Methodologies for investigating drug metabolism at the early drug discovery stage: Prediction of hepatic drug clearance and P450 contribution

Current Drug Metabolism

Volumn 11, Issue 8, 2010, Pages 678-685

  Emoto, Chie ^a   Murayama, Norie ^a   Rostami Hodjegan, Amin ^b   Yamazaki, Hiroshi ^a  

^a SHOWA PHARMACEUTICAL UNIVERSITY   (Japan)

^b UNIVERSITY OF MANCHESTER   (United Kingdom)

Author keywords

Human liver microsomes; Intrinsic clearance; Metabolism; Prediction; Recombinant P450 microsomes; Scaling factor

Indexed keywords

1 AMINOBENZOTRIAZOLE; CYTOCHROME P450; CYTOCHROME P450 1A2; CYTOCHROME P450 2C19; CYTOCHROME P450 2C9; CYTOCHROME P450 2D6; CYTOCHROME P450 3A4; CYTOCHROME P450 3A5; CYTOCHROME P450 INHIBITOR; DRUG METABOLIZING ENZYME; GLUCURONOSYLTRANSFERASE; PROADIFEN;

ARTICLE; AUTOMATION; BINDING ASSAY; COMPUTER MODEL; DEPLETION; DRUG CLEARANCE; DRUG DEVELOPMENT; DRUG EFFICACY; DRUG METABOLISM; DRUG OXIDATION; DRUG TRANSFORMATION; GENE EXPRESSION; GLUCURONIDATION; HUMAN; IC 50; INHIBITION KINETICS; LIVER CLEARANCE; LIVER MICROSOME; METHODOLOGY; PHENOTYPE; PROTEIN BINDING;

ADULT; ANIMALS; CYTOCHROME P-450 ENZYME SYSTEM; DRUG DESIGN; DRUG DISCOVERY; DRUG INDUSTRY; HUMANS; LIVER; MICROSOMES, LIVER; PHARMACEUTICAL PREPARATIONS; PROTEIN BINDING;

EID: 79952343050     PISSN: 13892002     EISSN: None     Source Type: Journal    
DOI: 10.2174/138920010794233503     Document Type: Article

References (65)

1. Li, A. P. Screening for human ADME/Tox drug properties in drug discovery. Drug Discov. Today, 2001, 6(7), 357-366. (Pubitemid 32208650)
2. Kola, I.; Landis, J. Can the pharmaceutical industry reduce attrition rates? Nat. Rev. Drug Discov., 2004, 3(8), 711-715. (Pubitemid 39173511)
3. Wienkers, L. C.; Heath, T. G. Predicting in vivo drug interactions from in vitro drug discovery data. Nat. Rev. Drug Discov., 2005, 4(10), 825-833. (Pubitemid 41553963)
4. Williams, J. A.; Hyland, R.; Jones, B. C.; Smith, D. A.; Hurst, S.; Goosen, T. C.; Peterkin, V.; Koup, J. R.; Ball, S. E. Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure (AUCi/AUC) ratios. Drug Metab. Dispos., 2004, 32(11), 1201-1208. (Pubitemid 39410902)
5. Christrup, L. L. Morphine metabolites. Acta. Anaesthesiol Scand., 1997, 41 (1 Pt 2), 116-122. (Pubitemid 27072914)
6. Püchler, K.; Sierakowski, B.; Roots, I. Single dose and steady state pharmacokinetics of temocapril and temocaprilat in young and elderly hypertensive patients. Br. J. Clin. Pharmacol., 1998, 46(4), 363-367.
7. Nelson, D. R.; Koymans, L.; Kamataki, T.; Stegeman, J. J.; Feyereisen, R.; Waxman, D. J.; Waterman, M. R.; Gotoh, O.; Coon, M. J.; Estabrook, R. W.; Gunsalus, I. C.; Nebert, D. W. P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics, 1996, 6(1), 1-42. (Pubitemid 26096749)
8. Krishna, D. R.; Klotz, U. Extrahepatic metabolism of drugs in humans. Clin. Pharmacokinet., 1994, 26(2), 144-160. (Pubitemid 24064238)
9. Mugford, C. A.; Mortillo, M.; Mico, B. A.; Tarloff, J. B. 1-Aminobenzotriazole-induced destruction of hepatic and renal cytochromes P450 in male Sprague-Dawley rats. Fundam. Appl. Toxicol., 1992, 19(1), 43-49.
10. Emoto, C.; Murase, S.; Sawada, Y.; Iwasaki, K. In vitro inhibitory effect of 1-aminobenzotriazole on drug oxidations in human liver microsomes: a comparison with SKF-525A. Drug Metab. Pharmacokinet., 2005, 20(5), 351-357.
11. Balani, S. K.; Zhu, T.; Yang, T. J.; Liu, Z.; He, B.; Lee, F. W. Effective dosing regimen of 1-aminobenzotriazole for inhibition of antipyrine clearance in rats, dogs, and monkeys. Drug Metab. Dispos., 2002, 30(10), 1059-1062.
12. Emoto, C.; Murase, S.; Sawada, Y.; Jones, B. C.; Iwasaki, K. In vitro inhibitory effect of 1-aminobenzotriazole on drug oxidations catalyzed by human cytochrome P450 enzymes: a comparison with SKF-525A and ketoconazole. Drug Metab. Pharmacokinet., 2003, 18(5), 287-295.
13. Ono, S.; Hatanaka, T.; Hotta, H.; Satoh, T.; Gonzalez, F. J.; Tsutsui, M. Specificity of substrate and inhibitor probes for cytochrome P450s: evaluation of in vitro metabolism using cDNA-expressed human P450s and human liver microsomes. Xenobiotica, 1996, 26(7), 681-693. (Pubitemid 26233022)
14. Linder, C. D.; Renaud, N. A.; Hutzler, J. M. Is 1-aminobenzotriazole an appropriate in vitro tool as a nonspecific cytochrome P450 inactivator? Drug Metab. Dispos., 2009, 37(1), 10-13.
15. Taylor, C.; Janisewski, J.; Whalen, K. Integrated high-throughput ADME: a 384-well human liver microsome assay to determine metabolic profiles of 1800 compounds per week. Annual Meeting of American Association of Pharmaceutical Scientists, 2006, Poster session.
16. Obach, R. S. 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(11), 1350-1359.
17. Banker, M. J.; Clark, T. H.; Williams, J. A. Development and validation of a 96-well equilibrium dialysis apparatus for measuring plasma protein binding. J. Pharm. Sci., 2003, 92(5), 967-974. (Pubitemid 36523442)
18. Yamazaki, K.; Kanaoka, M. Computational prediction of the plasma protein-binding percent of diverse pharmaceutical compounds. J. Pharm. Sci., 2004, 93(6), 1480-1494. (Pubitemid 38725020)
19. Lobell, M.; Sivarajah, V. In silico prediction of aqueous solubility, human plasma protein binding and volume of distribution of compounds from calculated pKa and AlogP98 values. Mol. Divers., 2003, 7(1), 69-87. (Pubitemid 38095175)
20. Austin, R. P.; Barton, P.; Cockroft, S. L.; Wenlock, M. C.; Riley, R. J. The influence of nonspecific microsomal binding on apparent intrinsic clearance, and its prediction from physicochemical properties. Drug Metab. Dispos., 2002, 30(12), 1497-1503. (Pubitemid 35397059)
21. Hallifax, D.; Houston, J. B. Binding of drugs to hepatic microsomes: comment and assessment of current prediction methodology with recommendation for improvement. Drug Metab. Dispos., 2006, 34(4), 724-726.
22. Turner, D. B.; Rowland-Yeo, K.; Tucker, G. T.; Rostami-Hodjegan, A. Prediction of non-specific hepatic microsomal binding from readily available physicochemical properties. Drug Metab. Rev., 2006, 38 (Suppl. 1), 162.
23. Skaggs, S. M.; Foti, R. S.; Fisher, M. B. A streamlined method to predict hepatic clearance using human liver microsomes in the presence of human plasma. J. Pharmacol. Toxicol. Methods, 2006, 53(3), 284-290.
24. Shibata, Y.; Takahashi, H.; Ishii, Y. A convenient in vitro screening method for predicting in vivo drug metabolic clearance using isolated hepatocytes suspended in serum. Drug Metab. Dispos., 2000, 28(12), 1518-1523.
25. Barter, Z. E.; Chowdry, J. E.; Harlow, J. R.; Snawder, J. E.; Lipscomb, J. C.; Rostami-Hodjegan, A. Covariation of human microsomal protein per gram of liver with age: absence of influence of operator and sample storage may justify interlaboratory data pooling. Drug Metab. Dispos., 2008, 36(12), 2405-2409.
26. Chao, P.; Uss, A. S.; Cheng, K. C. Use of intrinsic clearance for prediction of human hepatic clearance. Expert Opin. Drug Metab. Toxicol., 2010, 6(2), 189-198.
27. Reddy, A.; Heimbach, T.; Freiwald, S.; Smith, D.; Winters, R.; Michael, S.; Surendran, N.; Cai, H. Validation of a semi-automated human hepatocyte assay for the determination and prediction of intrinsic clearance in discovery. J. Pharm. Biomed. Anal., 2005, 37(2), 319-326. (Pubitemid 40222303)
28. th North American Regional ISSX Meeting, 2009, 128.
29. Soars, M. G.; Burchell, B.; Riley, R. J. In vitro analysis of human drug glucuronidation and prediction of in vivo metabolic clearance. J. Pharmacol. Exp. Ther., 2002, 301(1), 382-390. (Pubitemid 34250317)
30. Brown, H. S.; Griffin, M.; Houston, J. B. Evaluation of cryopreserved human hepatocytes as an alternative in vitro system to microsomes for the prediction of metabolic clearance. Drug Metab. Dispos., 2007, 35(2), 293-301. (Pubitemid 46148743)
31. Kilford, P. J.; Stringer, R.; Sohal, B.; Houston, J. B.; Galetin, A. Prediction of drug clearance by glucuronidation from in vitro data: use of combined cytochrome P450 and UDP-glucuronosyltransferase cofactors in alamethicin-activated human liver microsomes. Drug Metab. Dispos., 2009, 37(1), 82-89.
32. Bjornsson, 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.; Snikeris, F.; Sullivan, J. T.; Tweedie, D.; Vega, J. M.; Walsh, J.; Wrighton, S. A. The conduct of in vitro and in vivo drug-drug interaction studies: a Pharmaceutical Research and Manufacturers of America (PhRMA) perspective. Drug Metab. Dispos., 2003, 31(7), 815-832. (Pubitemid 36759050)
33. Bjornsson, 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, S. R.; Roberts, S.; Roe, A.; Shah, A.; Snikeris, F.; Sullivan, J. T.; Tweedie, D.; Vega, J. M.; Walsh, J.; Wrighton, S. A. The conduct of in vitro and in vivo drug-drug interaction studies: a PhRMA perspective. J. Clin. Pharmacol., 2003, 43(5), 443-469. (Pubitemid 36506147)
34. Spatzenegger, M.; Jaeger, W. Clinical importance of hepatic cytochrome P450 in drug metabolism. Drug Metab. Rev., 1995, 27(3), 397-417.
35. Rendic, S. Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab. Rev., 2002, 34 (1-2), 83-448. (Pubitemid 34311090)
36. McGinnity, D. F.; Parker, A. J.; Soars, M.; Riley, R. J. Automated definition of the enzymology of drug oxidation by the major human drug metabolizing cytochrome P450s. Drug Metab. Dispos., 2000, 28(11), 1327-1334.
37. Rodrigues, A. D.; Rushmore, T. H. Cytochrome P450 pharmacogenetics in drug development: in vitro studies and clinical consequences. Curr. Drug Metab., 2002, 3(3), 289-309. (Pubitemid 34625041)
38. Nakamura, K.; Goto, F.; Ray, W. A.; McAllister, C. B.; Jacqz, E.; Wilkinson, G. R.; Branch, R. A. Interethnic differences in genetic polymorphism of debrisoquin and mephenytoin hydroxylation between Japanese and Caucasian populations. Clin. Pharmacol. Ther., 1985, 38(4), 402-408. (Pubitemid 16250313)
39. Kimura, M.; Ieiri, I.; Mamiya, K.; Urae, A.; Higuchi, S. Genetic polymorphism of cytochrome P450s, CYP2C19, and CYP2C9 in a Japanese population. Ther. Drug Monit., 1998, 20(3), 243-247. (Pubitemid 28248841)
40. Huang, W.; Lin, Y. S.; McConn, D. J. II; Calamia, J. C.; Totah, R. A.; Isoherranen, N.; Glodowski, M.; Thummel, K. E. Evidence of significant contribution from CYP3A5 to hepatic drug metabolism. Drug Metab. Dispos., 2004, 32(12), 1434-1445. (Pubitemid 39564564)
41. Venkatakrishnan, K.; von Moltke, L. L.; Greenblatt, D. J. Relative quantities of catalytically active CYP 2C9 and 2C19 in human liver microsomes: application of the relative activity factor approach. J. Pharm. Sci., 1998, 87(7), 845-853. (Pubitemid 28319415)
42. Uttamsingh, V.; Lu, C.; Miwa, G.; Gan, L. S. Relative contributions of the five major human cytochromes P450, 1A2, 2C9, 2C19, 2D6, and 3A4, to the hepatic metabolism of the proteasome inhibitor bortezomib. Drug Metab. Dispos., 2005, 33(11), 1723-1728. (Pubitemid 41539972)
43. Soars, M. G.; Gelboin, H. V.; Krausz, K. W.; Riley, R. J. A comparison of relative abundance, activity factor and inhibitory monoclonal antibody approaches in the characterization of human CYP enzymology. Br. J. Clin. Pharmacol., 2003, 55(2), 175-181. (Pubitemid 36237863)
44. Emoto, C.; Murase, S.; Iwasaki, K. Approach to the prediction of the contribution of major cytochrome P450 enzymes to drug metabolism in the early drug-discovery stage. Xenobiotica, 2006, 36(8), 671-683. (Pubitemid 44195982)
45. Emoto, C.; Iwasaki, K. Approach to predict the contribution of cytochrome P450 enzymes to drug metabolism in the early drugdiscovery stage: the effect of the expression of cytochrome b5 with recombinant P450 enzymes. Xenobiotica, 2007, 37(9), 986-999. (Pubitemid 47482949)
46. Obach, R. S.; Reed-Hagen, A. E. Measurement of Michaelis constants for cytochrome P450-mediated biotransformation reactions using a substrate depletion approach. Drug Metab. Dispos., 2002, 30(7), 831-837. (Pubitemid 34671096)
47. Proctor, N. J.; Tucker, G. T.; Rostami-Hodjegan, A. Predicting drug clearance from recombinantly expressed CYPs: intersystem extrapolation factors. Xenobiotica, 2004, 34(2), 151-178. (Pubitemid 38299716)
48. Nakajima, M.; Tane, K.; Nakamura, S.; Shimada, N.; Yamazaki, H.; Yokoi, T. Evaluation of approach to predict the contribution of multiple cytochrome P450s in drug metabolism using relative activity factor: effects of the differences in expression levels of NADPH-cytochrome P450 reductase and cytochrome b5 in the expression system and the differences in the marker activities. J. Pharm. Sci., 2002, 91(4), 952-963. (Pubitemid 34640919)
49. Venkatakrishnan, K.; von Moltke, L. L.; Court, M. H.; Harmatz, J. S.; Crespi, C. L.; Greenblatt, D. J. Comparison between cytochrome P450 (CYP) content and relative activity approaches to scaling from cDNA-expressed CYPs to human liver microsomes: ratios of accessory proteins as sources of discrepancies between the approaches. Drug Metab. Dispos., 2000, 28(12), 1493-1504.
50. Westlind, A.; Malmebo, S.; Johansson, I.; Otter, C.; Andersson, T. B.; Ingelman-Sundberg, M.; Oscarson, M. Cloning and tissue distribution of a novel human cytochrome p450 of the CYP3A subfamily, CYP3A43. Biochem. Biophys. Res. Commun., 2001, 281(5), 1349-1355. (Pubitemid 32924568)
51. Shimada, T.; Yamazaki, H.; Mimura, M.; Inui, Y.; Guengerich, F. P. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J. Pharmacol. Exp. Ther., 1994, 270(1), 414-423. (Pubitemid 24229655)
52. Wrighton, S. A.; Brian, W. R.; Sari, M. A.; Iwasaki, M.; Guengerich, F. P.; Raucy, J. L.; Molowa, D. T.; Vandenbranden, M. Studies on the expression and metabolic capabilities of human liver cytochrome P450IIIA5 (HLp3). Mol. Pharmacol., 1990, 38(2), 207-213. (Pubitemid 20255306)
53. Kuehl, P.; Zhang, J.; Lin, Y.; Lamba, J.; Assem, M.; Schuetz, J.; Watkins, P. B.; Daly, A.; Wrighton, S. A.; Hall, S. D.; Maurel, P.; Relling, M.; Brimer, C.; Yasuda, K.; Venkataramanan, R.; Strom, S.; Thummel, K.; Boguski, M. S.; Schuetz, E. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat. Genet., 2001, 27(4), 383-391. (Pubitemid 32268418)
54. Niwa, T.; Murayama, N.; Emoto, C.; Yamazaki, H. Comparison of kinetic parameters for drug oxidation rates and substrate inhibition potential mediated by cytochrome P450 3A4 and 3A5. Curr. Drug Metab., 2008, 9(1), 20-33. (Pubitemid 351201667)
55. *6, in a Japanese population. Pharmacogenetics, 2002, 12(4), 331-334. (Pubitemid 34620661)
56. Saeki, M.; Saito, Y.; Nakamura, T.; Murayama, N.; Kim, S. R.; Ozawa, S.; Komamura, K.; Ueno, K.; Kamakura, S.; Nakajima, T.; Saito, H.; Kitamura, Y.; Kamatani, N.; Sawada, J. Single nucleotide polymorphisms and haplotype frequencies of CYP3A5 in a Japanese population. Hum. Mutat., 2003, 21(6), 653.
57. Yamaori, S.; Yamazaki, H.; Iwano, S.; Kiyotani, K.; Matsumura, K.; Saito, T.; Parkinson, A.; Nakagawa, K.; Kamataki, T. Ethnic differences between Japanese and Caucasians in the expression levels of mRNAs for CYP3A4, CYP3A5 and CYP3A7: lack of coregulation of the expression of CYP3A in Japanese livers. Xenobiotica, 2005, 35(1), 69-83. (Pubitemid 40459218)
58. Komori, M.; Nishio, K.; Kitada, M.; Shiramatsu, K.; Muroya, K.; Soma, M.; Nagashima, K.; Kamataki, T. Fetus-specific expression of a form of cytochrome P-450 in human livers. Biochemistry, 1990, 29(18), 4430-4433. (Pubitemid 20153646)
59. Wrighton, S. A.; Stevens, J. C. The human hepatic cytochromes P450 involved in drug metabolism. Crit. Rev. Toxicol., 1992, 22(1), 1-21.
60. Gibbs, M. A.; Thummel, K. E.; Shen, D. D.; Kunze, K. L. Inhibition of cytochrome P-450 3A (CYP3A) in human intestinal and liver microsomes: comparison of Ki values and impact of CYP3A5 expression. Drug Metab. Dispos., 1999, 27(2), 180-187. (Pubitemid 29072069)
61. Cook, C. S.; Berry, L. M.; Kim, D. H.; Burton, E. G. Involvement of CYP3A in the metabolism of eplerenone in humans and dogs: differential metabolism by CYP3A4 and CYP3A5. Drug Metab. Dispos., 2002, 30(12), 1344-1351. (Pubitemid 35397036)
62. Emoto, C.; Iwasaki, K. Enzymatic characteristics of CYP3A5 and CYP3A4: a comparison of in vitro kinetic and drug-drug interaction patterns. Xenobiotica, 2006, 36 (2-3), 219-233.
63. Okada, Y.; Murayama, N.; Yanagida, C.; Shimizu, M.; Guengerich, F. P.; Yamazaki, H. Drug interactions of thalidomide with midazolam and cyclosporine A: heterotropic cooperativity of human cytochrome P450 3A5. Drug Metab. Dispos., 2009, 37(1), 18-23.
64. Stringer, R. A.; Strain-Damerell, C.; Nicklin, P.; Houston, J. B. Evaluation of recombinant cytochrome P450 enzymes as an in vitro system for metabolic clearance predictions. Drug Metab. Dispos., 2009, 37(5), 1025-1034.
65. *3 and CYP3A4 expression for use in the prediction of metabolic clearance in virtual populations. Biopharm Drug Dispos., 2010, in press