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 318 hydrocodone 273 kinetic principle 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB) 17 – inactivation 44 4-hydroxyaniline motif 251 para-hydroxynefazodone 344 l a-hydroxytamoxifen 22 L-739,010 108 para-hydroxytrazodone 285 L-745,870 112 hypersensitivity 369 L-754,394 108 hypothemycin 318 lactam – bicyclic 320 i – monocyclic 320 ibufenac 289ff. b-lactam 95ff. ibuprofen 289ff. – antibiotic 131, 281f., 321 idiosyncratic adverse drug reaction – intrinsic electrophilicity 131 (IADR) 186, 241, 351 – toxicity 131 – competing detoxification b-lactamase 321 pathway 341 b-lactone 320ff. – dose size 342 lamotrigine 282 – duration of treatment 345 – metabolic activation 284 – multifactorial nature 348 lansoprazole 291 – risk 347 lapatinib 318 – risk assessment 327ff. levofloxacin 297ff., 336 – risk–benefit analysis 357ff. levothyroxine 273ff. ifosfamide 154f. leupeptin 322ff. imidazotriazene 148 5-lipooxygenase inhibitor 108 iminium methide species 113 lisdexamfetamine 290 immune-mediated toxicity 7ff. lisinopril 273, 294ff. in silico approach liver transaminase level – chemical reactivity 328 (ALT) 364 inactivation 60 losartan – cytochrome P450 enzyme 47ff. – oxidative bioactivation 298 – pharmacokinetic principle 46 lorazepam 297ff. – quasi-irreversible 47 lovastatin 302f. inactivator 45 lumiracoxib 101 – cytochrome P450 enzyme 49 – metabolic activation 102 inhibitor lyrica 290 382j Index

m mitochondrial toxicity 349 MAO-A inhibitor 61f. mitomycin 168ff. MAO-B inhibitor 61f. mitomycin C 168 maraviroc 365f. – reductive activation 171 MDMA, see mitosene 168 methylenedioxymethamphetamine mitozolomide 149 medicinal chemistry MK-0524 112 – reactive metabolite formation 241 mometasone 302f. MeIQx, see 2-amino-3,8-dimethylimidazo[4,5-f] monoamine oxidase (MAO) 61 quinoxaline – inactivation 63 meloxicam 302ff., 338 – inactivator 62 memantine 290 montelukast 273ff. menthofuran 207 MPTP, see N-methyl-1,2,3,6-tetrahydropyridine metabolic activation 275 MTIC, see 5-[3-methyl-1-triazenyl]imidazole-4- metabolite identification study 234 carboxamide metabolite-intermediate (MI) complex 48 mutagenesis 1 metal chelator 93 mutagenicity metal complexing functional group 96 – drug discovery 29 metformin 274 mylotarg 165 methoxsalen 55 methoxy 4-O-aryl quinoline n derivative 141 namenda 290 methyl sulfone 134 NAPQI, see N-acetyl-para-benzoquinone imine N-methyl-1,2,3,6-tetrahydropyridine naproxen 291 (MPTP) 64 NAT, see N-acetyltransferase 5-[3-methyl-1-triazenyl]imidazole-4- natural product 203ff. carboxamide (MTIC) 149 nefazodone 52, 336ff., 349 methylenedioxymethamphetamine neocarzinostatin chromophore 161 (MDMA) 51 neratinib 319 methylenedioxyphenyl compound 51 neurontin 290 methylenedioxyphenyl motif 115f. niacin 282ff. – metabolic activation 117 niacinamide 288 3-methylindole 216f. nicotine 204 – bioactivation 217 nilvadipine 327 – metabolic activation 113 nitrile 2-methylindole derivative – heteroaromatic 324 – metabolic activation 114 nitroarene 103f. 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol nitroaromatic chloromustard (NNAL) 17 – bioactivation 175 4-(methylnitrosamino)-1-(3-pyridyl)-1- nitroaromatic compound butanone (NNK) 17 – bioreductive activation 174 methylphenidate 290 nitrogen mustard 96, 152 methylprednisolone 300 – DNA alkylation 96 6-(2-methylpyridinyloxy)-5-cyanopyrimidine nitroquinoline mustard derivative 139f. – reductive activation 176 4-methylsulfonyl-2-pyridone 137 nitrosamine 18, 219 metoprolol 273ff. – adduct with nucleic acid base 219 metyrapone 97 – carcinogenicity 17 MI, see metabolite-intermediate complex nitroso-imidacloprid 60 Michael acceptor 317f. N0-nitrosonornicotine (NNN) 17 – reactivity 329 nitrosourea 147f. mibefradil 58, 197f. nomifensine 189 mifepristone 56, 120 nonergot dopamine receptor milacemide 64 agonist 340 Index j383 nonsteroidal anti-inflammatory drug polycyclic azaheterocyclic compound 216 (NSAID) 186ff., 359 potassium clavulanate 282ff. nortriptyline 287, 344 practolol 187 pramipexole 339f. o prasugrel 152 odanacatib 324 eins ist wahrscheinlich ein pravastatin 302f. Tippfehler prednisolone 300 odanacitib 326 prednisone 303 off target 186 pregabalin 290 olanzapine 304ff., 342f. primary pharmacology 190ff. olmesartan 339 procainamide 187 omeprazole 277, 291 proline-rich tyrosine kinase 2 (PYK2) 253 – acid-catalyzed bioactivation 146 – inhibitor 254 on target 186 protein adduct 49 onglyza 324 protein kinase B (AKT) inhibitor 244ff. orlistat 322f. protein target oseltamivir 300ff. – reactive metabolite 197 oxazaphosphorine 152 protein-reactive metabolite oxidative metabolism 145 – bioactivation of vinyl chloride 27 oxidative stress – bioactivation pathway of tamoxifen 21 – reactive metabolite cytotoxicity 5 proton pump inhibitor 145f., 277ff., 291 pulegone 207 p purinoreceptor antagonist 277 p53 3 pyridine-2-sulfonamide 138 pantoprazole 291 pyrrolizidine alkaloid 210 paroxetine 51, 116, 292f. – bioactivation 211 PCI-3765 320 pelitinib 319 q penem 320 qualitative electrophile trapping assay 227 penicillin G 321 quantitative electrophile trapping assay 230 pennyroyal oil 207 quantitative whole-body autoradiography peptidyl aldehyde 322 (qWBA) 236 PF-0299804 319 quetiapine 290, 302ff., 336 pharmacokinetic principle quinone 19, 52 – inactivation 46 – antibiotic 168 pharmacokinetic/pharmacodynamic (PK/PD) – anticancer drug 21 prediction 346ff. – carcinogenicity 19 pharmacological action 145 – ortho-quinone 19 – reactive metabolite 145 quinone imine 52 pharmacological target 346 quinone methide 52ff. phenanthrene 2 quinone methide intermediate phencyclidine 53 – reactive 173 1,2,4-phenylenetriamine-based inhibitor 255 quinone methide metabolite 20 phenylhydrazine – metabolic activation 106 r PhIP, see 2-amino-1-methyl-6-phenylimidazo rabeprazole 291 [4,5-b]pyridine radicicol A 318 pioglitazone 191, 343ff. radiolabeled metabolism 235 piperazine derivative raloxifene 53, 292 – 1,3-disubstituted 259f. – bioactivation pathway 295 piperazine ring system 256 ramipril 294ff. plant–animal warfare 204 ranitidine 302f., 339 PNU-10912 137 reactive metabolite PNU-140690 137 – cytotoxicity 5 384j Index

– detection 3, 225 side effect monitoring 367 – drug-induced toxicity 71ff. sildenafil 290 – false positive 289 simvastatin 274, 302, 350 – false structure–toxicity relationship 192 sitagliptin 290 – genotoxicity 13ff. SPD-304 112 – immune-mediated toxicity 7 structural alert 226, 269ff. – metabolic activation 275 – drug design 336 – origin and historical perspective 1ff. – identification 225 – pharmacological action 145 – reactive metabolite formation 338 – protein target 197 structural alert–positive drug 303 – risk assessment 329 structure toxicity trend 302 – toxicophore 98 structure–toxicity relationship 337 – validation 198 – false 192 reactive metabolite analysis 269ff. – retrospective analysis 185ff. reactive metabolite detection 3, 225ff. strychnine 204 – assay 227 sudoxicam 304f., 338 reactive metabolite formation 8 sulfamethoxazole 282ff. – drug discovery 241 sulfonamide 134 – genetic influence 5 sulfotransferase (SULT) 16 – rational chemistry approach 242ff. sunitinib 346 – structural alert 338 suprofen 193 – toxicophore 93 reactive metabolite trapping 29ff. t reactive metabolite–positive compound 340 TA, see tienilic acid – competing, detoxification pathway 341 tacrine 364 – drug discovery 335 tadalafil 116, 292ff. reductive scission tamoxifen 19, 53f. – artemisinin 167 – bioactivation pathway 21 remoxipride 198f. tamsulosin 303 reversible pharmacology 10 targeted covalent drug 313 riddelliine 212 targeted covalent inhibitor 317 risk assessment 327ff. telaprevir 322ff. risk–benefit analysis 357ff. temozolomide 149 – IADR 357 terbinafine 121 rivastigmine 321ff. tetrodotoxin 204 rofecoxib 192ff. teucrin A 205f. rosiglitazone 191, 350 TFA, see trifluoroacetic acid rosuvastatin 339 TFA (trifluoroacetic acid)–protein adduct 78f. rupintrivir 319f. TFAC, see trifluoroacetyl chloride thiabendazole s – metabolism 112 S9/NADPH-dependent mutagenic thiazole 109ff. response 30ff. – oxidative ring scission 110 safrole thienotetrahydropyridine 150 – bioactivation pathway 22 thioamide 111 salbutamol 274ff. – metabolic activation 111 Salmonella reverse mutation assay 32 thiophene 53ff., 109 saxagliptin 324ff. – bioactivation 110 saxitoxin 204 thiourea 111 secondary pharmacology 192 – metabolic activation 111 – irreversible 189f. thrombin inhibitor 336 SelzentryÒ 365 thrombopoietin (Tpo) serine hydrolase inhibitor 321 – agonist 246 sertraline 290 – receptor 242 Index j385 tianeptine 197, 342f. u ticlopidine 151, 372 uridine diphospho glucuronosyltransferase tienilic acid (TA) 82, 193 (UGT) 338 – metabolism 83 uridine glucuronosyl transferase (UGT) 72 tiotropium 303, 339 tirapazamine 157 v tissue binding 236 valdecoxib 194f. tolbutamide 195 valsartan 290 tolcapone 338f., 349 vascular endothelial growth factor receptor 2 tolmetin 115 (VEGFR2) 319 toxicity 186 verapamil 303 – biomarker 369 vildagliptin 324ff. – clinical drug toxicity 359 vinyl halide – drug-induced 71ff. – bioactivation into DNA- and protein-reactive – immune-mediated 7 metabolites 27 – innate electrophilicity 135 – carcinogenicity 26 – b-lactam antibiotic 131ff. vyvanse 290 – multifactorial mechanisms 196 – rules and laws 363 w – validation of reactive metabolites 198 warfare toxicity risk 313 – plant–animal warfare 204 toxicophore 93ff. warhead 315ff. – bioactivation 98 – optimization of chemical – intrinsically reactive 93 reactivity 326 tramadol 290 – selection 316 trazodone 282ff. warning 367 – metabolic activation 286 whole-body autoradiography (WBA) 236 triazene derivative 148 – quantitative (qWBA) 236 triaziquone 170 trifluoroacetic acid (TFA) 7 x trifluoroacetyl chloride (TFAC) 7 xenobiotic 116 trimelamol 153 – furan-based 107 trimethoprim 282ff. ximelagatran 336 troglitazone 191, 342ff. trovafloxacin 297ff., 336 z tubocurarine 204 zafirlukast 112 tyrosine kinase FMS inhibitor 255f. zolpidem 302ff., 336 tyrosine kinase inhibitor 346 zomepirac 115