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J.Health Sci., 56(3), 239-256, 2010
-Review-
Comparison of the Contributions of Cytochromes P450 3A4 and 3A5 in Drug Oxidation Rates and Substrate Inhibition
Toshiro Niwa, Norie Murayama,
and Hiroshi Yamazaki*
Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, 3-3165, Higashi-tamagawa Gakuen, Machida 194-8583, Japan
A meta-analysis was performed on the reported literature regarding followings. First, values of the Michaelis-Menten constants (Km), maximal velocities (Vmax), and intrinsic clearance (Vmax/Km) and the metabolic activities mediated by human cytochrome P450 3A4 and/or 3A5; second, inhibition constants (Ki); and third, maximum inactivation rate constants (kinact) to establish the contribution of P450 3A5 to drug metabolism. At least 120 of the 127 metabolic reactions investigated (>94%) were catalyzed by P450 3A4 and by P450 3A5. In the 73 metabolic reactions for which data were available, the mean P450 3A5/P450 3A4 ratios of Km, Vmax, and Vmax/Km values were 1.93, 1.25, and 1.20, respectively, but the median ratios were 1.17, 0.64, and 0.56, respectively. In 14-18% of the metabolic reactions, the Vmax and Vmax/Km values for P450 3A5 were more than twice those for P450 3A4. The Ki values for P450 3A5 were on average approximately 5 times those for P450 3A4. Five of 13 mechanism-based inhibitors of P450 3A4 (38%) did not exhibit similar mechanism-based inhibition of P450 3A5. These collective findings give insight into the contribution of polymorphic P450 3A5 to drug metabolism and adverse drug interactions.
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