A SIGNIFICANT DRUG-METABOLIZING ROLE FOR CYP3A5?

J. Andrew Williams; Jack Cook; Susan I. Hurst

doi:10.1124/dmd.31.12.1526

Abstract

Recent research on CYP3A5 in vitro and in humans has provided discordant information on whether CYP3A5 plays a significant role in the metabolism of CYP3A substrates in vivo. For example, six separate studies have reported CYP3A5 to contribute between 2 and 60% of the total hepatic CYP3A. Suggested explanations for the reported differences in hepatic CYP3A5 levels are evaluated in this article. Furthermore, a sensitivity analysis of the contribution of CYP3A5 (in addition to CYP3A4) to the metabolism of a “midazolam”-type substrate based on recently published in vitro and clinical data is compared with the results of two in vivo studies that investigated the influence of CYP3A5 genotype on midazolam pharmacokinetics. The sensitivity analysis predicts an approximately 3-fold lower AUC_oral for midazolam for those expressing the highest hepatic and intestinal levels of CYP3A5 (e.g., possessing CYP3A5^*1 alleles) compared with those individuals who express insignificant amounts of CYP3A5, assuming CYP3A4 levels are the same in both groups and that CYP3A5 levels do not exceed those of CYP3A4 in CYP3A5^*1 homozygotes. In contrast, the two in vivo studies show no statistically significant influence of CYP3A5 genotype on midazolam pharmacokinetics. The discordance between the prediction and the results from the two in vivo studies is discussed.

Footnotes

↵1 Abbreviation used is: P450, cytochrome P450.
The question discussed in this article was addressed in part by J.A.W. at the 20th Annual Meeting of the New England Membrane Enzyme Group (NUTMEG) in Salem, Massachusetts, in November 2002.
J. Andrew Williams received a B.S. in Genetics from the University of Wales, Swansea in 1989, a M.S. in Toxicology from the University of Birmingham, England in 1991, and a Ph.D. in Pharmacology (Thesis title: Induction of Cytochrome P4503A—with Professor Gabrielle M. Hawksworth and Dr. Richard Chenery) from the University of Aberdeen, Scotland in 1995. This was followed by postdoctoral research into developmental toxicology (St. George's Hospital, London, with Professor Nigel A. Brown), human breast and prostate carcinogenesis (Institute of Cancer Research/Royal Marsden Hospital, London, with Professor David H. Phillips), and in vitro drug metabolism (Lilly Research Laboratories, Indianapolis, Indiana, with Dr Steven A. Wrighton). In 2001, he joined the Department of Pharmacokinetics, Dynamics and Metabolism at Pfizer Global Research and Development in Ann Arbor, Michigan. His current research interests include ligand interactions with human CYP3A and UGT enzymes and novel approaches to simulate and/or predict metabolic clearance and metabolic drug-drug interactions.
Jack Cook is a Director in the Clinical Pharmacokinetics and Pharmacodynamics Department at Pfizer Global Research and Development, Ann Arbor, Michigan. He received B.S. degrees in Pharmacy and Applied Mathematics from Ferris State College in 1981 and a Ph.D. from the University of Michigan in 1987. Prior to joining Pfizer in 1990, Dr. Cook was a group leader at Sterling Drug, Inc. and served as an adjunct faculty member at Albany College of Pharmacy. His current interests include predicting drug interactions from in vitro data, improving therapy by optimizing drug delivery, and the use of modeling in the development of CNS drugs.
Susan Hurst received her B.S. degree in Pharmacy from Purdue University in 1987. Subsequently, she worked as a staff pharmacist for several years at Ball Memorial Hospital in Muncie, Indiana. She received her Ph.D. from the University of Washington, Seattle in 1999 (Thesis title: Roles of Cytochromes P450 and Microsomal Epoxide Hydrolase in Drug-Drug Interactions Involving Valproic Acid and Its Analogs; Advisor: Rene H. Levy, Ph.D.). This was followed by postdoctoral research at Parke-Davis with Dr. Mike Sinz. In 2000 she joined Pfizer Global Research and Development as a permanent colleague in the Department of Pharmacokinetics, Dynamics, and Metabolism, in Ann Arbor, Michigan. Her current interests include novel approaches for the prediction of in vivo metabolic clearances and drug-drug interactions from in vitro data and extrahepatic metabolism.
- Received April 2, 2003.
- Accepted June 4, 2003.