Role of biotransformation in drug-induced toxicity: Influence of intra- and inter-species differences in drug metabolism

Drug Metabolism and Pharmacokinetics

Volumn 26, Issue 1, 2011, Pages 15-29

  Baillie, Thomas A ^a   Rettie, Allan E ^a  

^a UNIVERSITY OF WASHINGTON   (United States)

Author keywords

Drug interactions; Drug toxicity; Pharmacogenomics; Reactive metabolites; Safety evaluation; Species differences

Indexed keywords

ALPIDEM; AMODIAQUINE; ASTEMIZOLE; BENOXAPROFEN; BROMFENAC; CISAPRIDE; DICLOFENAC; DROPERIDOL; DRUG METABOLITE; FEXOFENADINE; GREPAFLOXACIN; IBUFENAC; IPRONIAZID; LAPATINIB; LEVACETYLMETHADOL; NEFAZODONE; PARACETAMOL; SERTINDOLE; SUDOXICAM; TACRINE; TERFENADINE; TERODILINE; TIENILIC ACID; TOLRESTAT; TRAZODONE; TROGLITAZONE; TROVAFLOXACIN; UNINDEXED DRUG; ZILEUTON; ZOMEPIRAC;

ADVERSE DRUG REACTION; ALLERGY; DRUG DEVELOPMENT; DRUG INDUCED TOXICITY; DRUG INDUSTRY; DRUG INTERACTION; DRUG MECHANISM; DRUG METABOLISM; DRUG OVERDOSE; DRUG STRUCTURE; DRUG TRANSFORMATION; FIRST PASS EFFECT; HUMAN; LIVER TOXICITY; NONHUMAN; QT INTERVAL; QT PROLONGATION; REVIEW; SIDE EFFECT; SPECIES DIFFERENCE;

EID: 79952756154     PISSN: 13474367     EISSN: 18800920     Source Type: Journal    
DOI: 10.2133/dmpk.DMPK-10-RV-089     Document Type: Review

References (91)

1. Baillie, T. A.: Metabolism and toxicity of drugs. Two decades of progress in industrial drug metabolism. Chem. Res. Toxicol., 21: 129-137 (2008).
2. Korfmacher, W. A.: Advances in the integration of drug metabolism into the lead optimization paradigm. Mini Rev. Med. Chem., 9: 703-716 (2009).
3. Olson, H., Betton, G., Robinson, D., Thomas, K., Monro, A., Kolaja, G., Lilly, P., Sanders, J., Sipes, G., Bracken, W., Dorato, M., Van Deun, K., Smith, P., Berger, B. and Heller, A.: Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul. Toxicol. Pharmacol., 32: 56-67 (2000).
4. Greaves, P., Williams, A. and Eve, M.: First dose of potential new medicines to humans: how animals help. Nat. Rev. Drug Discovery, 3: 226-236 (2004).
5. Peters, T. S.: Do preclinical testing strategies help predict human hepatotoxic potentials? Toxicol. Pathol., 33: 146-154 (2005).
6. Park, B. K., Pirmohamed, M. and Ketteringham, N.: Role of drug disposition in drug hypersensitivity: a chemical, molecular, and clinical perspective. Chem. Res. Toxicol., 11: 969-988 (1998).
7. Smith, D. A. and Obach, R. S.: Metabolites in safety testing: considerations of mechanisms of toxicity with dose, abundance, and duration of treatment. Chem. Res. Toxicol., 22: 267-279 (2009).
8. Lee, W. M.: Drug-induced hepatotoxicity. N. Engl. J. Med., 349: 474-485 (2003).
9. Kaplowitz, N.: Idiosyncratic drug hepatotoxicity. Nat. Rev. Drug Discovery, 4: 489-499 (2005).
10. Stevens, J. and Baker, T. K.: The future of drug safety testing: expanding the view and narrowing the focus. Drug Discovery Today, 14: 162-167 (2009).
11. Smith, D. A. and Schmid, E. F.: Drug withdrawals and the lessons within. Curr. Opin. Drug Discovery Dev., 9: 38-46 (2006).
12. Uetrecht, J.: Screening for the potential of a drug candidate to cause idiosyncratic drug reactions. Drug Discovery Today, 8: 832-837 (2003).
13. Mitchell, J. R., Jollow, D. J., Potter, W. Z., Davis, D. C., Gillette, J. R. and Brodie, B. B.: Acetaminophen-induced hepatic necrosis. I. Role of drug metabolism. J. Pharmacol. Exp. Ther., 187: 185-194 (1973).
14. Copple, I. M., Goldring, C. E., Jenkins, R. E., Chia, A. J. L., Randle, L. E., Hayes, J. D., Kitteringham, N. R. and Park, B. K.: The hepatotoxic metabolite of acetaminophen directly activates the Keap1-Nrf2 cell defense system. Hepatology, 48: 1292-1301 (2008).
15. Williams, D. P.: Toxicophores: investigations in drug safety. Toxicology, 226: 1-11 (2006).
16. Corcoran, G. B. and Wong, B. K.: Role of glutathione in prevention of acetaminophen-induced hepatotoxicity by N-acetyl-L-cysteine in vivo: studies with N-acetyl-D-cysteine in mice. J. Pharmacol. Exp. Ther., 238: 54-61 (1986).
17. Tang, W.: The metabolism of diclofenac-enzymology and toxicology perspectives. Curr. Drug Metab., 4: 319-329 (2003).
18. Kalgutkar, A. S., Vaz, A. D. N., Lame, M. E., Henne, K. R., Soglia, J., Zhao, S. X., Abramov, Y. A., Lombardo, F., Collin, C., Hendsch, Z. S. and Hop, C. E. C. A.: 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 (2005).
19. Kalgutkar, A. S., Henne, K. R., Lame, M. E., Vaz, A. D., Collin, C., Soglia, J. R., Zhao, S. X. and Hop, C. E.: 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 (2005).
20. Madden, S., Spaldin, V., Hayes, R. N., Woolf, T. F., Pool, W. F. and Park, B. K.: Species variation in the bioactivation of tacrine by hepatic microsomes. Xenobiotica, 25: 103-116 (1995).
21. Jewell, H., Maggs, J. L., Harrison, A. C., OöNeill, P. M., Ruscoe, J. E. and Park, B. K.: Role of hepatic metabolism in the bioactivation and detoxication of amodiaquine. Xenobiotica, 25: 199-217 (1995).
22. Teng, W. C., Oh, J. W., New, L. S., Wahlin, M. D., Nelson, S. D., Ho, H. K. and Chan, E. C. Y.: Mechanism-based inactivation of cytochrome P450 3A4 by lapatinib. Mol. Pharmacol., doi:10.1124/mol.110.065839 (2010).
23. Kumar, S., Mitra, K., Kassahun, K. and Baillie, T. A.: Approaches for minimizing metabolic activation of new drug candidates in drug discovery. In Uetrecht, J. (ed.): Adverse Drug Reactions, Handbook of Experimental Pharmacology 196, Springer-Verlag, 2010, pp. 511-544.
24. Nelson, S. D.: Structure toxicity relationships-how useful are they in predicting toxicities of new drugs? In Dansette, P. M., Snyder, R., Delaforge, M., Gibson, G. G., Greim, H., Jollow, D. J., Monks, T. J. and Sipes, I. G. (eds.): Biological Reactive Intermediates VI, Kluwer Academic/Plenum Publishers, 2001, pp. 33-43.
25. Sawamura, R., Okudaira, N., Watanabe, K., Murai, T., Kobayashi, Y., Tachibana, M., Ohnuki, T., Masuda, K., Honma, H., Kurihara, A. and Okazaki, O.: Predictability of idiosyncratic drug toxicity risk for carboxylic acid-containing drugs based on the chemical stability of acyl glucuronide. Drug Metab. Dispos., doi:10.1124/dmd.110.034173 (2010).
26. Uetrecht, J.: Idiosyncratic drug reactions: past, present, and future. Chem. Res. Toxicol., 21: 84-92 (2008).
27. Kenna, J. G., Satoh, H., Christ, D. D. and Pohl, L. R.: Metabolic basis for a drug hypersensitivity: antibodies in sera from patients with halothane hepatitis recognize liver neoantigens that contain the trifluoroacetyl group derived from halothane. J. Pharmacol. Exp. Ther., 245: 1103-1109 (1988).
28. Lecoeur, S., André, C. and Beaune, P. H.: Tienilic acid-induced autoimmune hepatitis: anti-liver and -kidney microsomal type 2 autoantibodies recognize a three-site conformational epitope on cytochrome P4502C9. Mol. Pharmacol., 50: 326-333 (1996).
29. Kumar, S., Kassahun, K., Tschirret-Guth, R. A., Mitra, K. and Baillie, T. A.: Minimizing metabolic activation during pharmaceutical lead optimization: progress, knowledge gaps and future directions. Curr. Opin. Drug Discovery Dev., 11: 43-52 (2008).
30. Gram, T. E.: Chemically reactive intermediates and pulmonary xenobiotic toxicity. Pharmacol. Rev., 49: 297-341 (1997).
31. Yost, G. S.: Mechanisms of 3-methylindole pneumotoxicity. Chem. Res. Toxicol., 2: 273-279 (1989).
32. Lanza, D. L. and Yost, G. S.: Selective dehydrogenation/ oxygenation of 3-methylindole by cytochrome P450 enzymes. Drug Metab. Dispos., 29: 950-953 (2001).
33. Baer, B. R., Rettie, A. E. and Henne, K. R.: Bioactivation of 4-ipomeanol by CYP4B1: adduct characterization and evidence for an enedial intermediate. Chem. Res. Toxicol., 18: 855-864 (2005).
34. Buckpitt, A., Boland, B., Isbell, M., Morin, D., Shultz, M., Baldwin, R., Chan, K., Karlsson, A., Lin, C., Taff, A., West, J., Fanucchi, M., Van Winkle, L. and Plopper, C.: Naphthaleneinduced respiratory tract toxicity: metabolic mechanisms of toxicity. Drug Metab. Rev., 34: 791-820 (2002).
35. Koren, G.: The nephrotoxic potential of drugs and chemicals. Pharmacological basis and clinical relevance. Med. Toxicol. Adverse Drug Exper., 4: 59-72 (1989).
36. Anders, M. W. and Dekant, W.: Glutathione-dependent bioactivation of haloalkenes. Annu. Rev. Pharmacol. Toxicol., 38: 501-537 (1998).
37. Van Vleet, T. R. and Schnellmann, R. G.: Toxic nephropathy: environmental chemicals. Semin. Nephrol., 23: 500-508 (2003).
38. Constan, A. A., Sprankle, C. S., Peters, J. M., Kedderis, G. L., Everitt, J. I., Wong, B. A., Gonzalez, F. L. and Butterworth, B. E.: Metabolism of chloroform by cytochrome P450 2E1 is required for induction of toxicity in the liver, kidney, and nose of male mice. Toxicol. Appl. Pharmacol., 160: 120-126 (1999).
39. Fang, C., Behr, M., Xie, F., Lu, S., Doret, M., Luo, H., Yang, W., Aldous, K., Ding, X. and Gu, J.: Mechanism of chloroforminduced renal toxicity: non-involvement of hepatic cytochrome P450-dependent metabolism. Toxicol. Appl. Pharmacol., 227: 48-55 (2008).
40. Monahan, B. P., Ferguson, C. L., Killeavy, E. S., Lloyd, B. K., Troy, J. and Cantilena, L. R.: Torsades de pointes occurring in association with terfenadine use. JAMA, 264: 2788-2790 (1990).
41. Lagrutta, A. A., Trepakova, E. S. and Salata, J.: The hERG channel and risk of drug-acquired cardiac arrhythmia: an overview. Curr. Top. Med. Chem., 8: 1102-1112 (2008).
42. Björnsson, T. D., Callaghan, J. T., Einolf, H. J., Fischer, V., Gan, L., Grimm, S., Kao, J., King, S. P., Miwa, G., Ni, L., Kumar, G., McLeod, J., Obach, R. S., Roberts, S., Roe, A., Shah, A., Snickeris, F., Sullivan, J. T., Tweedie, D., Vega, J. M., Walsh, J. and Wrighton, S. A.: The conduct of in vitro and in vivo drug-drug interaction studies: a PhRMA perspective. J. Clin. Pharmacol., 43: 443-469 (2003).
43. Huang, S.-M., Temple, R., Throckmorton, D. C. and Lesko, L. J.: Drug interaction studies: study design, data analysis, and implications for dosing and labeling. Clin. Pharmacol. Ther., 81: 298-304 (2007).
44. Koudriakova, T., Iatsimirskaia, E., Utkin, I., Gangl, E., Vouros, P., Storozhuk, E., Orza, D., Marinina, J. and Gerber, N.: Metabolism of the human immunodeficiency virus protease inhibitors indinavir and ritonavir by human intestinal microsomes and expressed cytochrome P4503A4/3A5: mechanism-based inactivation of cytochrome P4503A4 by ritonavir. Drug Metab. Dispos., 26: 552-561 (1998).
45. Lin, J. H.: Species similarities and differences in pharmacokinetics. Drug Metab. Dispos., 23: 1008-1021 (1995).
46. Williams, J. A., Hyland, R., Jones, B. C., Smith, D. A., Hurst, S., Goosen, T. C., Peterkin, V., Koup, J. R. and Ball, S. E.: Drugdrug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab. Dispos., 32: 1201-1208 (2004).
47. Costa, L. G., Richter, R. J., Li, W. F., Cole, T., Guizzetti, M. and Furlong, C. E.: Paraoxonase (PON 1) as a biomarker of susceptibility for organophosphate toxicity. Biomarkers, 8: 1-12 (2003).
48. Court, M. H. and Greenblatt, D. J.: Molecular genetic basis for deficient acetaminophen glucuronidation by cats: UGT1A6 is a pseudogene, and evidence for reduced diversity of expressed hepatic UGT1A isoforms. Pharmacogenetics, 10: 355-369 (2000).
49. Trepanier, L. A., Ray, K., Winand, N. J., Spielberg, S. P. and Cribb, A. E.: Cytosolic arylamine N-acetyltransferase (NAT) deficiency in the dog and other canids due to an absence of NAT genes. Biochem. Pharmacol., 54: 73-80 (1997).
50. Martignoni, M., Groothuis, G. M. and de Kanter, R.: Species differences between mouse, rat, dog, monkey and human CY Pmediated drug metabolism, inhibition and induction. Expert Opin. Drug Metab. Toxicol., 2: 875-894 (2006).
51. Turpeinen, M., Ghiciuc, C., Opritoui, M., Tursas, L., Pelkonen, O. and Pasanen, M.: Predictive value of animal models for humancytochrome P450 (CYP)-mediated metabolism: a comparative study in vitro. Xenobiotica, 37: 1367-1377 (2007).
52. Chauret, N., Gauthier, A., Martin, J. and Nicoll-Griffith, D. A.: In vitro comparison of cytochrome P450-mediated metabolic activities in human, dog, cat, and horse. Drug Metab. Dispos., 25: 1130-1136 (1997).
53. Shou, M., Norcross, R., Sandig, G., Lu, P., Li, Y., Lin, Y., Mei, Q., Rodrigues, A. D. and Rushmore, T. H.: Substrate specificity and kinetic properties of seven heterologously expressed dog cytochromes P450. Drug Metab. Dispos., 31: 1161-1169 (2003).
54. Haining, R. L., Jones, J. P., Henne, K. R., Fisher, M. B., Koop, D. R., Trager, W. F. and Rettie, A. E.: Enzymatic determinants of the substrate specificity of CYP2C9: role of B$-C loop residues in providing the pi-stacking anchor site for warfarin binding. Biochemistry, 38: 3285-3292 (1999).
55. Iwasaki, K. and Uno, Y.: Cynomolgus monkey CYPs: a comparison with human CYPs. Xenobiotica, 39: 578-581 (2009).
56. Boyd, M. R. and Wilson, B. J.: Isolation and characterization of 4-ipomeanol, a lung-toxic furanoterpenoid produced by sweet potatoes (Ipomoea batatas). J. Agric. Food Chem., 20: 428-430 (1972).
57. Wolf, C. R., Statham, C. N., McMenamin, M. G., Bend, J. R., Boyd, M. R. and Philpot, R. M.: The relationship between the catalytic activities of rabbit pulmonary cytochrome P-450 isozymes and the lung-specific toxicity of the furan derivative, 4-ipomeanol. Mol. Pharmacol., 22: 738-744 (1982).
58. Christian, M. C., Wittes, R. E., Leyland-Jones, B., McLemore, T. L., Smith, A. C., Grieshaber, C. K., Chabner, B. A. and Boyd, M. R.: 4-Ipomeanol: a novel investigational new drug for lung cancer. J. Natl. Cancer Inst., 81: 1133-1143 (1989).
59. Zheng, Y. M., Fisher, M. B., Yokotani, N., Fujii-Kuriyama, Y. and Rettie, A. E.: Identification of a meander region proline residue critical for heme binding to cytochrome P450: implications for the catalytic function of human CYP4B1. Biochemistry, 37: 12847-12851 (1998).
60. Rowinsky, E. K., Noe, D. A., Ettinger, D. S., Christian, M. C., Lubejko, B. G., Fishman, E. K., Sartorius, S. E., Boyd, M. R. and Donehower, R. C.: Phase I and pharmacological study of the pulmonary cytotoxin 4-ipomeanol on a single dose schedule in lung cancer patients: hepatotoxicity is dose limiting in humans. Cancer Res., 53: 1794-1801 (1993).
61. Mutlib, A. E., Gerson, R. J., Meunier, P. C., Haley, P. J., Chen, H., Gan, L. S., Davies, M. H., Gemzik, B., Christ, D. D., Krahn, D. F., Markwalder, J. A., Seitz, S. P., Robertson, R. T. and Miwa, G. T.: The species-dependent metabolism of efavirenz produces a nephrotoxic glutathione conjugate in rats. Toxicol. Appl. Pharmacol., 169: 102-113 (2000).
62. Diamond, S., Boer, J., Maduskuie, T. P., Jr., Falahatpisheh, N., Li, Y. and Yeleswaram, S.: Species-specific metabolism of SGX523 by aldehyde oxidase and the toxicological implications. Drug Metab. Dispos., 38: 1277-1285 (2010).
63. Mise, M., Hashizume, T., Matsumoto, S., Terauchi, Y. and Fujii, T.: Identification of non-functional allelic variant of CYP1A2 in dogs. Pharmacogenetics, 14: 769-773 (2004).
64. Iyanagi, T.: Molecular basis of multiple UDP-glucuronosyltransferase isoenzyme deficiencies in the hyperbilirubinemic rat (Gunn rat). J. Biol. Chem., 266: 24048-24052 (1991).
65. Evans, W. E. and Relling, M. V.: Pharmacogenomics: translating functional genomics into rational therapeutics. Science, 286: 487-491 (1999).
66. Russmann, S., Jetter, A. and Kullak-Ublick, G. A.: Pharmacogenetics of drug-induced liver injury. Hepatology, 52: 748-761 (2010).
67. Daly, A. K., Donaldson, P. T., Bhatnagar, P., Shen, Y., Peöer, I., Floratos, A., Daly, M. J., Goldstein, D. B., John, S., Nelson, M. R., Graham, J., Park, B. K., Dillon, J. F., Bernal, W., Cordell, H. J., Pirmohamed, M., Aithal, G. P. and Day, C. P.: HLAB* 5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin. Nat. Genet., 41: 816-819 (2009).
68. Huang, Y. S., Chern, H. D., Su, W. J., Wu, J. C., Chang, S. C., Chiang, C. H., Chang, F. Y. and Lee, S. D.: Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis. Hepatology, 37: 924-930 (2003).
69. Huang, Y. S.: Genetic polymorphisms of drug-metabolizing enzymes and the susceptibility to antituberculosis drug-induced liver injury. Expert Opin. Drug Metab. Toxicol., 3: 1-8 (2007).
70. Daly, A. K., Aithal, G. P., Leathart, J. B., Swainsbury, R. A., Dang, T. S. and Day, C. P.: Genetic susceptibility to diclofenacinduced hepatotoxicity: contribution of UGT2B7, CYP2C8, and ABCC2 genotypes. Gastroenterology, 132: 272-281 (2007).
71. Lee, L. S., Nafziger, A. N. and Bertino, J. S., Jr.: Evaluation of inhibitory drug interactions during drug development: genetic polymorphisms must be considered. Clin. Pharmacol. Ther., 78: 1-6 (2005).
72. Yu, K. S., Yim, D. S., Cho, J. Y., Park, S. S., Park, J. Y., Lee, K. H., Jang, I. J., Yi, S. Y., Bae, K. S. and Shin, S. G.: Effect of omeprazole on the pharmacokinetics of moclobemide according to the genetic polymorphism of CYP2C19. Clin. Pharmacol. Ther., 69: 266-273 (2001).
73. Yasui-Furukori, N., Saito, M., Uno, T., Takahata, T., Sugawara, K. and Tateishi, T.: Effects of fluvoxamine on lansoprazole pharmacokinetics in relation to CYP2C19 genotypes. J. Clin. Pharmacol., 44: 1223-1229 (2004).
74. Zhou, H. H., Anthony, L. B., Wood, A. J. and Wilkinson, G. R.: Induction of polymorphic 4$-hydroxylation of S-mephenytoin by rifampicin. Br. J. Clin. Pharmacol., 30: 471-475 (1990).
75. Kumar, V., Brundage, R. C., Oetting, W. S., Leppik, I. E. and Tracy, T. S.: Differential genotype dependent inhibition of CYP2C9 in humans. Drug Metab. Dispos., 36: 1242-1248 (2008).
76. Mizutani, T.: PM frequencies of major CYPs in Asians and Caucasians. Drug Metab. Rev., 35: 99-106 (2003).
77. Baillie, T. A., Cayen, M. N., Fouda, H., Gerson, R. J., Grossman, S. J., Klunk, L. J., LeBlanc, B., Perkins, D. G. and Shipley, L. A.: Contemporary issues in toxicology. Drug metabolites in safety testing. Toxicol. Appl. Pharmacol., 182: 188-196 (2002).
78. U.S. Food and Drug Administration: Guidance for industry. Safety testing of drug metabolites. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm079266.pdf (2008).
79. International Conference on Harmonisation. ICH Topic M3 (R2): Non-clinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals. http://www.emea.europa.eu/pdfs/human/ich/028695en.pdf (2009).
80. U.S. Food and Drug Administration: Guidance for industry. M3 (R2) nonclinical safety studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073246.pdf (2010).
81. Guengerich, F. P. and MacDonald, J. S.: Applying mechanisms of chemical toxicity to predict drug safety. Chem. Res. Toxicol., 20: 344-369 (2007).
82. Baillie, T. A.: Approaches to the assessment of stable and chemically reactive drug metabolites in early clinical trials. Chem. Res. Toxicol., 22: 263-266 (2009).
83. Zhu, M., Ma, L., Zhang, D., Ray, K., Zhao, W., Humphreys, W. G., Skiles, G., Sanders, M. and Zhang, H.: Detection and characterization of metabolites in biological matrices using mass defect filtering of liquid chromatography/high resolution mass spectrometry data. Drug Metab. Dispos., 34: 1722-1733 (2006).
84. Prueksaritanont, T., Lin, J. H. and Baillie, T. A.: Complicatingfactors in safety testing of drug metabolites: kinetic differences between generated and preformed metabolites. Toxicol. Appl. Pharmacol., 217: 143-152 (2006).
85. Frank, D., Jaehde, U. and Fuhr, U.: Evaluation of probe drugs and pharmacokinetic metrics for CYP2D6 phenotyping. Eur. J. Clin. Pharmacol., 63: 321-333 (2007).
86. Corchero, J., Granvil, C. P., Akiyama, T. E., Hayhurst, G. P., Pimprale, S., Feigenbaum, L., Idle, J. R. and Gonzalez, F. J.: The CYP2D6 humanized mouse: effect of the human CYP2D6 transgene and HNF4alpha on the disposition of debrisoquine in the mouse. Mol. Pharmacol., 60: 1260-1267 (2001).
87. Kropshofer, H. and Singer, T.: Overview of cell-based tools for pre-clinical assessment of immunogenicity of biotherapeutics. J. Immunotoxicol., 3: 131-136 (2006).
88. Hung, S. I., Chung, W. H., Liu, Z. S., Chen, C. H., Hsih, M. S., Hui, R. C., Chu, C. Y. and Chen, Y. T.: Common risk allele in aromatic antiepileptic-drug induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Han Chinese. Pharmacogenomics, 11: 349-356 (2010).
89. Deng, X., Luyendyk, J. P., Ganey, P. E. and Roth, R. A.: Inflammatory stress and idiosyncratic hepatotoxicity: hints from animal models. Pharmacol. Rev., 61: 262-282 (2009).
90. Lappin, G. and Stevens, L.: Biomedical accelerator mass spectrometry: recent applications in metabolism and pharmacokinetics. Expert Opin. Drug Metab. Toxicol., 4: 1021-1033 (2008).
91. Uno, Y., Matsuno, K., Nakamura, C., Utoh, M. and Yamazaki, H.: Identification and characterization of CYP2B6 cDNA in cynomolgus monkeys (Macaca fascicularis). J. Vet. Med. Sci., 71: 1653-1056 (2009).