazo[4,5-f] fl a atoxin B1 (AFB1)2 quinoxaline (MeIQx) 216 – bioactivation 215 – bioactivation 218 AKT inhibitor, see protein kinase B inhibitor 2-amino-1-methyl-6-phenylimidazo[4,5-b] alanine transaminase (ALT) 363 pyridine (PhIP) 216 alclofenac – bioactivation 218 – metabolic activation 119 aminoazo dye 15 aldehyde oxidase 60 1-aminobenzotriazole (ABT) 58f. alendronic acid 290 aminoglutethimide 188 alkaloid 5-aminooxindole 253 – pyrrolizidine 210 – derivative 254 alkene ortho-aminophenol 101 – terminal 117f. para-aminophenol 101 3-alkyl pyrrole 112 2-aminothiazole 109 – activation 112 amitriptyline 282ff., 343f. alkylating species 173 – metabolism 287 2-alkylimidazole 57 amlodipine 274 3-alkylindole analogue 113 amodiaquine 252 3-alkylindole derivative 112 – metabolic activation 101 alkylpiperazine 258 amoxicillin 132, 273ff., 288 alkyne 56f. angiotensin converting enzyme – bioactivation 119f. inhibitor 294ff. – internal 120 angiotensin II receptor antagonist 298 Reactive Drug Metabolites, First Edition. Amit S. Kalgutkar, Deepak Dalvie, R. Scott Obach, and Dennis A. Smith. Ó 2012 Wiley-VCH Verlag GmbH & Co. KGaA. Published 2012 by Wiley-VCH Verlag GmbH & Co. KGaA. 378j Index anilide structural alert 299 b aniline 98, 188 benazepril 294ff. – metabolic activation 100 benzbromarone 373 aniline cancer 15 1,3-benzdioxole motif 115f. animal – metabolic activation 117 – plant–animal warfare 204 benzene oxide 4 anthracycline 157ff. benzo[a]pyrene 2 – antibiotic 158 benzodiazepine drug 297ff. – bioreductive activation 173 1,3-benzodioxole structural alert 292 anthramycin 318 benzoquinone 170 anti-HIV drug 108 – ortho-(1,2)-benzoquinone (BQ) 4 antianxiolytic drug 253 – para-(1,4)-benzoquinone (BQ) 4 antibiotic 131,158, 170, 281f., 297ff. BIBW2992 319 antibody 8 bile salt export pump (BSEP) inhibition 197, anticancer drug 21, 160 288, 348ff. – quinone-containing 21 bioactivation 203ff. antidepressant drug 253, 293, 344 – detection 233 antidiabetic agent 274, 282ff., 349 – herbal remedy 205 antihypertensive drug 297f. biomarker antimalarial agent 252 – toxicity 369 antipain 322ff. bioreduction antipsychotic 368 – adical intermediate 157 aplaviroc 366 black box warning 365 ar-tumerone 318 boceprevir 322ff. aripiprazole 343f. 2-bromo-2-chloro-1,1,1-trifluoroethane, Aristolochia 208 see halothane aristolochic acid 208 buprenorphine 300ff., 350 – bioactivation 209 buspirone 336 – metabolism 209 cis-2-butene-1,4-dial 23ff. aromatic amine 98ff. BZQ 170 – carcinogenicity 13 – metabolic activation 100 c aromatic carboxamide calcium channel antagonist 327 derivative 35 calcium receptor antagonist 36, 347 aromatic ring calcium sensing receptor (CaSR) – electron-rich 251 antagonist 346 artemisinin 166 calicheamicin 161 – bioactivation 167 calicheamicin c1 158 – derivative 166 – activation 163 arylindenopyrimidine derivative canertinib 319 – pyrrolidine-substituted 34 carbamate 320 aspartate transaminase (AST) 363 carbazilquinone 170 aspirin 322f. carboxylic acid 189 atenolol 187 carbutamide 195 atorvastatin 273 carcinogenesis 1 – metabolism 276 carcinogenic substance 14 ATPase carcinogenicity – gastric 278 – aromatic and heteroaromatic amines 13 augmentin 288 – dihaloalkane 28 azaheterocyclic compound – ethyl carbamate 26 – polycyclic 216 – furan 23 aziridinylbenzoquinone 170ff. – nitrosamine 17 – metabolic activation 172 – quinone 19 azithromycin 274 – vinyl halide 26 Index j379 carisoprodol 290 cyclophosphamide 154f. carvedilol 297 cysteine protease inhibitor 322ff. cathepsin inhibitor 324 cytochrome P450 (CYP) enzyme 1f., 16, 204 cathepsin K inhibitor 324 – bioactivation 43ff. celecoxib 193ff., 290 – inactivator 58 cephalosporin 320 – inactivation 43ff., 237 chemical reactivity 326ff. – inhibition 98 – experimental approach 326 – inhibitor 97 – in silico approach 328 – mechanism of inactivation 47 chemokine receptor type 5 (CCR5) cytotoxicity – antagonist 366 – reactive metabolite 5 – inhibitor 365 chloramphenicol 188 d 5-[3-(2-chloroethyl)-1-triazenyl]imidazole-4- dacarbazine 150 carboxamide (MCTIC) 149 daily dose trend 270 chlorpropamide 349 dapsone 188 chymostatin 322ff. DDI, see drug–drug interaction ciprofloxacin 297ff. detoxification 6 clavulanate 132 detoxification pathway clavulanic acid 321 – competing 341 clinical drug toxicity 359 diazepam 297ff. clonazepam 297ff. diaziquone 170 clopidogrel 151, 273ff. diclofenac 101 – clearance mechanism 281 – metabolic activation 102 – metabolic activation 279 dihaloalkane 28 clozapine 101, 302ff., 336ff., 368f. – bioactivation 28 – metabolic activation 103 – carcinogenicity 28 clozarilÒ 369 dipeptidyl peptidase (DPP IV) 324 co-trimoxole 282 DNA adduct 17 coltsfoot 210 DNA alkylation 94, 153 comfrey 210 – nitrogen mustard 96 concerta 290 DNA binding 3 coniine 204 DNA cleavage 162 contraindication 367 DNA cross-link formation 212 corticotropin-releasing factor-1 (CRF1) DNA-reactive metabolite receptor antagonist 253 – bioactivation of vinyl chloride 27 – pyrazinone-based 256 – bioactivation pathway of nitrosamines 18 covalent binding – bioactivation pathway of safrole 22 – reactive metabolite cytotoxicity 5 – bioactivation pathway of tamoxifen 21 covalent binding assay 231f. donepezil 300ff., 365 covalent inhibitor 313ff. dose size – reversible 326 – IADR 342 covalent modification doxorubicin – reversible 322 – bioreductive activation 173 covalent modifier drug – reversible 325 – bioreductive activation 153 CP-671,305 340 – nonenzymatically activated 145 cyanamide 324 – retrospective analysis of structure–toxicity cycasin 212f. relationship 185ff. – bioactivation 213 drug design cyclobenzaprine 292, 343 – structural alert 225, 336 – oxidative metabolism 296 drug discovery 29 cyclooxygenase-2 (COX-2)–selective – assay for metabolism-dependent inhibitor 192ff., 248 genotoxicity 28 380j Index – intrinsically electrophilic compound 131ff. – metabolic activation 301 – reactive metabolite formation 241 17a-ethinylsteroid 120 – reactive metabolite–positive ethyl carbamate 26 compound 335 – carcinogenicity 26 drug safety data 358 ezetimibe 302f. drug toxicity – rules and laws 363 f drug withdrawal 360ff. fatty acid amide hydrolase (FAAH) 322 drug–drug interaction (DDI) 46 – inhibitor 323 – amine-containing drug 51 felbamate 258ff. – cytochrome P450 time-dependent fetal hydantoin syndrome 10 inhibitor 50 fluconazole 282ff. drug-induced toxicity 4-fluorofelbamate 258ff. – reactive metabolite 71ff. fluoroquinolone antibiotic 297ff. drug-metabolizing enzyme fluoxetine 290 – bioactivation 43ff. FMS inhibitor, see tyrosine kinase inhibitor – inactivation 43ff. fosamax 290 dynemicin 163 frank electrophile 93 dynemicin A 158 furafylline 57 – bioactivation 164 furan 23, 55f. – carcinogenicity 23 e – metabolic activation 108 efavirenz 56, 121 – oxidative bioactivation 24 elastinal 322ff. – xenobiotic 107 electrophile trapping assay furosemide 282ff. – qualitative 227 – quantitative 230 g electrophilic compound gabapentin 290 – drug discovery 133ff. gefitinib 318 – drug toxicity 135 gemfibrozil 58f. – intrinsically 131ff. gemtuzumab ozogamicin 165 electrophilic functional group 94 genetic influence electrophilic intermediate – reactive metabolite formation 5 – bioreductive activation 168 genotoxicity enalapril 290ff. – drug discovery 28 enediyne 158ff. – reactive metabolite 13ff. – cycloaromatization 161 germander 205 – 9-membered ring system 160 glitazone 191 – 10-membered ring system 160 glutathione (GSH) 3, 207, 229f., 249 entacapone 338f. – electrophilic compound 134ff. enzyme kinetic principle glutathione transferase 28 – mechanism-based inactivation 44 glyburide 282ff., 349 epidermal growth factor receptor (EGFR) 317 – covalent EGFR inhibitor 319 h 1,2-epoxy-3,3,3-trichloropropane (TCPO) 10 halothane 7, 75ff. erlotinib 318 – hepatotoxicity 78 escitalopram 274 – metabolism 76 esomeprazole 273ff. – oxidative metabolism 77 esperamicins A1 158 – reactive metabolites in immune-mediated ester 320 toxicity 7 estradiol – reductive metabolism 77 – metabolism 20 helenalin 318 ethinylestradiol 56, 297, 350 heme adduct 48 – 17a-ethinylestradiol 120 hepatotoxicant 4 Index j381 hepatotoxicity 186 – covalent 315ff. – halothane administration 78 – irreversible 314 herbal remedy 205 – irreversible warhead 317 – bioactivation 205 – kinetic description 44 herbimycin A 318 – mechanism-based 198 heteroaromatic amine 13 intoxication 6 – carcinogenicity 13 isoniazid 60 heteroaromatic nitrile 324 – metabolic activation 106 heteroaromatic ring isosorbide mononitrate 290 – five-membered 107 isothiazole ring bioactivation 249f. heterocyclic ring system 242 N,N,N0,N0,N00,N00- j hexamethylmelamine 153ff. januvia 290 human leukocyte antigen (HLA) 370f. hydralazine 60, 79 k – metabolic activation 81 ketoconazole 349 – metabolism 80 kinase inhibitor hydrazine 105 – irreversible 319 hydrochlorothiazide 294 – reversible