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Review Article

Biotransformation and bioactivation reactions of alicyclic amines in drug molecules

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Pages 379-419 | Received 14 Feb 2014, Accepted 06 May 2014, Published online: 09 Jun 2014

References

  • Argikar UA. (2012). Unusual glucuronides. Drug Metab Dispos 40:1239–1251
  • Aubets J, Cardenas A, Salva M, et al. (2006). Disposition and metabolism of almotriptan in rats, dogs and monkeys. Xenobiotica 36:807–823
  • Avent KM, Usuki E, Eyles KR, et al. (1996). Haloperidol and its tetrahydropyridine derivative (hptp) are metabolized to potentially neurotoxic pyridinium species in the baboon. Life Sci 59:1473–1482
  • Avent KM, DeVoss JJ, Gillam EJM. (2006). Cytochrome P450-mediated metabolism of haloperidol and reduced haloperidol to pyridinium metabolites. Chem Res Toxicol 19:914–920
  • Baranczewski P, Edlund PO, Postlind H. (2006). Characterization of the cytochrome P450 enzymes and enzyme kinetic parameters for metabolism of BVT.2938 using different in vitro systems. J Pharm Biomed Anal 40:1121–1230
  • Basile AS, Janowsky A, Golembiowska K, et al. (2007). Characterization of the antinociceptive actions of bicifadine in models of acute, persistent, and chronic pain. J Pharmacol Exp Ther 321:1208–1225
  • Bauman JN, Frederick KS, Sawant A, et al. (2008). Comparison of the bioactivation potential of the antidepressant and hepatotoxin nefazodone with aripiprazole, a structural analog and marketed drug. Drug Metab Dispos 36:1016–1029
  • Beaumont KC, Cussans NJ, Nichols DJ, Smith DA. (1998). Pharmacokinetics and metabolism of darifenacin in the mouse, rat, dog and man. Xenobiotica 28:63–75
  • Becquemont L, Mouajjah S, Escaffre O, et al. (1999). Cytochrome P-450 3A4 and 2C8 are involved in zopiclone metabolism. Drug Metab Dispos 27:1068–1073
  • Benowitz NL, Jacob P. (1994a). Metabolism of nicotine to cotinine studied by a dual stable isotope method. Clin Pharm Ther 56:483–493
  • Benowitz NL, Jacob P, Fong I, Gupta S. (1994b). Nicotine metabolic profile in man: Comparison of cigarette smoking and transdermal nicotine. J Pharmacol Exp Ther 268:296–303
  • Brandänge S, Lindblom L. (1979). The enzyme “aldehyde oxidase” is an iminium oxidase. Reaction with nicotine Δ1′(5′) iminium ion. Biochem Biophys Res Commun 91:991–996
  • Breyer-Pfaff U, Wachsmuth H. (2001). Tertiary N-glucuronides of clozapine and its metabolite desmethylclozapine in patient urine. Drug Metab Dispos 29:1343–1348
  • Buchanan RW. (1995). Clozapine: Efficacy and safety. Schizoph Bull 21:579–591
  • Bücker M, Glatt HR, Platt KL, et al. (1979). Mutagenicity of phenanthrene and phenanthrene K-region derivatives. Mutat Res 66:337–348
  • Bundgaard H, Larsen C. (1978). Kinetics and mechanism of the sucrose-accelerated degradation of penicillins in aqueous solution. Int J Pharm 1:95–104
  • Bundgaard H, Hansen J. (1982). Reaction of ampicillin with serum albumin to produce penicilloyl-protein conjugates and a piperazinedione. J Pharm Pharmacol 34:304–309
  • Burns MJ. (2001). The pharmacology and toxicology of atypical antipsychotic agents. Clin Toxicol 39:1–14
  • Cascorbi I, Brockmöller J, Mrozikiewicz PM, et al. (1999). Arylamine N-acetyltransferase activity in man. Drug Metab Rev 31:489–502
  • Cashman JR, Park SB, Yang ZC, et al. (1992). Metabolism of nicotine by human liver microsomes: Stereoselective formation of trans-nicotine N′-oxide. Chem Res Toxicol 5:639–646
  • Cashman JR. (1995). Structural and catalytic properties of the mammalian flavin-containing monooxygenase. Chem Res Toxicol 8:165–181
  • Cashman JR. (2005). Some distinctions between flavin-containing and cytochrome P450 monooxygenases. Biochem Biophys Res Commun 338:599–604
  • Castagnoli N, Rimoldi JM, Bloomquist J, Castagnoli KP. (1997). Potential metabolic bioactivation pathways involving cyclic tertiary amines and azaarenes. Chem Res Toxicol 10:924–940
  • Chen G, Giambrone NE, Lazarus P. (2012). Glucuronidation of trans-3′-hydroxycotinine by UGT2B17 and UGT2B10. Pharmacogenet Genomics 22:183–190
  • Chiu SLEE, Huskey SW. (1998). 1996 ASPET N-Glucuronidation of xenobiotics symposium: Species difference in N-glucuronidation. Drug Metab Dispos 26:838–847
  • Choi S. (2003). Nefazodone (serzone) withdrawn because of hepatotoxicity. Can Med Assoc J 169:1187
  • Cramp S, Dyke HJ, Higgs C, et al. (2010). Identification and hit-to-lead exploration of a novel series of histamine H4 receptor inverse agonists. Bioorg Med Chem Lett 20:2516−2519
  • Dain J, Nicoletti J, Ballard F. (1997). Biotransformation of clozapine in humans. Drug Metab Dispos 25:1343–1348
  • Dequardo JR, Roberts M. (1996). Elevated clozapine levels after fluvoxamine initiation. Am J Psychiatry 153:840–851
  • DeSanty KP, Amabile CM. (2007). Antidepressant-induced liver injury. Ann Pharmacother 41:1201–1211
  • Di Monte DA, Royland JE, Irwin I, Langston JW. (1996). Astrocytes as the site for bioactivation of neurotoxins. Neurotoxicology 77:697–704
  • Doss GA, Miller RR, Zhang Z, et al. (2005). Metabolic activation of a 1,3-disubstituted piperazine derivative: Evidence for a novel ring contraction to an imidazoline. Chem Res Toxicol 18:271–276
  • Dragovic S, Boerma JS, van Bergen L, et al. (2010). Role of human glutathione S-transferases in the inactivation of reactive metabolites of clozapine. Chem Res Toxicol 23:1467–1476
  • Driscoll JP, Kornecki K, Wolkowski JP, et al. (2007). Bioactivation of phencyclidine in rat and human liver microsomes and recombinant P450 2B enzymes: Evidence for the formation of a novel quinone methide intermediate. Chem Res Toxicol 20:1488–1497
  • DuMartier G, Lochu A, Colon de Melo CP, et al. (1996). Elevated clozapine plasma concentrations after fluvoxamine initiation. Am J Psychiatry 153:738–739
  • Dykens JA, Jamieson JD, Marroquin LD, et al. (2008). In vitro assessment of mitochondrial dysfunction and cytotoxicity of nefazodone, trazodone, and buspirone. Toxicol Sci 103:335–345
  • Egger H, Bartlett F, Dreyfuss R, Karliner J. (1981). Metabolism of methylphenidate in dog and rat. Drug Metab Dispos 9:415–423
  • English AR, Huan HT, Sobin BA. (1960). 6-Aminopenicillanic acid in urine after oral administration of penicillins. Proc Soc Exp Biol Med 104:405–406
  • Erickson DA, Hollfelder S, Tenge J, et al. (2007). In vitro metabolism of the analgesic bicifadine in the mouse, rat, monkey, and human. Drug Metab Dispos 35:2232–2241
  • Erve JC, Vashishtha SC, Ojewoye O, et al. (2008). Metabolism of prazosin in rat and characterization of metabolites in plasma, urine, faeces, brain and bile using liquid chromatography/mass spectrometry (LC/MS). Xenobiotica 38:540–558
  • Evans DC, O’Connor D, Lake BG, et al. (2003). Eletriptan metabolism by human hepatic CYP450 enzymes and transport by human P-glycoprotein. Drug Metab Dispos 31:861–869
  • Evans DC, Watt AP, Nicoll-Griffith DA, Baillie TA. (2004). Drug-protein adducts: An industry perspective on minimizing the potential for drug bioactivation in drug discovery and development. Chem Res Toxicol 17:3–16
  • Eyles DW, Avent KM, Stedmar TJ, Pond SM. (1997). Two pyrldinlum metabolites of haloperidol are present in the brain of patients at post-mortem. Life Sci 60:529–534
  • Fang J, Mckay G, Song J, et al. (2001). In vitro characterization of the metabolism of haloperidol using recombinant cytochrome p450 enzymes and human liver microsomes. Drug Metab Dispos 12:1638–1643
  • Fauman B, Aldinger G, Fauman M, Rosen P. (1976). Psychiatric sequelae of phencyclidine abuse. Clin Toxicol 9:529–538
  • Fernandes NF, Martin RR, Schenker S. (2000). Trazodone-induced hepatotoxicity: A case report with comments on drug-induced hepatotoxicity. Am J Gastroenterol 95:532–535
  • Fischer V, Haar JA, Greiner L, et al. (1991). Possible role of free radical formation in clozapine (clorazil) induced agranulocytosis. Mol Pharmacol 40:846–853
  • Fontaine F, de Sousa G, Burcham PC, et al. (2000). Role of cytochrome P450 3A in the metabolism of mefloquine in human and animal hepatocytes. Life Sci 66:2193–2212
  • Gamage N, Barnett A, Hempel N, et al. (2006). Human sulfotransferases and their role in chemical metabolism. Toxicol Sci 90:5–22
  • Gaillot J, Heusse D, Houghton OW, et al. (1983). Pharmacokinetics and metabolism of zopiclone. Int Pharmacopsychiatr 17:76–91
  • Gao R, Li L, Xie C, Diao X, et al. (2012). Metabolism and pharmacokinetics of morinidazole in humans: Identification of diastereoisomeric morpholine N+-Glucuronides catalyzed by UDP glucuronosyltransferase 1A9. Drug Metab Dispos 40:556–567
  • García-Pando AC, García del Pozo J, Sánchez AS, et al. (2002). Hepatotoxicity associated with the new antidepressants. J Clin Psychiatry 63:135–137
  • Gerlach J, Casey D. (1988). Tardive dyskinesia. Acta Psychiatr Scand 77:369–378
  • Gerlach M, Riederer P, Przuntek H, Youdim MBH. (1991). MPTP mechanism of neurotoxicity and their implications for Parkinson’s disease. Eur J Pharmacol 208:273–286
  • Glatt HR, Ludewig G, Platt KL, et al. (1985). Arene imines, a new class of exceptionally potent mutagens in bacterial and mammalian cells. Cancer Res 45:2600–2607
  • Glatt HR, Robertson LW, Arand M, et al. (1986). Cis and trans-1, 2-diphenylaziridines: Induction of xenobiotic-metabolizing enzymes in rat liver and mutagenicity in Salmonella typhimurium. Arch Toxicol 59:242–248
  • Gleave RJ, Beswick PJ, Brown AJ, et al. (2010). Synthesis and evaluation of 3-amino-6-aryl-pyridazines as selective CB2 agonists for the treatment of inflammatory pain. Bioorg Med Chem Lett 20:465−468
  • Grant SM, Goa KL, Fitton A, Sorkin EM. (1990). Ketotifen: A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in asthma and allergic disorders. Drugs 40:412–448
  • Green MD, Bishop WP, Tephly TR. (1995). Expressed human UGT1.4 protein catalyzes the formation of quaternary ammonium-linked glucuronides. Drug Metab Dispos 23:299–302
  • Green MD, King CD, Mojarrabi B, et al. (1998). Glucuronidation of amines and other xenobiotics catalyzed by expressed human UDP-glucuronosyltransferase 1A3. Drug Metab Dispos 26:507–512
  • Hallström G, Kammerer RC, Nguyen CH, et al. (1983). Phencyclidine metabolism in vitro. The formation of a carbinolamine and its metabolites by rabbit liver preparations. Drug Metab Dispos 11:47–53
  • Hata Y, Watanabe M. (1994). Metabolism of aziridines and the mechanism of their cytotoxicity. Drug Metab Rev 26:575–604
  • Hawes EM. (1998). 1996 ASPET N-Glucuronidation of xenobiotics symposium: N+-Glucuronidation, a common pathway in human metabolism of drugs with a tertiary amine group. Drug Metab Dispos 26:830–837
  • Hecht SS, Hochalter JB, Villalta PW, et al. (2000). 2′-Hydroxylation of nicotine by cytochrome P450 2A6 and human liver microsomes: Formation of a lung carcinogen precursor. Proc Natl Acad Sci USA 97:12493–12497
  • Hibert J, Radwanski E, Weglein R, et al. (1987). Pharmacokinetics and dose proportionality of loratadine. J Clin Pharmacol 27:694–698
  • Hinson JA, Reid AB, McCullough SS, James LP. (2004). Acetaminophen-induced hepatotoxicity: Role of metabolic activation, reactive oxygen/nitrogen species, and mitochondrial permeability transition. Drug Metab Rev 36:805–822
  • Hoag MK, Trevor AJ, Kalir A, Castagnoli N. (1987). Phencyclidine iminium ion. NADPH-dependent metabolism, covalent binding to macromolecules, and inactivation of cytochrome(s) P-450. Drug Metab Dispos 15:485–490
  • Hop CECA, Wang Y, Kumar S, et al. (2002). Identification of metabolites of a substance p (neurokinin 1 receptor) antagonist in rat hepatocytes and rat plasma. Drug Metab Dispos 30:937–943
  • Igarashi K, Kasuyal F, Fukuil M, et al. (1995). Studies on the metabolism of haloperidol (hp): The role of cypba in the production of the neurotoxic pyridinium metabolite hpp+ found in rat brain following ip administration of hp. Life Sci 57:2439–2446
  • Jacob P, Shulgin AT, Benowitz NL. (1990). Synthesis of (3′R,5′S)-trans-3′-hydroxycotinine, a major metabolite of nicotine. Metabolic formation of 3′-hydroxycotinine in humans is highly stereoselective. J Med Chem 33:1888–1891
  • Jean DST, Fotsch C. (2012). Mitigating heterocycle metabolism in drug discovery. J Med Chem 55:6002−6020
  • Joule JA, Mills K. (2010). Heterocyclic chemistry-5th Edition. West Sussex, UK: Blackwell Publishing Ltd (33: Heterocycles in Medicine)
  • Jushchyshyn MI, Wahlstrom JL, Hollenberg PF, Wienkers LC. (2006). Mechanism of inactivation of human cytochrome P450 2B6 by phencyclidine. Drug Metab Dispos 34:1523–1529
  • Jushchyshyn MI, Kent UM, Hollenberg PF. (2003). The mechanism-based inactivation of human cytochrome P450 2B6 by phencyclidine. Drug Metab Dispos 31:46–52
  • Kang HJ, Lee SS, Lee CH, et al. (2006). Neurotoxic pyridinium metabolites of haloperidol are substrates of human organic cation transporters. Drug Metab Dispos 34:1145–1151
  • Kalgutkar AS, Dalvie DK, Donnell JPO, et al. (2002). On the diversity of oxidative bioactivation reactions on nitrogen containing xenobiotics. Curr Drug Metab 3:379–424
  • Kalgutkar AS, Taylor TJ, Venkatakrishnan K, Isin EM. (2003). Assessment of the contributions of CYP3A4 and CYP3A5 in the metabolism of the antipsychotic agent haloperidol to its potentially neurotoxic pyridinium metabolite and effect of antidepressants on the bioactivation pathway. Drug Metab Dispos 31:243–249
  • Kalgutkar AS, Nguyen HT. (2004). Identification of N-methyl-4-phenylpyridinium-like metabolite of the antidarrheal agent loperamide in human liver microsomes: Undelying reason(s) for the lack of neurotoxicity despite the bioactivation event. Drug Metab Dispos 32:943–952
  • Kalgutkar AS, Henne KR, Lame ME, et al. (2005). Metabolic activation of the nontricyclic antidepressant trazodone to electrophilic quinone-imine and epoxide intermediates in human liver microsomes and recombinant P4503A4. Chem Biol Interact 155:10–20
  • Kalgutkar AS, Vaz ADN, Lame ME, et al. (2005). Bioactivation of the nontricyclic antidepressant nefazodone to a reactive quinone-imine sepcies in human liver microsomes and recombinant cytochrome P450 3A4. Drug Metab Dispos 33:243–253
  • Kalgutkar AS, Dalvie DK, Aubrecht J, et al. (2007). Genotoxicity of 2-(3-chlorobenzyloxy)-6-(piperazinyl)pyrazine, a novel 5-hydroxytryptamine2c receptor agonist for the treatment of obesity: Role of metabolic activation. Drug Metab Dispos 35:848–858
  • Kalgutkar AS. (2008). Role of bioactivation in idiosyncratic drug toxicity: Structure–toxicity relationships. In: Elfarra, ed. Advances in Bioactivation Research. New York: Springer, 27–55
  • Kamel A, Obach RS, Colizza K, et al. (2010). 5-Hydroxytryptamine 1B receptor antagonist elzasonan in humans. Drug Metab Dispos 38:1984–1999
  • Khan AY, Preskorn SH. (2001). Increase in plasma levels of clozapine and norclozapine after administration of nefazodone. J Clin Psychiatry 62:375–376
  • Kirchhoff VD, Nguyen HTT, Soczynska JK, et al. (2009). Discontinued psychiatric drugs in 2008. Expert Opin Invest Drugs 18:1431–1443
  • Koponen HJ, Leinonen E, Lepola U. (1996). Fluvoxamine increases the serum clozapine levels significantly. Eur Neuropsychopharmacol 6:69–71
  • Krieter PA, Gohdes M, Musick TJ, et al. (2008). Pharmacokinetics, disposition, and metabolism of bicifadine in humans. Drug Metab Dispos 36:252–259
  • Kropp H, Sundelof JG, Hajdu R, Kahan FM. (1982). Metabolism of thienamycin and related carbapenem antibiotics by the renal dipeptidase, dehydropeptidase-I. Antimicrob Agents Chemother 22:62–70
  • Krueger SK, Williams DE. (2005). Mammalian flavin-containing monooxygenases: Structure/function, genetic polymorphisms and role in drug metabolism. Pharmacol Ther 106:357–387
  • Lau DHM, Alexander D, Sikic BI. (1989). Association of DNA cross-linking with potentiation of the morpholino derivative of doxorubicin by human liver microsomes. J Nat Cancer Inst 81:1034–1038
  • Le Bigot JF, Cresteilt T, Kiechel JA, Beaunet P. (1983). Metabolism of ketotifen by human liver microsomes: In vitro characterization of a tertiary amine glucuronidation. Drug Metab Dispos 22:129–138
  • Levine BB. (1960a). Degradation of benzylpenicillin at pH 7.5 to D-benzylpenicilloic acid. Nature 187:939–940
  • Levine BB. (1960b). Studies on the mechanism of the formation of the penicillin antigen. I. Delayed allergic cross-reactions among penicillin g and its degradation products. J Exp Med 112:1131–1156
  • Lin AH, Murray RW, Vidmar TJ, Marotti KR. (1997). The oxazolidinone eperezolid binds to the 50S ribosomal subunit and competes with the binding of chloramphenicol and lincomycin. Antimicrob Agents Chemother 41:2127–2131
  • Linnet K, Olesen OV. (1997). Metabolism of clozapine by cDNA-expressed human cytochrome P450 enzymes. Drug Metab Dispos 25:1379–1382
  • Liu ZC, Uetrecht JP. (1995). Clozapine is oxidized by activated human neutrophils to a reactive nitrenium ion that irreversibly binds to the cells. J Pharmacol Exp Therap 275:1476–1483
  • Lucena MI, Andrade RI, Gomej-Outes A, et al. (1999). Acute liver failure after treatment with nefazodone. Dig Dis Sci 44:2577–2579
  • Luo H, Hawes EM, McKay G, et al. (1991). N1-glucuronidation of aliphatic tertiary amines, a general phenomenon in the metabolism of H1-antihistamines in humans. Xenobiotica 21:1281–1288
  • Luo H, Hawes EM, McKay G, et al. (1995). N1-glucuronidation of aliphatic tertiary amines in human: Antidepressant versus antipsychotic drugs. Xenobiotica 25:291–301
  • Maggs JL, Williams D, Piromohamed M, Park BK. (1995). The metabolic formation of reactive intermediates from clozapine, a drug associated with agranulocytosis in man. J Pharmacol Exp Ther 275:1463–1475
  • Mandrioli R, Mercolini L, Raggi MA. (2008). Benzodiazepine metabolism: An analytical perspective. Curr Drug Metab 9:827–844
  • Mannens G, Huang ML, Meuldermans W, et al. (1993). Absorption, metabolism, and excretion of risperidone in humans. Drug Metab Dispos 21:1134–1141
  • Maret G, Testa B, Jenner P, et al. (1990). The MPTP story: MAO activates tetrahydropyridine derivatives to toxins causing Parkinsonism. Drug Metab Rev 22:291–332
  • Masic LJ. (2011). Role of cyclic tertiary amine bioactivation to reactive iminium species: Structure toxicity relationship. Curr Drug Metab 12:35–50
  • Mathijssen RHJ, van Alphen RJ, Verweij J, et al. (2001). Clinical Pharmacokinetics and Metabolism of Irinotecan (CPT-11). Clin Cancer Res 7:2182–2194
  • McKillop D, Hutchison M, Partridge EA, et al. (2004a). Metabolic disposition of gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, in rat, dog and man. Xenobiotica 34:917–934
  • McKillop D, McCormick AD, Miles GS. (2004b). In vitro metabolism of gefitinib in human liver microsomes. Xenobiotica 34:983–1000
  • Meng X, Jenkins RE, Berry NG, et al. (2011). Direct evidence for the formation of diastereoisomeric benzylpenicilloyl haptens from benzylpenicillin and benzylpenicillenic acid in patients. J Pharmacol Exp Ther 338:841–849
  • Metushi IG, Nakagawa T, Uetrecht J. (2012). Direct oxidation and covalent binding of isoniazid to rodent liver and human hepatic microsomes: Humans are more like mice than rats. Chem Res Toxicol 25:2567–2576
  • Mey U, Wachsmuth H, Breyer-Pfaff U. (1999). Conjugation of the enantiomers of ketotifen to four isomeric quaternary ammonium glucuronides in humans in vivo and in liver microsomes. Drug Metab Dispos 27:1281–1292
  • Miller R, Chouinard G. (1993). Loss of striatal cholinergic neurons as a basis for tardive dyskinesia and L-Dopa-induced dyskinesias, neuroleptic-induced supersensitivity psychosis and refractory schizophrenia. Biol Psychol 34: 713–738
  • Miller R, Doss G, Stearns R. (2004). Identification of a hydroxylamine glucuronide metabolite of an oral hypoglycemic agent. Drug Metab Dispos 32:178–185
  • Mirvish SS. (1995). Role of N-nitroso compounds (NOC) and N-nitrosation in etiology of gastric, esophageal, nasopharyngeal and bladder cancer and contribution to cancer of known exposures to NOC. Cancer Lett 93:17–48
  • Monneret C. (2001). Recent developments in the field of antitumour anthracyclines. Eur J Med Chem 36:483–493
  • Murphy P. (1973). Enzymatic oxidation of nicotine to nicotine Δ1′(5′) iminium ion. A newly discovered intermediate in the metabolism of nicotine. J Biol Chem 248:2796–2800
  • Musick TJ, Gohdes M, Duffy A, et al. (2008). Pharmacokinetics, disposition, and metabolism of bicifadine in the mouse, rat, and monkey. Drug Metab Dispos 36:241–251
  • Nakashima M, Uematsu T, Kosuge K, et al. (1995). Single- and multiple-dose pharmacokinetics of AM-1155, a new 6-fluoro-8-methoxy quinolone, in humans. Antimicrob Agents Chemother 39:2635–2640
  • Nguyen TL, Gruenke LD, Castagnoli N. (1979). Metabolic oxidation of nicotine to chemically reactive intermediates. J Med Chem 22:259–263
  • Noble S, Langtry HD, Lamb HM. (1998). Zopiclone: An update of its pharmacology, clinical efficacy and tolerability in the treatment of insomnia. Drugs 55:277–302
  • Notley LM, de Wolf CJF, Wunsch RM, et al. (2002). Bioactivation of tamoxifen by recombinant human cytochrome P450 enzymes. Chem Res Toxicol 15:614–622
  • Obach RS, Van Vunakis H. (1990). Radioimmunoassay of nicotine-delta 1′(5’)-iminium ion, an intermediate formed during the metabolism of nicotine to cotinine. Drug Metab Dispos 18:508–13
  • Oesch F, Fabian E, Oesch-Bartlomowicz B, et al. (2007). Drug-metabolizing enzymes in the skin of man, rat, and pig. Drug Metab Rev 39:659–698
  • Osawa Y, Coon MJ. (1989). Selective mechanism-based inactivation of the major phenobarbital-inducible P450 cytochrome from rabbit liver by phencyclidine and its oxidation product, the iminium compound. Drug Metab Dispos 17:7–13
  • Osawa Y, Davila JC, Nakatsuka M, et al. (1995). Inhibition of P450 cytochromes by reactive intermediates. Drug Metab Rev 27:61–72
  • Park SB, Jacob P, Benowitz NL, Cashman JR. (1993). Stereoselective metabolism of (S)-(-)-nicotine in humans: Formation of trans-(S)-(-)-nicotine N-1′-oxide. Chem Res Toxicol 6:880–888
  • Parkinson A, Ogilvie BW, Paris BL, et al. (2010). Human biotransformation. In: Nassar, ed. Biotransformation and metabolite elucidation of xenobiotics. New Jersey: Wiley, 1–77
  • Pirmohamed M, Williams D, Madden S, et al. (1995). Metabolism and bioactivation of clozapine by human liver in vitro. J Pharmacol Exp Therap 272:984–990
  • Pirmohamed M, Park K. (1997). Mechanism of clozapine-induced agranulocytosis: Current status of research and implications for drug development. CNS Drugs 7:139–158
  • Porter CC, Arison BH, Gruber VF, et al. (1975). Human metabolism of cyproheptadine. Drug Metab Dispos 3:189–197
  • Prior TI, Baker GB. (2003). Interactions between the cytochrome P450 system and the second-generation antipsychotics. J Psychiatry Neurosci 28:99–112
  • Prakash C, Sharma R, Gleave M, Nedderman A. (2008). In vitro screening techniques for reactive metabolites for minimizing bioactivation potential in drug discovery. Curr Drug Metab 9:952–964
  • Quintieri L, Geroni C, Fantin M, et al. (2005). Formation and antitumor activity of PNU-159682, a major metabolite of nemorubicin in human liver microsomes. Clin Cancer Res 11:1608–1617
  • Rawal J, Jones R, Payne A, Gardner I. (2008). Strategies to prevent N-acetyltransferase-mediated metabolism in a series of piperazine-containing pyrazalopyrimidine compounds. Xenobiotica 38:1219–1239
  • Roberts P, Kitteringham NR, Park BK. (1993). Elucidation of the structural requirements for the bioactivation of mianserin in-vitro. J Pharm Pharmacol 45:663–665
  • Rodriguez RJ, Proteau PJ, Marquez BI, et al. (1999). Flavin-containing monooxygenase-mediated metabolism of N-deacetyl ketoconazole by rat hepatic microsomes. Drug Metab Dispos 27:880–886
  • Roge R, Moller BK, Andersen CR, et al. (2012). Immunomodulatory effects of clozapine and their clinical implications: What we have learned so far? Schizophr Res 140:204–213
  • Safferman A, Lieberman JA, Kane JM, et al. (1991). Update on the clinical efficacy and side effects of clozapine. Schizoph Bull 17:247–261
  • Seppälä NH, Leinonen EVJ, Lehtonen ML, Kivistö KT. (1999). Clozapine serum concentrations are lower in smoking than in nonsmoking schizophrenic patients. Pharmacol Toxicol 85:244–246
  • Shebley M, Jushchyshyn MI, Hollenberg PF. (2006). Selective pathways for the metabolism of phencyclidine by cytochrome P450 2B enzymes: Identification of electrophilic metabolites, glutathione, and N-acetyl cysteine adducts. Drug Metab Dispos 34:375–383
  • Sheikh KH, Nies AS. (1983). Trazodone and intrahepatic cholestasis. Ann. Intern Med 99:572
  • Shigenaga MK, Trevor AJ, Castagnoli N. (1988). Metabolism-dependent covalent binding of (S)-[5-3H]nicotine to liver and lung microsomal macromolecules. Drug Metab Dispos 16:397–402
  • Shigenaga MK, Kim BH, Caldera-Munoz P, et al. (1989). Liver and lung microsomal metabolism of the tobacco alkaloid β-nicotyrine. Chem Res Toxicol 2:282–287
  • Shinabarger DL, Marotti KR, Murray RW, et al. (1997). Mechanism of actionof oxazolidinones: Effects of linezolid and eperezolid on translation reactions. Antimicrob Agents Chemother 41:2132–2136
  • Showalter CV, Thornton WE. (1977). Clinical pharmacology of phencyclidine toxicity. Am J Psychiatry 134:1234–1238
  • Siegel-Lakhai WS, Beijnen JH, Schellens JH. (2005). Current knowledge and future directions of the selective epidermal growth factor receptor inhibitors erlotinib (Tarceva) and gefitinib (Iressa). Oncologist 10:579–589
  • Sim E, Walters K, Boukouvala S. (2008). Arylamine N-acetyltransferases: From structure to function. Drug Metab Rev 40:479–510
  • Slatter JG, Stalker DJ, Feenstra KR, et al. (2001). Pharmacokinetics, metabolism, and excretion of linezolid following an oral dose of [14C]linezolid to healthy human subjects. Drug Metab Dispos 29:1136–1145
  • Slatter JG, Adams LA, Bush EC, et al. (2002). Pharmacokinetics, toxicokinetics, distribution, metabolism and excretion of linezolid in mouse, rat and dog. Xenobiotica 32:907–924
  • Sorgel F. (1989). Metabolism of Gyrase Inhibitors. Rev Infect Dis 11:S1119–S1129
  • Spigset O, Hagg S, Bate A. (2003). Hepatic injury and pancreatitis during treatment with serotonin reuptake inhibitors: Data from the World Health Organization (WHO) database of adverse drug reactions. Int Clin Psychopharmacol 18:157–161
  • Sridar C, D’Agostino J, Hollenberg PF. (2012). Bioactivation of the cancer chemopreventive agent tamoxifen to quinone methides by cytochrome P4502B6 and identification of the modified residue on the apoprotein. Drug Metab Dispos 40:2280–2288
  • Stepan AF, Walker DP, Bauman J, et al. (2011). Structural alerts/reactive metabolite concept as applied in medicinal chemistry to mitigate the risk of idiosyncratic drug toxicity: A perspective based on the critical examination of trends. Chem Res Toxicol 24:1345–1410
  • Streeter DG, Taylor DL, Acton EM, Peters JH. (1985). Comparative cytotoxicities of various morpholinyl anthracyclines. Cancer Chemother Pharmacol 14:160–164
  • Subramanyam B, Rollema H, Woolf T, Castagnoli N. (1990). Identification of a potentially neurotoxic pyridinium metabolite of haloperidol in rats. Biochem Biophys Res Commun 166:238–244
  • Subramanyam B, Woolf T, Castagnoli N. (1991). Studies on the in vitro conversion of haloperidol to a potentially neurotoxic pyridinium metabolite. Chem Res Toxicol 4:123–128
  • Sun H, Scott DO. (2011). Metabolism of 4-aminopiperidine drugs by cytochrome P450s: Molecular and quantum mechanical insights into drug design. ACS Med Chem Lett 2:638–643
  • Takakusa H, Masumoto H, Yukinaga H, et al. (2008). Covalent binding and tissue distribution/retention assessment of drugs associated with idiosyncratic drug toxicity. Drug Metab Dispos 36:1770–1779
  • Tang W, Lu AYH. (2010). Metabolic bioactivation and drug-related adverse effects: Current status and future directions from a pharmaceutical research perspective. Drug Metab Rev 42:225–249
  • Tarsy D, Baldessarini RJ. (1986) Movement disorders induced by psychotherapeutic agents. In: Shah N, Donald S, eds. Movement disorders, New York: Plenum Press, 365–389
  • Tugnait M, Hawes EM, McKay G, et al. (1999). Characterization of the human hepatic cytochromes P450 involved in the in vitro oxidation of clozapine. Chem Biol Interact 118:171–189
  • Uetrecht JP, Zahid N, Tehim A, et al. (1997). Structural features associated with reactive metabolite formation in clozapine analogues. Chem Biol Interact 104:117–129
  • Uetrecht J. (2008). Idiosyncratic drug reactions: Past, present, and future. Chem Res Toxicol 21:84–92
  • Uldam HK, Juhl M, Pedersen H, Dalgaard L. (2011). Biosynthesis and identification of an N-oxide/N-glucuronide metabolite and first synthesis of an N-O-glucuronide metabolite of Lu AA21004. Drug Metab Dispos 39:2264–2274
  • Usuki E, Pearce R, Parkinson A, Castagnoli Jr N. (1996). Studies on the conversion of haloperidol and its tetrahydropyridine dehydration product to potentially neurotoxic pyridinium metabolites by human liver microsomes. Chem Res Toxicol 9:800–806
  • van Cantfort J, de Graeve J, Puozzo C. (1989). Differences in the metabolism of epicainide in rats and man. Xenobiotica 19:11–23
  • van de Wetering-Krebbers SF, Jacobs PL, Kemperman GJ, et al. (2011). Metabolism and excretion of asenapine in healthy male subjects. Drug Metab Dispos 39:580–590
  • Van der Schyf CJ, Castagnoli K, Usuki E, et al. (1994). Metabolic studies on haloperidol and its tetrahydropyridine analog in C57BL/6 mice. Chem Res Toxicol 7:281–285
  • Van Heiningen PNM, Hatorp V, Nielsen KK, et al. (1999). Absorption, metabolism and excretion of a single oral dose of C14-repaglinide during repaglinide multiple dosing. Eur J Clin Pharmacol 55:521–525
  • Velaparthi U, Wittman M, Liu P, et al. (2008). Discovery and evaluation of 4-(2-(4-chloro-1H-pyrazol-1-yl)ethylamino)-3-(6-(1-(3-fluoropropyl)piperidin-4-yl)-4-methyl-1H-benzo[d]imidazol-2-yl)-pyridin-2(1H)-one (BMS-695735), an orally efficacious inhibitor of insulin-like growth factor-1 receptor kinase with broad spectrum in vivo antitumor activity. J Med Chem 51:5897–5900
  • Vickers S, Polsky SL. (2000). The biotransformation of nitrogen containing xenobiotics to lactams. Curr Drug Metab 1:357–389
  • Volotinen M, Turpeinen M, Tolonen A, Uusitalo J, et al. (2007). Timolol metabolism in human liver microsomes is mediated principally by CYP2D6. Drug Metab Dispos 35:1135–1141
  • Walkenstein SS, Chumakow N, Seifter J. (1954). Fate and sojourn of C14-dibenzyl-ethylenediamine (DBED) and C14-DBED dipenicillin G (Bicillin) following oral and intramuscular injection. Antibiotics Chemother 4:1245–1250
  • Ward D, Kalir A, Trevor A, et al. (1982). Metabolic formation of iminium species: The metabolism of phencyclidine. J Med Chem 25:491–492
  • Wen B, Ma L, Rodrigues AD, Zhu M. (2008). Detection of novel reactive metabolites of trazodone: Evidence for CYP2D6-mediated bioactivation of m-chlorophenylpiperazine. Drug Metab Dispos 36:841–850
  • Widman M, Nilsson LB, Bryske B, Lundstroem J. (1993). Disposition of remoxipride in different species. Species differences in metabolism. Arzneim-forsch Drug Res 43:287–297
  • Williams DE, Shigenaga MK, Castagnoli NJ. (1990). The role of cytochromes p-450 and flavin-containing monooxygenase in the metabolism of (S)-nicotine by rabbit lung. Drug Metab Dispos 18:418–428
  • Williams DP, Pirmohamed M, Naisbitt DJ, et al. (1997). Neutrophil cytotoxicity of the chemically reactive metabolite(s) of clozapine: Possible role in agranulocytosis. J Pharmacol Exp Therap 283:1375–1382
  • Williams DP, O’Donnell CJL, Maggs JL, et al. (2003). Bioactivation of clozapine by murine cardiac tissue in vivo and in vitro. Chem Res Toxicol 16:1359–1364
  • Wright AJ. (1999). The penicillins. Mayo Clinic proceedings 74:290–307
  • Wu Y-J, Davis CD, Dworetzky S, et al. (2003). Fluorine substitution can block CYP3A4 metabolism-dependent inhibition: Identification of (S)-N-[1-(4-fluoro-3- morpholin-4-ylphenyl)ethyl]-3-(4-fluorophenyl)acrylamide as an orally bioavailable KCNQ2 opener devoid of CYP3A4 metabolism-dependent inhibition. J Med Chem 46:3778–3781
  • Wynalda MA, Hauer MJ, Wienkers LC. (2000). Oxidation of the novel oxazolidinone antibiotic linezolid in human liver microsomes. Drug Metab Dispos 28:1014–1017
  • Yamanaka H, Nakajima M, Katoh M, et al. (2005). Trans-3′-hydroxycotinine O- and O-glucuronidations in human liver microsomes. Drug Metab Dispos 33:23–30
  • Yin W, Doss G, Stearns R. (2003). Tetramethyl piperidine moiety to a 2, 2-dimethyl pyrrolidine in human liver microsomes: Characterization by high resolution quadrupole-time-of-flight mass spectrometry. Drug Metab Dispos 31:215–222
  • Yin W, Mitra K, Stearns RA, et al. (2004). Conversion of the 2,2,6,6-tetramethylpiperidine moiety to a 2,2-dimethylpyrrolidine by cytochrome P450: Evidence for a mechanism involving nitroxide radicals and heme iron. Biochemistry 43:5455–5466
  • Zhang Z, Chen Q, Li Y, et al. (2005). In vitro bioactivation of dihydrobenzoxathiin selective estrogen receptor modulators by cytochrome P450 3A4 in human liver microsomes: Formation of reactive iminium and quinone type metabolites. Chem Res Toxicol 18:675–685
  • Zhang ZY, Chen M, Chen J, et al. (2009). Biotransformation and in vitro assessment of metabolism-associated drug-drug interaction for CRx-102, a novel combination drug candidate. J Pharm Biomed Anal 50:200–209

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