Comparison of the contributions of cytochromes P450 3A4 and 3A5 in drug oxidation rates and substrate inhibition

Abstract

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 (IQ); 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 IQ 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. © 2010 The Pharmaceutical Society of Japan.