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A SIGNIFICANT DRUG-METABOLIZING ROLE FOR CYP3A5?

Departments of Pharmacodynamics, Dynamics, and Metabolism (J.A.W., S.I.H.) and Clinical Pharmacokinetics and Pharmacodynamics (J.C.), Pfizer Global Research and Development, Ann Arbor Laboratories, Ann Arbor, Michigan

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.

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