Drug metabolites in safety testing.

This report summarizes the deliberations of a multidisciplinary committee, sponsored by the Pharmaceutical Research and Manufacturers of America, on current "best practices" within the U.S. pharmaceutical industry in assessing the role of drug metabolites as potential mediators of the toxicity of new drug products. Input to the document was obtained from numerous sources, including members of the pharmaceutical industry, academic investigators, and representatives of regulatory agencies who attended a workshop on the subject in November 2000. The overall goal of the paper is to define practical and scientifically based approaches to the use of metabolite data that address contemporary issues in the safety evaluation of drug candidates. Although there remains a lack of consensus on how best to deal with several aspects of this complex subject, this paper raises a number of points to consider, which emphasize the need to treat drug metabolite issues on a case-by-case basis. It is hoped that the discussion will promote continued dialog among industrial scientists and regulators charged with ensuring the clinical safety of new therapeutic agents.

[1]  T. Baillie,et al.  Mass spectrometry in the analysis of glutathione conjugates. , 1993, Biological mass spectrometry.

[2]  H. Yamazaki,et al.  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. , 1994, The Journal of pharmacology and experimental therapeutics.

[3]  E M Faed,et al.  Properties of acyl glucuronides: implications for studies of the pharmacokinetics and metabolism of acidic drugs. , 1984, Drug metabolism reviews.

[4]  A. Madan.  In vitro approaches for studying the inhibition of drug metabolism enzymes and identifying the drug-metabolizing enzymes responsible for the metabolism of drugs , 2002 .

[5]  A. D. Rodrigues,et al.  Drug-drug interactions , 2001, Atkinson's Principles of Clinical Pharmacology.

[6]  R. White,et al.  Short- and long-term projections about the use of drug metabolism in drug discovery and development. , 1998, Drug metabolism and disposition: the biological fate of chemicals.

[7]  M. Relling,et al.  Pharmacogenomics: translating functional genomics into rational therapeutics. , 1999, Science.

[8]  J. S. Miles,et al.  Relative expression of cytochrome P450 isoenzymes in human liver and association with the metabolism of drugs and xenobiotics. , 1992, The Biochemical journal.

[9]  A. Parkinson.  An Overview of Current Cytochrome P450 Technology for Assessing the Safety and Efficacy of New Materials , 1996, Toxicologic pathology.

[10]  M. Cayen.  Considerations in the Design of Toxicokinetic Programs , 1995, Toxicologic pathology (Print).

[11]  I. Horii,et al.  Toxicokinetics: its significance and practical problems. , 1993, The Journal of toxicological sciences.

[12]  Malcolm Rowland,et al.  Clinical pharmacokinetics : concepts and applications , 1989 .

[13]  L. Lasagna,et al.  Drug Development Process , 1996 .

[14]  S. Wrighton,et al.  Tissue distribution and interindividual variation in human UDP-glucuronosyltransferase activity: relationship between UGT1A1 promoter genotype and variability in a liver bank. , 2000, Pharmacogenetics.

[15]  Patrick Marroum,et al.  In vitro metabolic interaction studies: Experience of the Food and Drug Administration , 1999, Clinical pharmacology and therapeutics.

[16]  René H. Levy,et al.  Metabolic Drug Interactions , 2000 .