Drug Metabolism Research as an Integral Part of the Drug Discovery Process

Drug Metabolism in Drug Design and Development: Basic Concepts and Practice

Volumn , Issue , 2007, Pages 237-260

  Humphreys, W Griffith ^a  

^a BRISTOL MYERS SQUIBB   (United States)

Author keywords

Drug metabolism reactions; Pharmacological inactivation biotransformation; Qualitative metabolite profiling

Indexed keywords

EID: 84889489960     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1002/9780470191699.ch8     Document Type: Chapter

References (91)

1. Amacher DE. Reactive intermediates and the pathogenesis of adverse drug reactions:the toxicology perspective. Curr Drug Metab 2006;7:219-229.
2. Anari MR, Baillie, TA. Bridging cheminformatic metabolite prediction and tandem mass spectrometry. Drug Discov Today 2005;10:711-717.
3. Andrews CW, Bennett L, Yu LX. Predicting human oral bioavailability of a compound:development of a novel quantitative structure-bioavailability relationship. Pharm Res 2000;17:639-644.
4. Argoti D, Liang L, Conteh A, Chen L, Bershas D, Yu CP, Vouros P, Yang E. 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 2005;18:1537-1544.
5. Baillie, TA. Future of toxicology-metabolic activation and drug design: challenges and opportunities in chemical toxicology. Chem Res Toxicol 2006;19:889-893.
6. Balakin KV, Ivanenkov YA, Savchuk NP, Ivashchenko AA, Ekins S. Comprehensive computational assessment of ADME properties using mapping techniques. Curr Drug Discov Technol 2005;2:99-113.
7. Balani SK, Zhu T, Yang TJ, Liu Z, He B, Lee FW. Effective dosing regimen of 1-aminobenzotriazole for inhibition of antipyrine clearance in rats, dogs, and monkeys. Drug Metab Dispos 2002;30:1059-1062.
8. Buch H, Buzello W, Heymann E, Krisch, K. Inhibition of phenacetin-and acetanilideinduced methemoglobinemia in the rat by the carboxylesterase inhibitor bis-[pnitrophenyl] phosphate. Biochem Pharmacol 1969;18:801-811.
9. Chen WG, Zhang C, Avery MJ, Fouda HG. Reactive metabolite screen for reducing candidate attrition in drug discovery. Adv Exp Med Biol 2001;500:521-524.
10. Clader JW. The discovery of ezetimibe: a view from outside the receptor. J Med Chem 2004;47:1-9.
11. Cox KA, White RE, Korfmacher WA. Rapid determination of pharmacokinetic properties of new chemical entities: in vivo approaches. Comb Chem High Throughput Screen 2002;5:29-37.
12. de Groot MJ, Ekins S. Pharmacophore modeling of cytochromes P450. Adv Drug Deliv Rev 2002;54:367-383.
13. Dieckhaus CM, Fernandez-Metzler CL, King R, Krolikowski PH, Baillie TA. Negative ion tandem mass spectrometry for the detection of glutathione conjugates. Chem Res Toxicol 2005;18:630-638.
14. Egnash LA, Ramanathan R. Comparison of heterogeneous and homogeneous radioactivity flow detectors for simultaneous profiling and LC-MS/MS characterization of metabolites. J Pharm Biomed Anal 2002;27:271-284.
15. Ekins S, Andreyev S, Ryabov A, Kirillov E, Rakhmatulin EA, Bugrim A, Nikolskaya T. Computational prediction of human drug metabolism. Expert Opin Drug Metab Toxicol 2005;1:303-324.
16. Ekins S, Obach RS. Three-dimensional quantitative structure activity relationship computational approaches for prediction of human in vitro intrinsic clearance. J Pharmacol Exp Ther 2000;295:463-473.
17. Erhardt PW. A human drug metabolism database: potential roles in the quantitative predictions of drug metabolism and metabolism-related drug-drug interactions. Curr Drug Metab 2003;4:411-422.
18. Evans DC, Watt AP, Nicoll-Griffith DA, Baillie TA. Drug-protein adducts: an industry perspective on minimizing the potential for drug bioactivation in drug discovery and development. Chem Res Toxicol 2004;17:3-16.
19. Fisher MB, Campanale K, Ackermann BL, VandenBranden M, Wrighton SA. In vitro glucuronidation using human liver microsomes and the pore-forming peptide alamethicin. Drug Metab Dispos 2000;28:560-566.
20. Fisher MB, Yoon K, Vaughn ML, Strelevitz TJ, Foti RS. Flavin-containing monooxygenase activity in hepatocytes and microsomes: in vitro characterization and in vivo scaling of benzydamine clearance. Drug Metab Dispos 2002;30:1087-1093.
21. Fura A. Role of pharmacologically-active metabolites in drug discovery and development. Drug Discov Today 2006;11:133-142.
22. Fura A, Shu YZ, Zhu M, Hanson RL, Roongta V, Humphreys WG. Discovering drugs through biological transformation: role of pharmacologically active metabolites in drug discovery. J Med Chem 2004;47:4339-4351.
23. Gan J, Harper TW, Hsueh MM, Qu Q, Humphreys WG. Dansyl glutathione as a trapping agent for the quantitative estimation and identification of reactive metabolites. Chem Res Toxicol 2005;18:896-903.
24. Grime K, Riley RJ. The impact of in vitro binding on in vitro-in vivo extrapolations, projections of metabolic clearance and clinical drug-drug interactions. Curr Drug Metab 2006;7:251-264.
25. Guengerich FP. Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity. Chem Res Toxicol 2001;14:611-650.
26. Guengerich FP. Cytochrome P450 oxidations in the generation of reactive electrophiles:epoxidation and related reactions. Arch Biochem Biophys 2003;409:59-71.
27. Guengerich FP. Principles of covalent binding of reactive metabolites and examples of activation of bis-electrophiles by conjugation. Arch Biochem Biophys 2005;433:369-378.
28. Guengerich FP. Cytochrome P450S and other enzymes in drug metabolism and toxicity. AAPS J 2006;8:E101-E111.
29. Hawkins DR. Use and value of metabolism databases. Drug Discov Today 1999;4:466-471.
30. Hellriegel ET, Bjornsson TD, Hauck WW. Interpatient variability in bioavailability is related to the extent of absorption: implications for bioavailability and bioequivalence studies. Clin Pharmacol Ther 1996;60:601-607.
31. Houston JB, Carlile DJ. Prediction of hepatic clearance from microsomes, hepatocytes, and liver slices. Drug Metab Rev 1997;29:891-922.
32. Houston JB, Kenworthy KE. In vitro-in vivo scaling of CYP kinetic data not consistent with the classical Michaelis-Menten model. Drug Metab Dispos 2000;28:246-254.
33. Ito K, Iwatsubo T, Kanamitsu S, Nakajima Y, Sugiyama Y. Quantitative prediction of in vivo drug clearance and drug interactions from in vitro data on metabolism, together with binding and transport. Annu Rev Pharmacol Toxicol 1998;38:461-499.
34. Jones JP, Mysinger M, Korzekwa, KR. Computational models for cytochrome P450:a predictive electronic model for aromatic oxidation and hydrogen atom abstraction. Drug Metab Dispos 2002;30:7-12.
35. Ju C, Uetrecht JP. Mechanism of idiosyncratic drug reactions: reactive metabolite formation, protein binding and the regulation of the immune system. Curr Drug Metab 2002;3:367-377.
36. Kaplowitz N. Idiosyncratic drug hepatotoxicity. Nat Rev Drug Discov 2005;4:489-499.
37. Kim HJ, Cho JH, Klaassen CD. Depletion of hepatic 3'-phosphoadenosine 5'-phosphosulfate (PAPS) and sulfate in rats by xenobiotics that are sulfated. J Pharmacol Exp Ther 1995;275:654-658.
38. Lau YY, Sapidou E, Cui X, White RE, Cheng, KC. Development of a novel in vitro model to predict hepatic clearance using fresh, cryopreserved, and sandwich-cultured hepatocytes. Drug Metab Dispos 2002;30:1446-1454.
39. Lave T, Coassolo P, Reigner B. Prediction of hepatic metabolic clearance based on interspecies allometric scaling techniques and in vitro-in vivo correlations. Clin Pharmacokinet 1999;36:211-231.
40. Lave T, Dupin S, Schmitt C, Chou RC, Jaeck D, Coassolo P. Integration of in vitro data into allometric scaling to predict hepatic metabolic clearance in man: application to 10 extensively metabolized drugs. J Pharm Sci 1997;86:584-590.
41. Lave T, Luttringer O, Zuegge J, Schneider G, Coassolo P, Theil FP. Prediction of human pharmacokinetics based on preclinical in vitro and in vivo data. Ernst Schering Res Found Workshop 2002;81-104
42. Lecoeur S, Bonierbale E, Challine D, Gautier JC, Valadon P, Dansette PM, Catinot R, Ballet F, Mansuy D, Beaune PH. Specificity of in vitro covalent binding of tienilic acid metabolites to human liver microsomes in relationship to the type of hepatotoxicity: comparison with two directly hepatotoxic drugs. Chem Res Toxicol 1994;7:434-442.
43. Lewis DF. Quantitative structure-activity relationships (QSARs) within the cytochrome P450 system: QSARs describing substrate binding, inhibition and induction of P450s. Inflammopharmacology 2003;11:43-73.
44. Lewis DF. Quantitative structure-activity relationships (QSARs) for substrates of human cytochromes P450 CYP2 family enzymes. Toxicol In Vitro 2004;18:89-97.
45. Lewis DF. Human P450s in the metabolism of drugs: molecular modelling of enzyme-substrate interactions. Expert Opin Drug Metab Toxicol 2005;1:5-8.
46. Lewis DF, Ito Y, Goldfarb PS. Investigating human P450s involved in drug metabolism via homology with high-resolution P450 crystal structures of the CYP2C subfamily. Curr Drug Metab 2006;7:589-598.
47. Liebler DC, Guengerich FP. Elucidating mechanisms of drug-induced toxicity. Nat Rev Drug Discov 2005;4:410-420.
48. Lim HK, Stellingweif S, Sisenwine S, Chan KW. Rapid drug metabolite profiling using fast liquid chromatography, automated multiple-stage mass spectrometry and receptor-binding. J Chromatogr A 1999;831:227-241.
49. Lin JH. Applications and limitations of interspecies scaling and in vitro extrapolation in pharmacokinetics. Drug Metab Dispos 1998;26:1202-1212.
50. Lin JH, Wong BK. Complexities of glucuronidation affecting in vitro-in vivo extrapolation. Curr Drug Metab 2002;3:623-646.
51. Long A, Walker JD. Quantitative structure-activity relationships for predicting metabolism and modeling cytochrome p450 enzyme activities. Environ Toxicol Chem 2003;22:1894-1899.
52. Margolis JM, Obach RS. Impact of nonspecific binding to microsomes and phospholipid on the inhibition of cytochrome P4502 D6: implications for relating in vitro inhibition data to in vivo drug interactions. Drug Metab Dispos 2003;31:606-611.
53. Masubuchi Y, Igarashi S, Suzuki T, Horie T, Narimatsu S. Imipramine-induced inactivation of a cytochrome P450 2D enzyme in rat liver microsomes: in relation to covalent binding of its reactive intermediate. J Pharmacol Exp Ther 1996;279:724-731.
54. Mays DC, Hilliard JB, Wong DD, Chambers MA, Park SS, Gelboin HV, Gerber N. Bioactivation of 8-methoxypsoralen and irreversible inactivation of cytochrome P-450 in mouse liver microsomes: modification by monoclonal antibodies, inhibition of drug metabolism and distribution of covalent adducts. J Pharmacol Exp Ther 1990;254:720-731.
55. Mays DC, Pawluk LJ, Apseloff G, Davis WB, She ZW, Sagone AL, Gerber N. Metabolism of phenytoin and covalent binding of reactive intermediates in activated human neutrophils. Biochem Pharmacol 1995;50:367-380.
56. Miners JO, Knights KM, Houston JB, Mackenzie PI. In vitro-in vivo correlation for drugs and other compounds eliminated by glucuronidation in humans: pitfalls and promises. Biochem Pharmacol 2006;71:1531-1539.
57. Miners JO, Smith PA, Sorich MJ, McKinnon RA, Mackenzie PI. Predicting human drug glucuronidation parameters: application of in vitro and in silico modeling approaches. Annu Rev Pharmacol Toxicol 2004;44:1-25.
58. Mutlib A, Lam W, Atherton J, Chen H, Galatsis P, Stolle W. Application of stable isotope labeled glutathione and rapid scanning mass spectrometers in detecting and characterizing reactive metabolites. Rapid Commun Mass Spectrom 2005;19:3482-3492.
59. Naisbitt DJ, Farrell J, Gordon SF, Maggs JL, Burkhart C, Pichler WJ, Pirmohamed M, Park BK. Covalent binding of the nitroso metabolite of sulfamethoxazole leads to toxicity and major histocompatibility complex-restricted antigen presentation. Mol Pharmacol 2002;62:628-637.
60. Nassar AE, Bjorge SM, Lee DY. On-line liquid chromatography-accurate radioisotope counting coupled with a radioactivity detector and mass spectrometer for metabolite identification in drug discovery and development. Anal Chem 2003;75:785-790.
61. Nassar AE, Parmentier Y, Martinet M, Lee DY. Liquid chromatography-accurate radioisotope counting and microplate scintillation counter technologies in drug metabolism studies. J Chromatogr Sci 2004;42:348-353.
62. Obach RS. Nonspecific binding to microsomes: impact on scale-up of in vitro intrinsic clearance to hepatic clearance as assessed through examination of warfarin, imipramine, and propranolol. Drug Metab Dispos 1997;25:1359-1369.
63. Obach RS. 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 1999;27:1350-1359.
64. Obach RS. The prediction of human clearance from hepatic microsomal metabolism data. Curr Opin Drug Discov Devel 2001;4:36-44.
65. Obach RS, Baxter JG, Liston TE, Silber BM, Jones BC, MacIntyre F, Rance DJ, Wastall P. The prediction of human pharmacokinetic parameters from preclinical and in vitro metabolism data. J Pharmacol Exp Ther 1997;283:46-58.
66. Park BK, Kitteringham NR, Maggs JL, Pirmohamed M, Williams DP. The role of metabolic activation in drug-induced hepatotoxicity. Annu Rev Pharmacol Toxicol 2005;45:177-202.
67. Pirmohamed M, Kitteringham NR, Guenthner TM, Breckenridge AM, Park BK. An investigation of the formation of cytotoxic, protein-reactive and stable metabolites from carbamazepine in vitro. Biochem Pharmacol 1992;43:1675-1682.
68. Rane A, Wilkinson GR, Shand DG. Prediction of hepatic extraction ratio from in vitro measurement of intrinsic clearance. J Pharmacol Exp Ther 1997;200:420-424.
69. Samuel K, Yin W, Stearns RA, Tang YS, Chaudhary AG, Jewell JP, Lanza T Jr,Lin LS, Hagmann WK, Evans DC, Kumar S. 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 2003;38:211-221.
70. Shiran MR, Proctor NJ, Howgate EM, Rowland-Yeo K, Tucker GT, Rostami-Hodjegan A. Prediction of metabolic drug clearance in humans: in vitro-in vivo extrapolation vs allometric scaling. Xenobiotica 2006;36:567-580.
71. Shu YZ, Li W, Leet JE, Alberts J, Arora VK, Yeola S, Philip T, Qian-Cutrone J, Zhao N, Santone K, Humphreys WG, Dickinson K. Biogram enabled evaluation of active metabolites: an exploratory approach for detecting and characterizing active/toxic drug metabolites. Drug Metab Rev 2002;34 (1 Suppl):75.
72. Singh R, Silva Elipe MV, Pearson PG, Arison BH, Wong BK, White R, Yu X, Burgey CS, Lin JH, Baillie TA. 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 2003;16:198-207.
73. Smith D, Schmid E, Jones B. Do drug metabolism and pharmacokinetic departments make any contribution to drug discovery? Clin Pharmacokinet 2002;41:1005-1019.
74. Smith DA, Obach RS. Seeing through the mist: abundance versus percentage. Commentary on metabolites in safety testing. Drug Metab Dispos 2005;33:1409-1417.
75. Soars MG, Burchell B, Riley RJ. In vitro analysis of human drug glucuronidation and prediction of in vivo metabolic clearance. J Pharmacol Exp Ther 2002;301:382-390.
76. Soldner A, Spahn-Langguth H, Palm D, Mutschler E. A radioreceptor assay for the analysis of AT1-receptor antagonists. Correlation with complementary LC data reveals a potential contribution of active metabolites. J Pharm Biomed Anal 1998;17:111-124.
77. Taskinen J, Ethell BT, Pihlavisto P, Hood AM, Burchell B, Coughtrie MW. Conjugation of catechols by recombinant human sulfotransferases, UDPglucuronosyltransferases, and soluble catechol O-methyltransferase: structureconjugation relationships and predictive models. Drug Metab Dispos 2003;31:1187-1197.
78. Thompson TN. Optimization of metabolic stability as a goal of modern drug design. Med Res Rev 2001;21:412-449.
79. Tran TH, von Moltke LL, Venkatakrishnan K, Granda BW, Gibbs MA, Obach RS, Harmatz JS, Greenblatt DJ. Microsomal protein concentration modifies the apparent inhibitory potency of CYP3A inhibitors. Drug Metab Dispos 2002;30:1441-1445.
80. Uetrecht J. Screening for the potential of a drug candidate to cause idiosyncratic drug reactions. Drug Discov Today 2003;8:832-837.
81. Van De Waterbeemd H, Gifford E. ADMET in silico modelling: towards prediction paradise? Nat Rev Drug Discov 2003;2:192-204.
82. Van Heek M, France CF, Compton DS, McLeod RL, Yumibe NP, Alton KB, Sybertz EJ, Davis, HR Jr. In vivo metabolism-based discovery of a potent cholesterol absorption inhibitor, SCH58235, in the rat and rhesus monkey through the identification of the active metabolites of S CH48461. J Pharmacol Exp Ther 1997;283:157-163.
83. Walgren JL, Mitchell MD, Thompson DC. Role of metabolism in drug-induced idiosyncratic hepatotoxicity. Crit Rev Toxicol 2005;35:325-361.
84. Ward DP, Trevor AJ, Kalir A, Adams JD, Baillie TA, Castagnoli N Jr. Metabolism of phencyclidine. The role of iminium ion formation in covalent binding to rabbit microsomal protein. Drug Metab Dispos 1982;10:690-695.
85. Watt AP, Mortishire-Smith RJ, Gerhard U, Thomas SR. Metabolite identification in drug discovery. Curr Opin Drug Discov Devel 2003;6:57-65.
86. White IN, De Matteis F, Gibbs AH, Lim CK, Wolf CR, Henderson C, Smith LL. Species differences in the covalent binding of [14C]tamoxifen to liver microsomes and the forms of cytochrome P450 involved. Biochem Pharmacol 1995;49:1035-1042.
87. White, RE. High-throughput screening in drug metabolism and pharmacokinetic support of drug discovery. Annu Rev Pharmacol Toxicol 2000;40:133-157.
88. Yamamoto T, Itoga H, Kohno Y, Nagata K, Yamazoe Y. Prediction of oral clearance from in vitro metabolic data using recombinant CYPs: comparison among well-stirred, parallel-tube, distributed and dispersion models. Xenobiotica 2005;35:627-646.
89. Yan Z, Maher N, Torres R, Caldwell GW, Huebert N. Rapid detection and characterization of minor reactive metabolites using stable-isotope trapping in combination with tandem mass spectrometry. Rapid Commun Mass Spectrom 2005;19:3322-3330.
90. Yoshida F, Topliss JG. QSAR model for drug human oral bioavailability. J Med Chem 2000;43:2575-2585.
91. Ziegler DM. An overview of the mechanism, substrate specificities, and structure of FMOs. Drug Metab Rev 2002;34:503-511.