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Approaches for Minimizing Metabolic Activation of New Drug Candidates in Drug Discovery

  • Sanjeev KumarEmail author
  • Kaushik Mitra
  • Kelem Kassahun
  • Thomas A. Baillie
Chapter
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 196)

Abstract

A large body of circumstantial evidence suggests that metabolic activation of drug candidates to chemically reactive electrophilic metabolites that are capable of covalently modifying cellular macromolecules may result in acute and/or immune system-mediated idiosyncratic toxicities in humans. Thus, minimizing the potential for metabolic activation of new drug candidates during the drug discovery and lead optimization stage represents a prudent strategy to help discover and develop the next generation of safe and effective therapeutic agents. In the present chapter, we discuss the scientific methodologies that currently are available to industrial pharmaceutical scientists for assessing and minimizing metabolic activation during drug discovery, their attributes and limitations, and future scientific directions that have the potential to help advance progress in this field. We also propose a roadmap that should help utilize the armamentarium of available scientific tools in a logical way and contribute to addressing metabolic activation issues in the drug discovery-setting in a rapid, scientifically appropriate, and resource-conscious manner.

Keywords

Metabolic activation Bioactivation Reactive intermediates Covalent binding Drug discovery 

Abbreviations

GSH

Glutathione

KCN

Potassium cyanide

TZD

Thiazolidinedione

OZD

Oxazolidinedione

Notes

Acknowledgments

The authors would like to thank Drs. Alana Upthagrove and Timothy Schultz-Utermoehl for some of the studies discussed in this chapter.

References

  1. Adams CP, Brantner VV (2006) Estimating the cost of new drug development: is it really 802 million dollars? Health Aff (Millwood) 25:420-428Google Scholar
  2. 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 19:1106-1116PubMedGoogle Scholar
  3. Argoti D, Liang L, Conteh A, Chen L, Bershas D, Yu CP, Vouros P, Yang E (2005) Cyanide trapping of iminium ion reactive intermediates followed by detection and structure identification using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Chem Res Toxicol 18:1537-1544PubMedGoogle Scholar
  4. Azuma H, Paulk N, Ranade A, Dorrell C, Al Dhalimy M, Ellis E, Strom S, Kay MA, Finegold M, Grompe M (2007) Robust expansion of human hepatocytes in Fah-/-/Rag2-/-/Il2rg-/- mice. Nat Biotechnol 25:903-910PubMedGoogle Scholar
  5. Baillie TA (2006) Future of toxicology-metabolic activation and drug design: challenges and opportunities in chemical toxicology. Chem Res Toxicol 19:889-893PubMedGoogle Scholar
  6. Baillie TA (2008) Metabolism and toxicity of drugs. Two decades of progress in industrial drug metabolism. Chem Res Toxicol 21:129-137PubMedGoogle Scholar
  7. Baillie TA, Davis MR (1993) Mass spectrometry in the analysis of glutathione conjugates. Biol Mass Spectrom 22:319-325PubMedGoogle Scholar
  8. Bateman KP, Castro-Perez J, Wrona M, Shockcor JP, Yu K, Oballa R, Nicoll-Griffith DA (2007) MSE with mass defect filtering for in vitro and in vivo metabolite identification. Rapid Commun Mass Spectrom 21:1485-1496PubMedGoogle Scholar
  9. Baudoin R, Corlu A, Griscom L, Legallais C, Leclerc E (2007) Trends in the development of microfluidic cell biochips for in vitro hepatotoxicity. Toxicol In Vitro 21:535-544PubMedGoogle Scholar
  10. Boelsterli UA, Ho HK, Zhou S, Leow KY (2006) Bioactivation and hepatotoxicity of nitroaromatic drugs. Curr Drug Metab 7:715-727PubMedGoogle Scholar
  11. Bolton JL, Trush MA, Penning TM, Dryhurst G, Monks TJ (2000) Role of quinones in toxicology. Chem Res Toxicol 13:135-160PubMedGoogle Scholar
  12. Castro-Perez J, Plumb R, Liang L, Yang E (2005) A high-throughput liquid chromatography/tandem mass spectrometry method for screening glutathione conjugates using exact mass neutral loss acquisition. Rapid Commun Mass Spectrom 19:798-804PubMedGoogle Scholar
  13. Chauret N, Guay D, Li C, Day S, Silva J, Blouin M, Ducharme Y, Yergey JA, Nicoll-Griffith DA (2002) Improving metabolic stability of phosphodiesterase-4 inhibitors containing a substituted catechol: prevention of reactive intermediate formation and covalent binding. Bioorg Med Chem Lett 12:2149-2152PubMedGoogle Scholar
  14. Chen WG, Zhang C, Avery MJ, Fouda HG (2001) Reactive metabolite screen for reducing candidate attrition in drug discovery. In: Biological Reactive Intermediates VI: Chemical and Biological Mechanisms in Susceptibility to and Prevention of Environmental Diseases, Dansette PM, Snyder R, Delaforge M, Gibson GG, Greim H, Jollow DJ, Monks TJ, Sipes IG (eds.). Kluwer Academic/Plenum Press: New York 521-524Google Scholar
  15. Chen LJ, DeRose EF, Burka LT (2006) Metabolism of furans in vitro: ipomeanine and 4-ipomeanol. Chem Res Toxicol 19:1320-1329PubMedGoogle Scholar
  16. Dalvie DK, Kalgutkar AS, Khojasteh-Bakht SC, Obach RS, O'Donnell JP (2002) Biotransformation reactions of five-membered aromatic heterocyclic rings. Chem Res Toxicol 15:269-299PubMedGoogle Scholar
  17. Day SH, Mao A, White R, Schulz-Utermoehl T, Miller R, Beconi MG (2005) A semi-automated method for measuring the potential for protein covalent binding in drug discovery. J Pharmacol Toxicol Methods 52:278-285PubMedGoogle Scholar
  18. Dennehy MK, Richards KA, Wernke GR, Shyr Y, Liebler DC (2006) Cytosolic and nuclear protein targets of thiol-reactive electrophiles. Chem Res Toxicol 19:20-29PubMedGoogle Scholar
  19. Dieckhaus CM, Fernandez-Metzler CL, King R, Krolikowski PH, Baillie TA (2005) Negative ion tandem mass spectrometry for the detection of glutathione conjugates. Chem Res Toxicol 18:630-638PubMedGoogle Scholar
  20. DiMasi JA, Hansen RW, Grabowski HG (2003) The price of innovation: new estimates of drug development costs. J Health Econ 22:151-185PubMedGoogle Scholar
  21. Doss GA, Miller RR, Zhang Z, Teffera Y, Nargund RP, Palucki B, Park MK, Tang YS, Evans DC, Baillie TA, Stearns RA (2005) Metabolic activation of a 1, 3-disubstituted piperazine derivative: evidence for a novel ring contraction to an imidazoline. Chem Res Toxicol 18:271-276PubMedGoogle Scholar
  22. Erve JC (2006) Chemical toxicology: reactive intermediates and their role in pharmacology and toxicology. Expert Opin Drug Metab Toxicol 2:923-946PubMedGoogle Scholar
  23. Evans DC, Baillie TA (2005) Minimizing the potential for metabolic activation as an integral part of drug design. Curr Opin Drug Discov Dev 8:44-50Google Scholar
  24. 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 17:3-16PubMedGoogle Scholar
  25. Gan J, Harper TW, Hsueh MM, Qu Q, Humphreys WG (2005) Dansyl glutathione as a trapping agent for the quantitative estimation and identification of reactive metabolites. Chem Res Toxicol 18:896-903PubMedGoogle Scholar
  26. Gatzidou ET, Zira AN, Theocharis SE (2007) Toxicogenomics: a pivotal piece in the puzzle of toxicological research. J Appl Toxicol 27:302-309PubMedGoogle Scholar
  27. Gorrod JW, Whittlesea CM, Lam SP (1991) Trapping of reactive intermediates by incorporation of 14C-sodium cyanide during microsomal oxidation. Adv Exp Med Biol 283:657-664PubMedGoogle Scholar
  28. Grillo MP, Hua F, Knutson CG, Ware JA, Li C (2003a) Mechanistic studies on the bioactivation of diclofenac: identification of diclofenac-S-acyl-glutathione in vitro in incubations with rat and human hepatocytes. Chem Res Toxicol 16:1410-1417PubMedGoogle Scholar
  29. Grillo MP, Knutson CG, Sanders PE, Waldon DJ, Hua F, Ware JA (2003b) Studies on the chemical reactivity of diclofenac acyl glucuronide with glutathione: identification of diclofenac-S-acyl-glutathione in rat bile. Drug Metab Dispos 31:1327-1336PubMedGoogle Scholar
  30. Hanzlik RP, Koen YM, Theertham B, Dong Y, Fang J (2007) The reactive metabolite target protein database (TPDB)-a web-accessible resource. BMC Bioinformat 8:95Google Scholar
  31. He K, Iyer KR, Hayes RN, Sinz MW, Woolf TF, Hollenberg PF (1998) Inactivation of cytochrome P450 3A4 by bergamottin, a component of grapefruit juice. Chem Res Toxicol 11:252-259PubMedGoogle Scholar
  32. Jushchyshyn MI, Kent UM, Hollenberg PF (2003) The mechanism-based inactivation of human cytochrome P450 2B6 by phencyclidine. Drug Metab Dispos 31:46-52PubMedGoogle Scholar
  33. Jushchyshyn MI, Wahlstrom JL, Hollenberg PF, Wienkers LC (2006) Mechanism of inactivation of human cytochrome P450 2B6 by phencyclidine. Drug Metab Dispos 34:1523-1529PubMedGoogle Scholar
  34. Kalgutkar AS, Soglia JR (2005) Minimising the potential for metabolic activation in drug discovery. Expert Opin Drug Metab Toxicol 1:91-142PubMedGoogle Scholar
  35. Kalgutkar AS, Dalvie DK, O'Donnell JP, Taylor TJ, Sahakian DC (2002) On the diversity of oxidative bioactivation reactions on nitrogen-containing xenobiotics. Curr Drug Metab 3:379-424PubMedGoogle Scholar
  36. Kalgutkar AS, Gardner I, Obach RS, Shaffer CL, Callegari E, Henne KR, Mutlib AE, Dalvie DK, Lee JS, Nakai Y, O'Donnell JP, Boer J, Harriman SP (2005) A comprehensive listing of bioactivation pathways of organic functional groups. Curr Drug Metab 6:161-225PubMedGoogle Scholar
  37. Kalgutkar AS, Dalvie DK, Aubrecht J, Smith EB, Coffing SL, Cheung JR, Vage C, Lame ME, Chiang P, McClure KF, Maurer TS, Coelho RV Jr, Soliman VF, Schildknegt K (2007a) 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 35:848-858PubMedGoogle Scholar
  38. Kalgutkar AS, Obach RS, Maurer TS (2007b) Mechanism-based inactivation of cytochrome P450 enzymes: chemical mechanisms, structure-activity relationships and relationship to clinical drug-drug interactions and idiosyncratic adverse drug reactions. Curr Drug Metab 8:407-447PubMedGoogle Scholar
  39. Kassahun K, Pearson PG, Tang W, McIntosh I, Leung K, Elmore C, Dean D, Wang R, Doss G, Baillie TA (2001) Studies on the metabolism of troglitazone to reactive intermediates in vitro and in vivo. Evidence for novel biotransformation pathways involving quinone methide formation and thiazolidinedione ring scission. Chem Res Toxicol 14:62-70PubMedGoogle Scholar
  40. Katoh M, Yokoi T (2007) Application of chimeric mice with humanized liver for predictive ADME. Drug Metab Rev 39:145-157PubMedGoogle Scholar
  41. Katoh M, Sawada T, Soeno Y, Nakajima M, Tateno C, Yoshizato K, Yokoi T (2007) In vivo drug metabolism model for human cytochrome P450 enzyme using chimeric mice with humanized liver. J Pharm Sci 96:428-437PubMedGoogle Scholar
  42. Khetani SR, Bhatia SN (2006) Engineering tissues for in vitro applications. Curr Opin Biotechnol 17:524-531PubMedGoogle Scholar
  43. Khetani SR, Bhatia SN (2008) Microscale culture of human liver cells for drug development. Nat Biotechnol 26:120-126PubMedGoogle Scholar
  44. Khojasteh-Bakht SC, Chen W, Koenigs LL, Peter RM, Nelson SD (1999) Metabolism of (R)-(+)-pulegone and (R)-(+)-menthofuran by human liver cytochrome P-450s: evidence for formation of a furan epoxide. Drug Metab Dispos 27:574-580PubMedGoogle Scholar
  45. Koen YM, Gogichaeva NV, Alterman MA, Hanzlik RP (2007) A proteomic analysis of bromobenzene reactive metabolite targets in rat liver cytosol in vivo. Chem Res Toxicol 20:511-519PubMedGoogle Scholar
  46. Kolbanovskiy A, Kuzmin V, Shastry A, Kolbanovskaya M, Chen D, Chang M, Bolton JL, Geacintov NE (2005) Base selectivity and effects of sequence and DNA secondary structure on the formation of covalent adducts derived from the equine estrogen metabolite 4-hydroxyequilenin. Chem Res Toxicol 18:1737-1747PubMedGoogle Scholar
  47. Kumar S, Kassahun K, Tschirret-Guth RA, Mitra K, Baillie TA (2008) Minimizing metabolic activation during pharmaceutical lead optimization: Progress, knowledge gaps and future directions. Curr Opin Drug Discov Dev 11:43-52Google Scholar
  48. Levesque JF, Day SH, Chauret N, Seto C, Trimble L, Bateman KP, Silva JM, Berthelette C, Lachance N, Boyd M, Li L, Sturino CF, Wang Z, Zamboni R, Young RN, Nicoll-Griffith DA (2007) Metabolic activation of indole-containing prostaglandin D2 receptor 1 antagonists: impacts of glutathione trapping and glucuronide conjugation on covalent binding. Bioorg Med Chem Lett 17:3038-3043PubMedGoogle Scholar
  49. Li C, Grillo MP, Benet LZ (2003a) In vivo mechanistic studies on the metabolic activation of 2-phenylpropionic acid in rat. J Pharmacol Exp Ther 305:250-256PubMedGoogle Scholar
  50. Li C, Olurinde MO, Hodges LM, Grillo MP, Benet LZ (2003b) Covalent binding of 2-phenylpropionyl-S-acyl-CoA thioester to tissue proteins in vitro. Drug Metab Dispos 31: 727-730PubMedGoogle Scholar
  51. Liebler DC (2008) Protein damage by reactive electrophiles: targets and consequences. Chem Res Toxicol 21:117-128PubMedGoogle Scholar
  52. Liebler DC, Guengerich FP (2005) Elucidating mechanisms of drug-induced toxicity. Nat Rev Drug Discov 4:410-420PubMedGoogle Scholar
  53. Lin HL, Kent UM, Hollenberg PF (2005) The grapefruit juice effect is not limited to cytochrome P450 (P450) 3A4: evidence for bergamottin-dependent inactivation, heme destruction, and covalent binding to protein in P450s 2B6 and 3A5. J Pharmacol Exp Ther 313:154-164PubMedGoogle Scholar
  54. Liu X, Pisha E, Tonetti DA, Yao D, Li Y, Yao J, Burdette JE, Bolton JL (2003) Antiestrogenic and DNA damaging effects induced by tamoxifen and toremifene metabolites. Chem Res Toxicol 16:832-837PubMedGoogle Scholar
  55. Liu H, Liu J, van Breemen RB, Thatcher GR, Bolton JL (2005a) Bioactivation of the selective estrogen receptor modulator desmethylated arzoxifene to quinoids: 4′-fluoro substitution prevents quinoid formation. Chem Res Toxicol 18:162-173PubMedGoogle Scholar
  56. Liu J, Liu H, van Breemen RB, Thatcher GR, Bolton JL (2005b) Bioactivation of the selective estrogen receptor modulator acolbifene to quinone methides. Chem Res Toxicol 18:174-182PubMedGoogle Scholar
  57. Masubuchi Y (2006) Metabolic and non-metabolic factors determining troglitazone hepatotoxicity: a review. Drug Metab Pharmacokinet 21:347-356PubMedGoogle Scholar
  58. Masubuchi Y, Horie T (2007) Toxicological significance of mechanism-based inactivation of cytochrome p450 enzymes by drugs. Crit Rev Toxicol 37:389-412PubMedGoogle Scholar
  59. Masubuchi N, Makino C, Murayama N (2007) Prediction of in vivo potential for metabolic activation of drugs into chemically reactive intermediate: correlation of in vitro and in vivo generation of reactive intermediates and in vitro glutathione conjugate formation in rats and human. Chem Res Toxicol 20:455-464PubMedGoogle Scholar
  60. Meneses-Lorente G, Sakatis MZ, Schulz-Utermoehl T, De Nardi C, Watt AP (2006) A quantitative high-throughput trapping assay as a measurement of potential for bioactivation. Anal Biochem 351:266-272PubMedGoogle Scholar
  61. Miller JA (1994) Brief history of chemical carcinogenesis. Cancer Lett 83:9-14PubMedGoogle Scholar
  62. Miller JA (1998) The metabolism of xenobiotics to reactive electrophiles in chemical carcinogenesis and mutagenesis: a collaboration with Elizabeth Cavert Miller and our associates. Drug Metab Rev 30:645-674PubMedGoogle Scholar
  63. Mutlib AE, Chen H, Nemeth GA, Markwalder JA, Seitz SP, Gan LS, Christ DD (1999) Identification and characterization of efavirenz metabolites by liquid chromatography/mass spectrometry and high field NMR: species differences in the metabolism of efavirenz. Drug Metab Dispos 27:1319-1333PubMedGoogle Scholar
  64. Mutlib AE, Gerson RJ, Meunier PC, Haley PJ, Chen H, Gan LS, Davies MH, Gemzik B, Christ DD, Krahn DF, Markwalder JA, Seitz SP, Robertson RT, Miwa GT (2000) The species-dependent metabolism of efavirenz produces a nephrotoxic glutathione conjugate in rats. Toxicol Appl Pharmacol 169:102-113PubMedGoogle Scholar
  65. Mutlib A, Lam W, Atherton J, Chen H, Galatsis P, Stolle W (2005) Application of stable isotope labeled glutathione and rapid scanning mass spectrometers in detecting and characterizing reactive metabolites. Rapid Commun Mass Spectrom 19:3482-3492PubMedGoogle Scholar
  66. Nassar AE, Lopez-Anaya A (2004) Strategies for dealing with reactive intermediates in drug discovery and development. Curr Opin Drug Discov Dev 7:126-136Google Scholar
  67. Nelson SD (2001) Structure toxicity relationships-how useful are they in predicting toxicities of new drugs? Adv Exp Med Biol 500:33-43PubMedGoogle Scholar
  68. Olsen J, Li C, Bjornsdottir I, Sidenius U, Hansen SH, Benet LZ (2005) In vitro and in vivo studies on acyl-coenzyme A-dependent bioactivation of zomepirac in rats. Chem Res Toxicol 18:1729-1736PubMedGoogle Scholar
  69. Olsen J, Li C, Skonberg C, Bjornsdottir I, Sidenius U, Benet LZ, Hansen SH (2007) Studies on the metabolism of tolmetin to the chemically reactive acyl-coenzyme A thioester intermediate in rats. Drug Metab Dispos 35:758-764PubMedGoogle Scholar
  70. Park K, Williams DP, Naisbitt DJ, Kitteringham NR, Pirmohamed M (2005) Investigation of toxic metabolites during drug development. Toxicol Appl Pharmacol 207:425-434PubMedGoogle Scholar
  71. Park KB, Dalton-Brown E, Hirst C, Williams DP (2006) Selection of new chemical entities with decreased potential for adverse drug reactions. Eur J Pharmacol 549:1-8PubMedGoogle Scholar
  72. Peterson LA (2006) Electrophilic intermediates produced by bioactivation of furan. Drug Metab Rev 38:615-626PubMedGoogle Scholar
  73. Potter WZ, Davis DC, Mitchell JR, Jollow DJ, Gillette JR, Brodie BB (1973) Acetaminophen-induced hepatic necrosis. 3. Cytochrome P-450-mediated covalent binding in vitro. J Pharmacol Exp Ther 187:203-210PubMedGoogle Scholar
  74. Potter WZ, Thorgeirsson SS, Jollow DJ, Mitchell JR (1974) Acetaminophen-induced hepatic necrosis. V. Correlation of hepatic necrosis, covalent binding and glutathione depletion in hamsters. Pharmacology 12:129-143PubMedGoogle Scholar
  75. Ruan Q, Peterman S, Szewc MA, Ma L, Cui D, Humphreys WG, Zhu M (2008) An integrated method for metabolite detection and identification using a linear ion trap/Orbitrap mass spectrometer and multiple data processing techniques: application to indinavir metabolite detection. J Mass Spectrom 43:251-261Google Scholar
  76. Sahali-Sahly Y, Balani SK, Lin JH, Baillie TA (1996) In vitro studies on the metabolic activation of the furanopyridine L-754, 394, a highly potent and selective mechanism-based inhibitor of cytochrome P450 3A4. Chem Res Toxicol 9:1007-1012PubMedGoogle Scholar
  77. Samuel K, Yin W, Stearns RA, Tang YS, Chaudhary AG, Jewell JP, Lanza T Jr, Lin LS, Hagmann WK, Evans DC, Kumar S (2003) Addressing the metabolic activation potential of new leads in drug discovery: a case study using ion trap mass spectrometry and tritium labeling techniques. J Mass Spectrom 38:211-221PubMedGoogle Scholar
  78. Senekeo-Effenberger K, Chen S, Brace-Sinnokrak E, Bonzo JA, Yueh MF, Argikar U, Kaeding J, Trottier J, Remmel RP, Ritter JK, Barbier O, Tukey RH (2007) Expression of the human UGT1 locus in transgenic mice by 4-chloro-6-(2, 3-xylidino)-2-pyrimidinylthioacetic acid (WY-14643) and implications on drug metabolism through peroxisome proliferator-activated receptor alpha activation. Drug Metab Dispos 35:419-427PubMedGoogle Scholar
  79. Shibutani S, Ravindernath A, Suzuki N, Terashima I, Sugarman SM, Grollman AP, Pearl ML (2000) Identification of tamoxifen-DNA adducts in the endometrium of women treated with tamoxifen. Carcinogenesis 21:1461-1467PubMedGoogle Scholar
  80. Shin NY, Liu Q, Stamer SL, Liebler DC (2007) Protein targets of reactive electrophiles in human liver microsomes. Chem Res Toxicol 20:859-867PubMedGoogle Scholar
  81. Singh R, Silva Elipe MV, Pearson PG, Arison BH, Wong BK, White R, Yu X, Burgey CS, Lin JH, Baillie TA (2003) Metabolic activation of a pyrazinone-containing thrombin inhibitor. Evidence for novel biotransformation involving pyrazinone ring oxidation, rearrangement, and covalent binding to proteins. Chem Res Toxicol 16:198-207PubMedGoogle Scholar
  82. Sivaraman A, Leach JK, Townsend S, Iida T, Hogan BJ, Stolz DB, Fry R, Samson LD, Tannenbaum SR, Griffith LG (2005) A microscale in vitro physiological model of the liver: predictive screens for drug metabolism and enzyme induction. Curr Drug Metab 6:569-591PubMedGoogle Scholar
  83. Smith MT (2003) Mechanisms of troglitazone hepatotoxicity. Chem Res Toxicol 16:679-687PubMedGoogle Scholar
  84. Soglia JR, Contillo LG, Kalgutkar AS, Zhao S, Hop CE, Boyd JG, Cole MJ (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 19:480-490PubMedGoogle Scholar
  85. Stachulski AV (2007) The chemistry and biological activity of acyl glucuronides. Curr Opin Drug Discov Dev 10:58-66Google Scholar
  86. Tang W (2007) Drug metabolite profiling and elucidation of drug-induced hepatotoxicity. Expert Opin Drug Metab Toxicol 3:407-420PubMedGoogle Scholar
  87. Tang C, Subramanian R, Kuo Y, Krymgold S, Lu P, Kuduk SD, Ng C, Feng DM, Elmore C, Soli E, Ho J, Bock MG, Baillie TA, Prueksaritanont T (2005) Bioactivation of 2,3-diaminopyridine-containing bradykinin B1 receptor antagonists: irreversible binding to liver microsomal proteins and formation of glutathione conjugates. Chem Res Toxicol 18:934-945PubMedGoogle Scholar
  88. Tarloff JB, Khairallah EA, Cohen SD, Goldstein RS (1996) Sex- and age-dependent acetaminophen hepato- and nephrotoxicity in Sprague-Dawley rats: role of tissue accumulation, nonprotein sulfhydryl depletion, and covalent binding. Fundam Appl Toxicol 30:13-22PubMedGoogle Scholar
  89. Tassaneeyakul W, Guo LQ, Fukuda K, Ohta T, Yamazoe Y (2000) Inhibition selectivity of grapefruit juice components on human cytochromes P450. Arch Biochem Biophys 378:356-363PubMedGoogle Scholar
  90. Uetrecht J (2006) Evaluation of which reactive metabolite, if any, is responsible for a specific idiosyncratic reaction. Drug Metab Rev 38:745-753PubMedGoogle Scholar
  91. Uetrecht J (2007) Idiosyncratic drug reactions: current understanding. Annu Rev Pharmacol Toxicol 47:513-539PubMedGoogle Scholar
  92. Uetrecht J (2008) Idiosyncratic drug reactions: past, present, and future. Chem Res Toxicol 21:84-92PubMedGoogle Scholar
  93. van Herwaarden AE, Smit JW, Sparidans RW, Wagenaar E, van der Kruijssen CM, Schellens JH, Beijnen JH, Schinkel AH (2005) Midazolam and cyclosporin a metabolism in transgenic mice with liver-specific expression of human CYP3A4. Drug Metab Dispos 33:892-895PubMedGoogle Scholar
  94. van Waterschoot RA, van Herwaarden AE, Lagas JS, Sparidans RW, Wagenaar E, van der Kruijssen CM, Goldstein JA, Zeldin DC, Beijnen JH, Schinkel AH (2007) Midazolam metabolism in Cytochrome P450 3A knockout mice can be attributed to upregulated CYP2C enzymes. Mol Pharmacol 73:1029-1036Google Scholar
  95. Woods CG, Heuvel JP, Rusyn I (2007) Genomic profiling in nuclear receptor-mediated toxicity. Toxicol Pathol 35:474-494PubMedGoogle Scholar
  96. Yan Z, Caldwell GW (2004) Stable-isotope trapping and high-throughput screenings of reactive metabolites using the isotope MS signature. Anal Chem 76:6835-6847PubMedGoogle Scholar
  97. Yan Z, Maher N, Torres R, Caldwell GW, Huebert N (2005) Rapid detection and characterization of minor reactive metabolites using stable-isotope trapping in combination with tandem mass spectrometry. Rapid Commun Mass Spectrom 19:3322-3330PubMedGoogle Scholar
  98. Yin W, Doss GA, Stearns RA, Chaudhary AG, Hop CE, Franklin RB, Kumar S (2003) A novel P450-catalyzed transformation of the 2,2,6,6-tetramethyl piperidine moiety to a 2,2-dimethyl pyrrolidine in human liver microsomes: characterization by high resolution quadrupole-time-of-flight mass spectrometry and 1H-NMR. Drug Metab Dispos 31:215-223PubMedGoogle Scholar
  99. Yin W, Mitra K, Stearns RA, Baillie TA, Kumar S (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 43:5455-5466PubMedGoogle Scholar
  100. Zhang F, Swanson SM, van Breemen RB, Liu X, Yang Y, Gu C, Bolton JL (2001) Equine estrogen metabolite 4-hydroxyequilenin induces DNA damage in the rat mammary tissues: formation of single-strand breaks, apurinic sites, stable adducts, and oxidized bases. Chem Res Toxicol 14:1654-1659PubMedGoogle Scholar
  101. Zhang Z, Chen Q, Li Y, Doss GA, Dean BJ, Ngui JS, Silva EM, Kim S, Wu JY, Dininno F, Hammond ML, Stearns RA, Evans DC, Baillie TA, Tang W (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 18:675-685PubMedGoogle Scholar
  102. Zhou S, Chan E, Duan W, Huang M, Chen YZ (2005) Drug bioactivation, covalent binding to target proteins and toxicity relevance. Drug Metab Rev 37:41-213PubMedGoogle Scholar
  103. Zhu M, Ma L, Zhang D, Ray K, Zhao W, Humphreys WG, Skiles G, Sanders M, Zhang H (2006) Detection and characterization of metabolites in biological matrices using mass defect filtering of liquid chromatography/high resolution mass spectrometry data. Drug Metab Dispos 34:1722-1733PubMedGoogle Scholar
  104. Zhu M, Ma L, Zhang H, Humphreys WG (2007) Detection and structural characterization of glutathione-trapped reactive metabolites using liquid chromatography-high-resolution mass spectrometry and mass defect filtering. Anal Chem 79:8333-8341PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  • Sanjeev Kumar
    • 1
    Email author
  • Kaushik Mitra
  • Kelem Kassahun
  • Thomas A. Baillie
  1. 1.Department of Drug Metabolism and PharmacokineticsMerck Research LaboratoriesRahwayUSA

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