Metabolism and toxicity of drugs. Two decades of progress in industrial drug metabolism

Chemical Research in Toxicology

Volumn 21, Issue 1, 2008, Pages 129-137

  Baillie, Thomas A ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

6 MERCAPTOPURINE DERIVATIVE; 7 ETHYL 10 HYDROXYCAMPTOTHECIN; AZATHIOPRINE; BETA LACTAM ANTIBIOTIC; CLOPIDOGREL; CYTOCHROME P450 3A4; IRINOTECAN; LEAD; MICROSOME ENZYME; OMEPRAZOLE;

BIOTRANSFORMATION; CHEMICAL ANALYSIS; COLORECTAL CANCER; COVALENT BOND; DRUG ABSORPTION; DRUG ELIMINATION; DRUG INDUSTRY; DRUG METABOLISM; DRUG RESEARCH; DRUG SAFETY; GENETIC ANALYSIS; HUMAN; LIVER; LYMPHOBLASTOMA; MOLECULAR BIOLOGY; NONHUMAN; PREDICTION; REVIEW; RHESUS MONKEY; RISK ASSESSMENT;

ANIMALS; BIOTRANSFORMATION; DRUG INDUSTRY; HUMANS; PHARMACEUTICAL PREPARATIONS; PHARMACOKINETICS;

EID: 38949088196     PISSN: 0893228X     EISSN: None     Source Type: Journal    
DOI: 10.1021/tx7002273     Document Type: Review

References (79)

1. Prentiss, R. A., Lis, Y., and Walker, S. R. (1988) Pharmaceutical innovation by the seven UK-owned pharmaceutical companies (1964-1985). Br. J. Clin. Pharmacol. 25, 387-396.
2. Kola, I., and Landis, J. (2004) Can the pharmaceutical industry reduce attrition rates? Nat. Rev. Drug Discovery 3, 711-715.
3. Lin, J., Sahakian, D. C., de Morais, S. M. F., Xu, J. J., Polzer, R. J., and Winter, S. M. (2003) The role of absorption, distribution, metabolism, excretion and toxicity in drug discovery. Curr. Top. Med. Chem. 3, 1125-1154.
4. Lipinski, C., and Hopkins, A. (2004) Navigating chemical space for biology and medicine. Nature 432, 855-861.
5. Guengerich, F. P., and MacDonald, J. S. (2007) Applying mechanisms of chemical toxicity to predict drug safety. Chem. Res. Toxicol. 20, 344-369.
6. Nassar, A.-E. F., and Lopez-Anaya, A. (2004) Strategies for dealing with reactive intermediates in drug discovery and development. Curr. Opin. Drug Discovery Dev. 7, 126-136.
7. Kalgutkar, A. S., and Soglia, J. R. (2005) Minimising the potential for metabolic activation in drug discovery. Expert Opin. Drug Metab. Toxicol. 1, 91-142.
8. Park, K. B., Dalton-Brown, E., Hirst, C., and Williams, D. P. (2006) Selection of new chemical entities with decreased potential for adverse drug reactions. Eur. J. Pharmacol. 549, 1-8.
9. Hutzler, M., Messing, D. M., and Weinkers, L. C. (2005) Predicting drug-drug interactions in drug discovery: where are we now and where are we going? Curr. Opin. Drug Discovery Dev. 8, 51-58.
10. Zhou, S., Chan, S. Y., Goh, B. C., Chan, E., Duan, W., Huang, M., and McLeod, H. L. (2005) Mechanism-based inhibition of cytochrome P450 3A4 by therapeutic drugs. Clin. Pharmacokinet. 44, 279-304.
11. Faller, B., Wang, J., Zimmerlin, A., Bell, L., Hamon, J., Witebread, S., Azzaoui, K., Bojanic, D., and Urban, L. (2006) High-throughput in vitro profiling assays: lessons learned from experiences at Novartis. Expert Opin. Drug Metab. Toxicol. 2, 823-833.
12. Lam, J. L., Okochi, H., and Benet, L. Z. (2006) In vitro and in vivo correlation of hepatic transporter effects on erythromycin metabolism: characterizing the importance of transporter-enzyme interplay. Drug Metab. Dispos. 34, 1336-1344.
13. Chinn, L. W., and Kroetz, D. L. (2007) ABCB1 Pharmacogenetics: progress, pitfalls, and promise. Clin. Pharmacol. Ther. 81, 265-269.
14. Lau, Y. Y., Okochi, H., and Benet, L. Z. (2006) Multiple transporters affect the disposition of atorvastatin and its two active hydroxyl metabolites: application of in vitro and ex situ systems. J. Pharmacol. Exp. Ther. 316, 762-771.
15. Lau, Y. Y., Huang, Y., Frassetto, L., and Benet, L. Z. (2007) Effect of OAT1B1 on the pharmacokinetics of atorvastatin in healthy volunteers. Clin. Pharmacol. Ther. 81, 194-204.
16. MacCoss, M., and Baillie, T. A. (2004) Organic chemistry in drug discovery. Science 303, 1810-1813.
17. Tang, W., Wang, R. W., and Lu, A. Y. H. (2005) Utility of recombinant cytochrome P450 enzymes: a drug metabolism perspective. Curr. Drug Metab. 6, 503-517.
18. Urquhart, B. L., Tirona, R. G., and Kim, R. B. (2007) Nuclear receptors and the regulation of drug-metabolizing enzymes and drug transporters: implications for interindividual variability in response to drugs. J. Clin. Pharmacol. 47, 566-578.
19. Rodrigues, A. D., and Rushmore, T. H. (2002) Cytochrome P450 pharmacogenetics in drug development: in vitro studies and clinical consequences. Curr. Drug Metab. 3, 289-309.
20. Wilke, R. A., Reif, D. M., and Moore, J. H. (2005) Combinatorial pharmacogenetics. Nat. Rev. Drug Discovery 4, 911-918.
21. Kirchheiner, J., Roots, I., Goldammer, M., Rosenkrantz, B., and Brockmoller, J. (2005) Effect of genetic polymorphisms in cytochrome P450 (CYP) 2C9 and CYP2C8 on the pharmacokinetics of oral antidiabetic drugs: clinical relevance. Clin. Pharmacokinet. 44, 1209-1225.
22. Lin, J. H. (2007) Pharmacokinetic and pharmacodynamic variability: a daunting challenge in drug therapy. Curr. Drug Metab. 8, 109-136.
23. Evans, W. E. (2004) Pharmacogenetics of thiopurine S-methyltransferase and thiopurine therapy. Ther. Drug Monit. 26, 186-191.
24. Wang, L., and Weinshilboum, R. (2006) Thiopurine S-methyltransferase pharmacogenetics: insights, challenges, and future directions. Oncogene 25, 1629-1638.
25. Bosch, T. M., Meijerman, I., Beijnen, J. H., and Schellens, J. H. (2006) Genetic polymorphisms of drug transporters in the chemotherapeutic treatment of cancer. Clin. Pharmacokinet. 45, 253-285.
26. Korfmacher, W. A. (2006) Use of mass spectrometry for drug metabolism studies. Curr. Drug Metab. 7, 455-563.
27. Castro-Perez, J., Plumb, R., Granger, J. H., Beattie, L., Joncour, K., and Wright, A. (2005) Increasing throughput and information content for in vitro drug metabolism experiments using ultra-performance liquid chromatography coupled to a quadrupole time-of-flight mass spectrometer. Rapid Commun. Mass Spectrom. 19, 843-848.
28. Sanders, M., Shipkova, P. A., Zhang, H. Y., and Warrack, B. M. (2006) Utility of the hybrid LTQ-FTMS for drug metabolism applications. Curr. Drug Metab. 7, 547-555.
29. Mortishire-Smith, R. J., O'Connor, D., Castro-Perez, J. M., and Kirby, J. (2005) Accelerated throughput metabolic route screening in early drug discovery using high resolution liquid chromatography/quadrupole time-of-flight mass spectrometry and automated data analysis. Rapid Commun. Mass Spectrom. 19, 2659-2670.
30. Brown, K., Tompkins, E. M., and White, I. N. H. (2006) Applications of accelerator mass spectrometry for pharmacological and toxicological research. Mass Spectrom. Rev. 25, 127-145.
31. Damon, B., and Abersold, R. (2006) Mass spectrometry and protein analysis. Science 312, 212-217.
32. Baillie, T. A., Cayen, M. N., Fouda, H., Gerson, R. J., Green, J. D., Grossman, S. J., Klunk, L. J., LeBlanc, B., Perkins, D. C., and Shipley, L. A. (2002) Drug metabolites in safety testing. Toxicol. Appl. Pharmacol. 182, 188-196.
33. Smith, D. A., and Obach, R. S. (2005) Seeing through the mist: abundance versus percentage. Commentary on metabolites in safety assessment. Drug Metab. Dispos. 33, 1409-1417.
34. Smith, D. A., and Obach, R. S. (2006) Metabolites and safety: what are the concerns, and how should we address them? Chem. Res. Toxicol. 19, 1570-1579.
35. Prueksaritanont, T., Lin, J. H., and Baillie, T. (2006) Complicating factors in safety testing of drug metabolites: kinetic differences between generated and preformed metabolites. Toxicol. Appl. Pharmacol. 217, 143-152.
36. Davis-Bruno, K. L., and Atrakchi, A. (2006) A regulatory perspective on issues and approaches in characterizing human metabolites. Chem. Res. Toxicol. 19, 1561-1563.
37. Humphreys, W. G., and Unger, S. E. (2006) Safety assessment of drug metabolites: characterization of chemically stable metabolites. Chem. Res. Toxicol. 19, 1564-1569.
38. Lappin, G., and Garner, R. C. (2005) The use of accelerator mass spectrometry to obtain early human ADME/PK data. Expert Opin. Drug Metab. Toxicol. 1, 23-31.
39. Bertino, J. S., Jr., Greenberg, H. E., and Reed, M. D. (2007) American College of Clinical Pharmacology position statement on the use of microdosing in the drug development process. J. Clin. Pharmacol. 47, 418-422.
40. E with mass defect filtering for in vitro and in vivo metabolite identification. Rapid Commun. Mass Spectrom. 21, 1485-1496.
41. Ganter, B., Snyder, R. D., Halbert, D. N., and Lee, M. D. (2006) Toxicogenomics in drug discovery and development: mechanistic analysis of compound/class-dependent effects using the DrugMatrix database. Pharmacogenomics 7, 1025-1044.
42. Williams, D. P. (2006) Toxicophores: investigations in drug safety. Toxicology 226, 1-11.
43. Williams, D. P., and Park, B. K. (2003) Idiosyncratic toxicity: the role of toxicophores and bioactivation. Drug Dev. Today 8, 1044-1050.
44. Kalgutkar, A. S., Gardner, I., Obach, R. S., Shaffer, C. L., Callegari, E., Henne, K. R., Mutlib, A. E., Dalvie, D. K., Lee, J. S., Nakai, Y., O'Donnell, J. P., Boer, J., and Harriman, S. P. (2005) A comprehensive listing of bioactivation pathways of organic functional groups. Curr. Drug Metab. 6, 161-225.
45. Guengerich, F. P. (2006) Cytochrome P450s and other enzymes in drug metabolism and toxicity. AAPS J. 8, E101-E111.
46. Baillie, T. A. (2006) Future of toxicology. Metabolic activation and drug design: challenges and opportunities in chemical toxicology. Chem. Res. Toxicol. 19, 889-893.
47. Erve, J. C. L. (2007) Chemical toxicology: reactive intermediates and their role in pharmacology and toxicology. Expert Opin. Drug Metab. Toxicol. 2, 923-946.
48. Evans, D. C., Watt, A. P., Nicoll-Griffith, D. A., and Baillie, T. A. (2004) Drug-protein covalent adducts: an industry perspective on minimizing the potential for drug bioactivation in drug discovery and development. Chem. Res. Toxicol. 17, 3-16.
49. Day, S. H., Mao, A., White, R., Schulz-Utermoehl, T., Miller, R., and Beconi, M. G. (2005) A semi-automated method for measuring the potential for protein covalent binding in drug discovery. J. Pharmacol. Toxicol. Methods 52, 278-285.
50. Zhang, L., Strong, J. M., Qiu, W., Lesko, L. J., and Huang, S.-M. (2006) Scientific perspectives on drug transporters and their role in drug interactions. Mol. Pharmaceutics 3, 62-69.
51. Lin, J. H. (2007) Transporter-mediated drug interactions: clinical implications and in vitro assessment. Expert Opin. Drug Metab. Toxicol. 3, 81-92.
52. de Fougerolles, A., Vornlocher, H.-P., Maraganore, J., and Lieberman, J. (2007) Interfering with disease: a progress report on siRNA-based therapeutics. Nat. Rev. Drug Discovery 6, 443-453.
53. van de Waterbeemd, H., and Gofford, E. (2003) ADMET in silico modeling: towards predicting paradise? Nat. Rev. Drug Discovery 2, 192-204.
54. Norinder, U., and Bergström, C. A. S. (2006) Prediction of ADMET properties. ChemMedChem 1, 920-937.
55. Miller, R., Ewy, W., Ouellet, D., Hermann, D., Kowalski, K. G., Lockwood, P., Koup, J. R., Donevan, S., El-Kattan, A., Li, C. S., Werth, J. L., Feltner, D. E., and Lalonde, R. L. (2005) How modeling and simulation have enhanced decision making in new drug development. J. Pharmacokinet. Pharmacodyn. 32, 185-197.
56. Bhattaram, V. A., Bonapace, C., Chilukuri, D. M., Duan, J. Z., Garnett, C., Gobburu, J. V. S., Jang, S. H., Kenna, L., Madabushi, R., Men, Y., Powell, J. R., Qiu, W., Ramchandani, R. P., Tornoe, C. W., Wang, Y., and Zheng, J. J. (2007) Impact of pharmacometrics on drug approval and labeling decisions - a survey of 31 new drug applications submitted between 2005 and 2006. Clin. Pharmacol. Ther. 81, 213-221.
57. König, J., Seithel, A., Gradhand, U., and Fromm, M. F. (2006) Pharmacogenomics of human OATP transporters. Naunyn-Schmiedeberg's Arch. Pharmacol. 372, 432-443.
58. Urban, T. J., Sebro, R., Hurowitz, E. H., Leabman, M. K., Badagnani, I., Lagpacan, L. L., Risch, N., and Giacomini, K. M. (2006) Functional genomics of membrane transporters in human populations. Genome Res. 16, 223-230.
59. Kimchi-Sarfaty, C., Oh, J. M., Kim, I.-W., Sauna, Z. E., Calcagno, A. M., Ambudkar, S. V., and Gottesman, M. M. (2007) A "silent" polymorphism in the MDR1 gene changes substrate specificity. Science 315, 525-528.
60. Woodcock, J. (2007) The prospects for "personalized medicine" in drug development and drug therapy. Clin. Pharmacol. Ther. 81, 164-169.
61. Oscarson, M. (2003) Pharmacogenetics of drug metabolizing enzymes: importance for personalized medicine. Clin. Lab. Med. 41, 573-580.
62. Kirchheiner, J., and Seeringer, A. (2007) Clinical implications of pharmacogenetics of cytochrome P450 drug metabolizing enzymes. Biochim. Biophys. Acta 1770, 489-494.
63. Katoh, M., and Yokoi, T. (2007) Application of chimeric mice with humanized liver for predictive ADME. Drug Metab. Rev. 39, 145-157.
64. Anari, M. R., Sanchez, R. I., Bakhtiar, R., Franklin, R. B., and Baillie, T. A. (2004) Integration of knowledge-based metabolic predictions with liquid chromatography data-dependent tandem mass spectrometry for drug metabolism studies: application to studies on the biotransformation of indinavir. Anal. Chem. 76, 823-832.
65. Sanchez-Ponce, R., and Guengerich, F. P. (2007) Untargeted analysis of mass spectrometry data for elucidation of metabolites and functions of enzymes. Anal. Chem. 79, 3355-3362.
66. Guevremont, R. (2004) High-field asymmetric waveform ion mobility spectroscopy: a new tool for mass spectrometry. J. Chromatogr., A 1058, 3-19.
67. Cooks, R. G., Ouyang, Z., Kakats, Z., and Wiseman, J. M. (2006) Detection technologies. Ambient mass spectrometry. Science 311, 1566-1570.
68. Reyzer, M. L., and Caprioli, R. M. (2007) MALDI-MS-based imaging of small molecules and proteins in tissues. Curr. Opin. Chem. Biol. 11, 29-35.
69. Stevens, J. L. (2006) Future of toxicology. Mechanisms of toxicity and drug safety: where do we go from here? Chem. Res. Toxicol. 19, 1393-1401.
70. Liu, J., Yang, X., van Breemen, R. B., Bolton, J. L., and Thatcher, G. R. J. (2005) Analysis of protein covalent modification by xenobiotics using a covert oxidatively activated tag: raloxifene proof-of-principle study. Chem. Res. Toxicol. 18, 1485-1496.
71. Dennehy, M. K., Richards, K. A. M., Wernke, G. W., Shyr, Y., and Liebler, D. C. (2006) Cytosolic and nuclear protein targets of thiol-reactive electrophiles. Chem. Res. Toxicol. 19, 20-29.
72. Shin, N.-Y., Liu, Q., Stamer, S. L., and Liebler, D. C. (2007) Protein targets of reactive electrophiles in human liver microsomes. Chem. Res. Toxicol. 20, 859-867.
73. Koen, Y. M., Gogichaeva, N. V., Alterman, M. A., and Hanzlik, R. P. (2007) A proteomic analysis of bromobenzene metabolite targets in rat liver cytosol in vivo. Chem. Res. Toxicol. 20, 511-519.
74. Li, A. P. (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.
75. Waring, J. F., and Anderson, M. G. (2005) Idiosyncratic toxicity: mechanistic insights gained from analysis of prior compounds. Curr. Opin. Drug Discovery Dev. 8, 59-65.
76. Uetrecht, J. (2007) Idiosyncratic drug reactions: current understanding. Annu. Rev. Pharmacol. Toxicol. 47, 513-539.
77. Lord, P. G., Nie, A., and McMillan, M. (2006) Application of genomics in preclinical drug safety evaluation. Basic Clin. Pharmacol. Toxicol. 98, 537-546.
78. Fielden, M. R., and Kolaja, K. L. (2006) The state-of-the-art in predictive toxicogenomics. Curr. Opin. Drug Discovery Dev. 9, 84-91.
79. Leone, A. M., Kao, L. M., McMillan, M. K., Nie, A. Y., Parker, J. B., Kelley, M. F., Usuki, E., Parkinson, A., Lord, P. G., and Johnson, M. D. (2007) Evaluation of felbamate and other antiepileptic drug toxicity potential based on hepatic covalent binding and gene expression. Chem. Res. Toxicol. 20, 600-608.