Practical approaches to resolving reactive metabolite liabilities in early discovery

References

• Adams DH, Ju C, Ramaiah SK, et al. (2010). Mechanisms of immune-mediated liver injury. Toxicol Sci 115:307–321
   PubMed Web of Science ®Google Scholar
• Alsenz J, Kansy M. (2007). High throughput solubility measurement in drug discovery and development. Adv Drug Deliv Rev 59:546–567
   PubMed Web of Science ®Google Scholar
• Alvarez-Sanchez R, Montavon F, Hartung T, Pahler A. (2006). Thiazolidinedione bioactivation: A comparison of the bioactivation potentials of troglitazone, rosiglitazone, and pioglitazone using stable isotope-labeled analogues and liquid chromatography tandem mass spectrometry. Chem Res Toxicol 19:1106–1116
   PubMed Web of Science ®Google Scholar
• Aranda-Michel J, Koehler A, Bejarano PA, et al. (1999). Nefazodone-induced liver failure: Report of three cases. Ann Intern Med 130:285–288
   PubMed Web of Science ®Google Scholar
• Argikar UA, Mangold JB, Harriman SP. (2011). Strategies and chemical design approaches to reduce the potential for formation of reactive metabolic species. Curr Topics Med Chem 11:419–449
   PubMed Web of Science ®Google Scholar
• Avdeef A. (2005). The rise of PAMPA. Expert Opin Drug Metab Toxicol 1:325–342
   PubMedGoogle Scholar
• Baer BR, Wienkers LC, Rock DA. (2007). Time-dependent inactivation of P450 3A4 by raloxifene: Identification of Cys239 as the site of apoprotein alkylation. ChemRes Toxicol 20:954–964
   PubMed Web of Science ®Google Scholar
• Baillie TA. (2006). Future of toxicology-metabolic activation and drug design: Challenges and opportunities in chemical toxicology. Chem Res Toxicol 19:889–893
   PubMed Web of Science ®Google Scholar
• Barbier O, Albert C, Martineau I, et al. (2001). Glucuronidation of the nonsteroidal antiestrogen EM-652 (SCH 57068), by human and monkey steroid conjugating UDP-glucuronosyltransferase enzymes. Molec Pharmacol 59:636–645
   PubMed Web of Science ®Google Scholar
• Bauman JN, Kelly JM, Tripathy S, et al. (2009). Can in vitro metabolism-dependent covalent binding data distinguish hepatotoxic from nonhepatotoxic drugs? An analysis using human hepatocytes and liver S-9 fraction. Chem Res Toxicol 22:332–340
   PubMed Web of Science ®Google Scholar
• Bavetsias V, Large JM, Sun C, et al. (2010). Imidazo[4,5-b]pyridine derivatives as inhibitors of Aurora kinases: Lead optimization studies toward the identification of an orally bioavailable preclinical development candidate. J Med Chem 53:5213–5228
   PubMed Web of Science ®Google Scholar
• Boelsterli UA. (2003). Disease-related determinants of susceptibility to drug-induced idiosyncratic hepatotoxicity. Curr Opin Drug Discov Devel 6:81–91
   PubMed Web of Science ®Google Scholar
• Braggio S, Montanari D, Rossi T, Ratti E. (2010). Drug efficiency: A new concept to guide lead optimization programs towards the selection of better clinical candidates. Expert Opin Drug Discov 5:609–618
   PubMed Web of Science ®Google Scholar
• Chang G, Steyn SJ, Umland JP, Scott DO. (2010). Strategic use of plasma and microsome binding to exploit in vitro clearance in early drug discovery. ACS Med Chem Lett 1:50–53
   PubMed Web of Science ®Google Scholar
• Chen Q, Ngui JS, Doss GA, et al. (2002). Cytochrome P450 3A4-mediated bioactivation of raloxifene: Irreversible enzyme inhibition and thiol adduct formation. Chem Res Toxicol 15:907–914
   PubMed Web of Science ®Google Scholar
• Chen WG, Zhang C, Avery MJ, Fouda HG. (2001). Reactive metabolite screen for reducing candidate attrition in drug discovery. Adv Exp Med Biol 500:521–524
   PubMed Web of Science ®Google Scholar
• Cox CD, Breslin MJ, Whitman DB, et al. (2010). Discovery of the dual orexin receptor antagonist [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the treatment of insomnia. J Med Chem 53:5320–5332
   PubMed Web of Science ®Google Scholar
• Cox PJ, Ryan DA, Hollis FJ, et al. (2000). Absorption, disposition, and metabolism of rosiglitazone, a potent thiazolidinedione insulin sensitizer, in humans. Drug Metab Dispos 28:772–780
   PubMed Web of Science ®Google Scholar
• Crawford JJ, Kenny PW, Bowyer J, et al. (2012). Pharmacokinetic benefits of 3,4-dimethoxy substitution of a phenyl ring and design of isosteres yielding orally available cathepsin K inhibitors. J Med Chem 55:8827–8837
   PubMed Web of Science ®Google Scholar
• Dalvie D, Kang P, Zientek M, et al. (2008). Effect of intestinal glucuronidation in limiting hepatic exposure and bioactivation of raloxifene in humans and rats. Chem Res Toxicol 21:2260–2271
   PubMed Web of Science ®Google Scholar
• Dalvie D, Obach RS, Kang P, et al. (2009). Assessment of three human in vitro systems in the generation of major human excretory and circulating metabolites. Chem Res Toxicol 22:357–368
   PubMed Web of Science ®Google Scholar
• de Morais SM, Chow SY, Wells PG. (1992a). Biotransformation and toxicity of acetaminophen in congenic RHA rats with or without a hereditary deficiency in bilirubin UDP-glucuronosyltransferase. Toxicol Appl Pharmacol 117:81–87
   PubMed Web of Science ®Google Scholar
• de Morais SM, Uetrecht JP, Wells PG. (1992b). Decreased glucuronidation and increased bioactivation of acetaminophen in Gilbert's syndrome. Gastroenterology 102:577–586
   PubMed Web of Science ®Google Scholar
• de Morais SM, Wells PG. (1988). Deficiency in bilirubin UDP-glucuronyl transferase as a genetic determinant of acetaminophen toxicity. J Pharmacol Exp Therapeut 247:323–331
   PubMed Web of Science ®Google Scholar
• de Morais SM, Wells PG. (1989). Enhanced acetaminophen toxicity in rats with bilirubin glucuronyl transferase deficiency. Hepatology 10:163–167
   PubMed Web of Science ®Google Scholar
• Di L, Feng B, Goosen TC, et al. (2013). A perspective on the prediction of drug pharmacokinetics and disposition in drug research and development. Drug Metab Dispos 41:1975–1993
   PubMed Web of Science ®Google Scholar
• Di L, Trapa P, Obach RS, et al. (2012). A novel relay method for determining low-clearance values. Drug Metab Dispos 40:1860–1865
   PubMed Web of Science ®Google Scholar
• Di L, Whitney-Pickett C, Umland JP, et al. (2011). Development of a new permeability assay using low-efflux MDCKII cells. J Pharm Sci 100:4974–4985
   PubMed Web of Science ®Google Scholar
• Doss GA, Baillie TA. (2006). Addressing metabolic activation as an integral component of drug design. Drug Metab Rev 38:641–649
   PubMed Web of Science ®Google Scholar
• Dowers TS, Qin ZH, Thatcher GR, Bolton JL. (2006). Bioactivation of selective estrogen receptor modulators (SERMs). Chem Res Toxicol 19:1125–1137
   PubMed Web of Science ®Google Scholar
• Eckland DA, Danhof M. (2000). Clinical pharmacokinetics of pioglitazone. Exp Clin Endocrinol Diabetes 108:234–242
   Web of Science ®Google Scholar
• Eloubeidi MA, Gaede JT, Swaim MW. (2000). Reversible nefazodone-induced liver failure. Digest Dis Sci 45:1036–1038
   PubMed Web of Science ®Google Scholar
• Evans DC, Baillie TA. (2005). Minimizing the potential for metabolic activation as an integral part of drug design. Curr Opin Drug Discov Dev 8:44–50
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• Finlay HJ, Lloyd J, Vaccaro W, et al. (2012). Discovery of ((S)-5-(methoxymethyl)-7-(1-methyl-1H-indol-2-yl)-2-(trifluoromethyl)-4,7-dihydropyrazolo[1,5-a]pyrimidin-6-yl)((S)-2-(3-methylisoxazol-5-yl)pyrrolidin-1-yl)metha none as a potent and selective I(Kur) inhibitor. J Med Chem 55:3036–3048
   PubMed Web of Science ®Google Scholar
• Gan J, Harper TW, Hsueh MM, et al. (2005). Dansyl glutathione as a trapping agent for the quantitative estimation and identification of reactive metabolites. Chem Res Toxicol 18:896–903
   PubMed Web of Science ®Google Scholar
• Gan J, Ruan Q, He B, et al. (2009). In vitro screening of 50 highly prescribed drugs for thiol adduct formation – comparison of potential for drug-induced toxicity and extent of adduct formation. Chem Res Toxicol 22:690–698
   PubMed Web of Science ®Google Scholar
• Gardner I, Leeder JS, Chin T, et al. (1998a). A comparison of the covalent binding of clozapine and olanzapine to human neutrophils in vitro and in vivo. Molec Pharmacol 53:999–1008
   PubMed Web of Science ®Google Scholar
• Gardner I, Zahid N, MacCrimmon D, Uetrecht JP. (1998b). A comparison of the oxidation of clozapine and olanzapine to reactive metabolites and the toxicity of these metabolites to human leukocytes. Molec Pharmacol 53:991–998
   PubMed Web of Science ®Google Scholar
• Guengerich FP, MacDonald JS. (2007). Applying mechanisms of chemical toxicity to predict drug safety. Chem Res Toxicol 20:344–369
   PubMed Web of Science ®Google Scholar
• Haas DW, Mootsikapun P, Ruxrungtham K, Podzamczer D; Nevirapine Toxicogenomics Study T. (2012). Clinical perspectives on human genetic screening to prevent nevirapine toxicity. Pers Med 9:773–782
   PubMed Web of Science ®Google Scholar
• Hagmann WK. (2008). The discovery of taranabant, a selective cannabinoid-1 receptor inverse agonist for the treatment of obesity. Archiv Pharmazie 341:405–411
   PubMed Web of Science ®Google Scholar
• Hardy KD, Wahlin MD, Papageorgiou I, et al. (2014). Studies on the role of metabolic activation in tyrosine kinase inhibitor-dependent hepatotoxicity: Induction of CYP3A4 enhances the cytotoxicity of lapatinib in HepaRG cells. Drug Metab Dispos 42:162–171
   PubMed Web of Science ®Google Scholar
• Harrelson JP, Stamper BD, Chapman JD, et al. (2012). Covalent modification and time-dependent inhibition of human CYP2E1 by the meta-isomer of acetaminophen. Drug Metab Dispos 40:1460–1465
   PubMed Web of Science ®Google Scholar
• Hartman NR, Cysyk RL, Bruneau-Wack C, et al. (2002). Production of intracellular 35S-glutathione by rat and human hepatocytes for the quantification of xenobiotic reactive intermediates. Chem Biol Interact 142:43–55
   PubMed Web of Science ®Google Scholar
• Hartz RA, Ahuja VT, Zhuo X, et al. (2009). A strategy to minimize reactive metabolite formation: Discovery of (S)-4-(1-cyclopropyl-2-methoxyethyl)-6-[6-(difluoromethoxy)-2,5-dimethylpyridin-3 -ylamino]-5-oxo-4,5-dihydropyrazine-2-carbonitrile as a potent, orally bioavailable corticotropin-releasing factor-1 receptor antagonist. J Med Chem 52:7653–7668
   PubMed Web of Science ®Google Scholar
• Heringa M. (2003). Review on raloxifene: Profile of a selective estrogen receptor modulator. Int J Clin Pharmacol Ther 41:331–345
   PubMed Web of Science ®Google Scholar
• Hochner-Celnikier D. (1999). Pharmacokinetics of raloxifene and its clinical application. Eur J Obstet Gyn Reprod Biol 85:23–29
   PubMed Web of Science ®Google Scholar
• Holme JA, Hongslo JK, Bjorge C, Nelson SD. (1991). Comparative cytotoxic effects of acetaminophen (N-acetyl-p-aminophenol), a non-hepatotoxic regioisomer acetyl-m-aminophenol and their postulated reactive hydroquinone and quinone metabolites in monolayer cultures of mouse hepatocytes. Biochem Pharmacol 42:1137–1142
   PubMed Web of Science ®Google Scholar
• Kalgutkar AS. (2011). Handling reactive metabolite positives in drug discovery: What has retrospective structure-toxicity analyses taught us? Chem Biol Interact 192:46–55
   PubMed Web of Science ®Google Scholar
• Kalgutkar AS, Didiuk MT. (2009). Structural alerts, reactive metabolites, and protein covalent binding: How reliable are these attributes as predictors of drug toxicity? Chem Biodivers 6:2115–2137
   PubMed Web of Science ®Google Scholar
• Kalgutkar AS, Gardner I, Obach RS, et al. (2005a). A comprehensive listing of bioactivation pathways of organic functional groups. Curr Drug Metab 6:161–225
   PubMed Web of Science ®Google Scholar
• Kalgutkar AS, Griffith DA, Ryder T, et al. (2010). Discovery tactics to mitigate toxicity risks due to reactive metabolite formation with 2-(2-hydroxyaryl)-5-(trifluoromethyl)pyrido[4,3-d]pyrimidin-4(3h)-one derivatives, potent calcium-sensing receptor antagonists and clinical candidate(s) for the treatment of osteoporosis. Chem Res Toxicol 23:1115–1126
   PubMed Web of Science ®Google Scholar
• Kalgutkar AS, Mascitti V, Sharma R, et al. (2011). Intrinsic electrophilicity of a 4-substituted-5-cyano-6-(2-methylpyridin-3-yloxy)pyrimidine derivative: Structural characterization of glutathione conjugates in vitro. Chem Res Toxicol 24:269–278
   PubMed Web of Science ®Google Scholar
• Kalgutkar AS, Ryder TF, Walker GS, et al. (2013). Reactive metabolite trapping studies on imidazo- and 2-methylimidazo[2,1-b]thiazole-based inverse agonists of the ghrelin receptor. Drug Metab Dispos 41:1375–1388
   PubMed Web of Science ®Google Scholar
• Kalgutkar AS, Soglia JR. (2005). Minimising the potential for metabolic activation in drug discovery. Expert Opin Drug Metab Toxicol 1:91–142
   PubMedGoogle Scholar
• Kalgutkar AS, Vaz AD, Lame ME, et al. (2005b). Bioactivation of the nontricyclic antidepressant nefazodone to a reactive quinone-imine species in human liver microsomes and recombinant cytochrome P450 3A4. Drug Metab Dispos 33:243–253
   PubMed Web of Science ®Google Scholar
• Kantharaj E, Ehmer PB, Tuytelaars A, et al. (2005). Simultaneous measurement of metabolic stability and metabolite identification of 7-methoxymethylthiazolo[3,2-a]pyrimidin-5-one derivatives in human liver microsomes using liquid chromatography/ion-trap mass spectrometry. RCM 19:1069–1074
   Google Scholar
• Kantharaj E, Tuytelaars A, Proost PE, et al. (2003). Simultaneous measurement of drug metabolic stability and identification of metabolites using ion-trap mass spectrometry. RCM 17:26612668
   Google Scholar
• Kaplowitz N. (2005). Idiosyncratic drug hepatotoxicity. Nature Rev Drug Discov 4:489–499
   PubMed Web of Science ®Google Scholar
• Kenna JG. (2013). A new twist to an old tale: Novel insights into the differential toxicities of acetaminophen and its regioisomer N-acetyl-meta-aminophenol (AMAP). Arch Toxicol 87:15–18
   PubMed Web of Science ®Google Scholar
• Kumar S, Kassahun K, Tschirret-Guth RA, et al. (2008). Minimizing metabolic activation during pharmaceutical lead optimization: Progress, knowledge gaps and future directions. Curr Opin Drug Discov Dev 11:43–52
   PubMed Web of Science ®Google Scholar
• Lammert C, Einarsson S, Saha C, et al. (2008). Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury: Search for signals. Hepatology 47:2003–2009
   PubMed Web of Science ®Google Scholar
• Leung L, Kalgutkar AS, Obach RS. (2012). Metabolic activation in drug-induced liver injury. Drug Metab Rev 44:18–33
   PubMed Web of Science ®Google Scholar
• Li AP. (2002). A review of the common properties of drugs with idiosyncratic hepatotoxicity and the “multiple determinant hypothesis” for the manifestation of idiosyncratic drug toxicity. Chem Biol Interact 142:7–23
   PubMed Web of Science ®Google Scholar
• Li J, Uetrecht JP. (2010). The danger hypothesis applied to idiosyncratic drug reactions. Handb Exp Pharmacol 196:493–509
   PubMedGoogle Scholar
• Lim HK, Chan KW, Sisenwine S, Scatina JA. (2001). Simultaneous screen for microsomal stability and metabolite profile by direct injection turbulent-laminar flow LC-LC and automated tandem mass spectrometry. Analyt Chem 73:2140–2146
   PubMed Web of Science ®Google Scholar
• Liu J, Liu H, van Breemen RB, et al. (2005). Bioactivation of the selective estrogen receptor modulator acolbifene to quinone methides. Chem Res Toxicol 18:174–182
   PubMed Web of Science ®Google Scholar
• 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 Ther 275:1476–1483
   PubMed Web of Science ®Google Scholar
• Lucas A, Nolan D, Mallal S. (2007). HLA-B*5701 screening for susceptibility to abacavir hypersensitivity. J Antimicrob Chemother 59:591–593
   PubMed Web of Science ®Google Scholar
• Ma S, Subramanian R. (2006). Detecting and characterizing reactive metabolites by liquid chromatography/tandem mass spectrometry. JMS 41:1121–1139
   Google Scholar
• Ma S, Zhu M. (2009). Recent advances in applications of liquid chromatography-tandem mass spectrometry to the analysis of reactive drug metabolites. Chem Biol Interact 179:25–37
   PubMed Web of Science ®Google Scholar
• Mulder GJ, Le CT. (1988). A rapid, simple in vitro screening test, using [(3)H]glutathione and l-[(35)S]cysteine as trapping agents, to detect reactive intermediates of xenobiotics. Toxicol In Vitro 2:225–230
   PubMed Web of Science ®Google Scholar
• Myers TG, Dietz EC, Anderson NL, et al. (1995). A comparative study of mouse liver proteins arylated by reactive metabolites of acetaminophen and its nonhepatotoxic regioisomer, 3′-hydroxyacetanilide. Chem Res Toxicol 8:403–413
   PubMed Web of Science ®Google Scholar
• Nagele E, Fandino AS. (2007). Simultaneous determination of metabolic stability and identification of buspirone metabolites using multiple column fast liquid chromatography time-of-flight mass spectrometry. J Chromatogr A 1156:196–200
   PubMed Web of Science ®Google Scholar
• Nair SK, Matthews JJ, Cripps SJ, et al. (2013). N-(Pyridin-2-yl) arylsulfonamide inhibitors of 11beta-hydroxysteroid dehydrogenase type 1: Strategies to eliminate reactive metabolites. Bioorg Med Chem Lett 23:2344–2348
   PubMed Web of Science ®Google Scholar
• Nelson SD. (1982). Metabolic activation and drug toxicity. J Med Chem 25:753–765
   PubMed Web of Science ®Google Scholar
• Nelson SD. (2001a). Molecular mechanisms of adverse drug reactions. Curr Ther Res 62:885–899
   Web of Science ®Google Scholar
• Nelson SD. (2001b). Structure toxicity relationships – how useful are they in predicting toxicities of new drugs? Adv Exp Med Biol 500:33–43
   PubMed Web of Science ®Google Scholar
• Ng W, Lobach AR, Zhu X, et al. (2012). Animal models of idiosyncratic drug reactions. Adv Pharmacol 63:81–135
   PubMedGoogle Scholar
• Obach RS. (1999). Prediction of human clearance of twenty-nine drugs from hepatic microsomal intrinsic clearance data: An examination of in vitro half-life approach and nonspecific binding to microsomes. Drug Metab Dispos 27:1350–1359
   PubMed Web of Science ®Google Scholar
• Obach RS, Kalgutkar AS, Ryder TF, Walker GS. (2008a). In vitro metabolism and covalent binding of enol-carboxamide derivatives and anti-inflammatory agents sudoxicam and meloxicam: Insights into the hepatotoxicity of sudoxicam. Chem Res Toxicol 21:1890–1899
   PubMed Web of Science ®Google Scholar
• Obach RS, Kalgutkar AS, Soglia JR, Zhao SX. (2008b). Can in vitro metabolism-dependent covalent binding data in liver microsomes distinguish hepatotoxic from nonhepatotoxic drugs? An analysis of 18 drugs with consideration of intrinsic clearance and daily dose. Chem Res Toxicol 21:1814–1822
   PubMed Web of Science ®Google Scholar
• Park BK, Boobis A, Clarke S, et al. (2011a). Managing the challenge of chemically reactive metabolites in drug development. Nature Rev Drug Discov 10:292–306
   PubMed Web of Science ®Google Scholar
• Park BK, Kitteringham NR, Maggs JL, et al. (2005). The role of metabolic activation in drug-induced hepatotoxicity. Ann Rev Pharmacol Toxicol 45:177–202
   PubMed Web of Science ®Google Scholar
• Park BK, Laverty H, Srivastava A, et al. (2011b). Drug bioactivation and protein adduct formation in the pathogenesis of drug-induced toxicity. Chem Biol Interact 192:30–36
   PubMed Web of Science ®Google Scholar
• Pirmohamed M, Naisbitt DJ, Gordon F, Park BK. (2002). The danger hypothesis – potential role in idiosyncratic drug reactions. Toxicology 181–182:55–63
   PubMed Web of Science ®Google Scholar
• 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
   PubMed Web of Science ®Google Scholar
• Reese M, Sakatis M, Ambroso J, et al. (2011). An integrated reactive metabolite evaluation approach to assess and reduce safety risk during drug discovery and development. Chem Biol Interact 192:60–64
   PubMed Web of Science ®Google Scholar
• Roecklein BA, Sacks HJ, Mortko H, Stables J. (2007). Fluorofelbamate. Neurotherapeutics 4:97–101
   PubMed Web of Science ®Google Scholar
• Roth RA, Ganey PE. (2010). Intrinsic versus idiosyncratic drug-induced hepatotoxicity – two villains or one? J Pharmacol Exp Ther 332:692–697
   PubMed Web of Science ®Google Scholar
• Roth RA, Luyendyk JP, Maddox JF, Ganey PE. (2003). Inflammation and drug idiosyncrasy– is there a connection? J Pharmacol Exp Ther 307:1–8
   PubMed Web of Science ®Google Scholar
• Roujeau JC, Huynh TN, Bracq C, et al. (1987). Genetic susceptibility to toxic epidermal necrolysis. Arch Dermatol 123:1171–1173
   PubMed Web of Science ®Google Scholar
• Saltiel AR, Olefsky JM. (1996). Thiazolidinediones in the treatment of insulin resistance and type II diabetes. Diabetes 45:1661–1669
   PubMed Web of Science ®Google Scholar
• Sarabu R, Bizzarro FT, Corbett WL, et al. (2012). Discovery of piragliatin – first glucokinase activator studied in type 2 diabetic patients. J Med Chem 55:7021–7036
   PubMed Web of Science ®Google Scholar
• Shenton JM, Chen J, Uetrecht JP. (2004). Animal models of idiosyncratic drug reactions. Chem Biol Interact 150:53–70
   PubMed Web of Science ®Google Scholar
• Singer JB, Lewitzky S, Leroy E, et al. (2010). A genome-wide study identifies HLA alleles associated with lumiracoxib-related liver injury. Nature Genet 42:711–714
   PubMed Web of Science ®Google Scholar
• Siu M, Johnson TO, Wang Y, et al. (2009). N-(Pyridin-2-yl) arylsulfonamide inhibitors of 11beta-hydroxysteroid dehydrogenase type 1: Discovery of PF-915275. Bioorg Med Chem Lett 19:3493–3497
   PubMed Web of Science ®Google Scholar
• Soglia JR, Contillo LG, Kalgutkar AS, et al. (2006). A semiquantitative method for the determination of reactive metabolite conjugate levels in vitro utilizing liquid chromatography-tandem mass spectrometry and novel quaternary ammonium glutathione analogues. Chem Res Toxicol 19:480–490
   PubMed Web of Science ®Google Scholar
• Soglia JR, Harriman SP, Zhao S, et al. (2004). The development of a higher throughput reactive intermediate screening assay incorporating micro-bore liquid chromatography-micro-electrospray ionization-tandem mass spectrometry and glutathione ethyl ester as an in vitro conjugating agent. J Pharm Biomed Anal 36:105–116
   PubMed Web of Science ®Google Scholar
• Spencer CM, Markham A. (1997). Troglitazone. Drugs 54:89–101; discussion 102
   PubMed Web of Science ®Google Scholar
• Stachulski AV, Baillie TA, Park BK, et al. (2013). The generation, detection, and effects of reactive drug metabolites. Med Res Rev 33:985–1080
   PubMed Web of Science ®Google Scholar
• Stepan AF, Walker DP, Bauman J, et al. (2011). Structural alert/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 in the top 200 drugs marketed in the United States. Chem Res Toxicology 24:1345–1410
   PubMed Web of Science ®Google Scholar
• Subramanian R, Lee MR, Allen JG, et al. (2010). Cytochrome P450-mediated epoxidation of 2-aminothiazole-based AKT inhibitors: Identification of novel GSH adducts and reduction of metabolic activation through structural changes guided by in silico and in vitro screening. Chem Res Toxicol 23:653–663
   PubMed Web of Science ®Google Scholar
• Takakusa H, Masumoto H, Makino C, et al. (2009). Quantitative assessment of reactive metabolite formation using 35S-labeled glutathione. Drug Metab Pharmacokinet 24:100–107
   PubMed Web of Science ®Google Scholar
• Tang W, Lu AY. (2010). Metabolic bioactivation and drug-related adverse effects: Current status and future directions from a pharmaceutical research perspective. Drug Metab Rev 42:225–249
   PubMed Web of Science ®Google Scholar
• Teo YL, Saetaew M, Chanthawong S, et al. (2012). Effect of CYP3A4 inducer dexamethasone on hepatotoxicity of lapatinib: Clinical and in vitro evidence. Breast Cancer Res Treat 133:703–711
   PubMed Web of Science ®Google Scholar
• Tettey JN, Maggs JL, Rapeport WG, et al. (2001). Enzyme-induction dependent bioactivation of troglitazone and troglitazone quinone in vivo. Chem Res Toxicol 14:965–974
   PubMed Web of Science ®Google Scholar
• Thompson RA, Isin EM, Li Y, et al. (2011). Risk assessment and mitigation strategies for reactive metabolites in drug discovery and development. Chem Biol Interact 192:65–71
   PubMed Web of Science ®Google Scholar
• Thompson RA, Isin EM, Li Y, et al. (2012). In vitro approach to assess the potential for risk of idiosyncratic adverse reactions caused by candidate drugs. Chem Res Toxicol 25:1616–1632
   PubMed Web of Science ®Google Scholar
• Tirmenstein MA, Nelson SD. (1989). Subcellular binding and effects on calcium homeostasis produced by acetaminophen and a nonhepatotoxic regioisomer, 3′-hydroxyacetanilide, in mouse liver. J Biol Chem 264:9814–9819
   PubMed Web of Science ®Google Scholar
• Uetrecht J. (2007). Idiosyncratic drug reactions: Current understanding. Ann Rev Pharmacol Toxicol 47:513–539
   PubMed Web of Science ®Google Scholar
• Uetrecht J. (2008). Idiosyncratic drug reactions: Past, present, and future. Chem Res Toxicol 21:84–92
   PubMed Web of Science ®Google Scholar
• Uetrecht J, Naisbitt DJ. (2013). Idiosyncratic adverse drug reactions: Current concepts. Pharmacol Rev 65:779–808
   PubMed Web of Science ®Google Scholar
• Uetrecht J, Zahid N, Tehim A, et al. (1997). Structural features associated with reactive metabolite formation in clozapine analogues. Chem Biol Interact 104:117–129
   PubMed Web of Science ®Google Scholar
• Uetrecht JP. (1992). Metabolism of clozapine by neutrophils. Possible implications for clozapine-induced agranulocytosis. Drug Safety 7:51–56
   PubMedGoogle Scholar
• Uetrecht JP. (2000). Is it possible to more accurately predict which drug candidates will cause idiosyncratic drug reactions? Curr Drug Metab 1:133–141
   PubMed Web of Science ®Google Scholar
• Ulrich RG. (2007). Idiosyncratic toxicity: A convergence of risk factors. Ann Rev Med 58:17–34
   PubMed Web of Science ®Google Scholar
• Usansky HH, Sinko PJ. (2005). Estimating human drug oral absorption kinetics from Caco-2 permeability using an absorption-disposition model: Model development and evaluation and derivation of analytical solutions for k(a) and F(a). J Pharmacol Exp Ther 314:391–399
   PubMed Web of Science ®Google Scholar
• Walgren JL, Mitchell MD, Thompson DC. (2005). Role of metabolism in drug-induced idiosyncratic hepatotoxicity. Crit Rev Toxicol 35:325–361
   PubMed Web of Science ®Google Scholar
• Wen B, Fitch WL. (2009a). Analytical strategies for the screening and evaluation of chemically reactive drug metabolites. Expert Opin Drug Metab Toxicol 5:39–55
   PubMed Web of Science ®Google Scholar
• Wen B, Fitch WL. (2009b). Screening and characterization of reactive metabolites using glutathione ethyl ester in combination with Q-trap mass spectrometry. JMS 44:90–100
   Google Scholar
• Yan Z, Maher N, Torres R, Huebert N. (2007). Use of a trapping agent for simultaneous capturing and high-throughput screening of both “soft” and “hard” reactive metabolites. Analyt Chem 79:4206–4214
   PubMed Web of Science ®Google Scholar
• Yu L, Liu H, Li W, et al. (2004). Oxidation of raloxifene to quinoids: Potential toxic pathways via a diquinone methide and o-quinones. Chem Res Toxicol 17:879–888
   PubMed Web of Science ®Google Scholar
• Zhang X, Liu F, Chen X, et al. (2011). Involvement of the immune system in idiosyncratic drug reactions. Drug Metab Pharmacokinet 26:47–59
   PubMed Web of Science ®Google Scholar
• Zhang X, Tellew JE, Luo Z, et al. (2008). Lead optimization of 4-acetylamino-2-(3,5-dimethylpyrazol-1-yl)-6-pyridylpyrimidines as A2A adenosine receptor antagonists for the treatment of Parkinson's disease. J Med Chem 51:7099–7110
   PubMed Web of Science ®Google Scholar
• Zhao SX, Dalvie DK, Kelly JM, et al. (2007). NADPH-dependent covalent binding of [3H]paroxetine to human liver microsomes and S-9 fractions: Identification of an electrophilic quinone metabolite of paroxetine. Chem Res Toxicol 20:1649–1657
   PubMed Web of Science ®Google Scholar
• Zou P, Yu Y, Zheng N, et al. (2012). Applications of human pharmacokinetic prediction in first-in-human dose estimation. AAPS J 14:262–281
   PubMed Web of Science ®Google Scholar