Metabolism of fibrates by cytochrome P450s and UDP-glycosyltransferases in rat and human liver microsomes

Abstract

Fibrates are widely used for the treatment of dyslipidemia. However, the contributions of the phase I and phase II metabolic pathways to the clearance of fibrates are unclear. In this study, we investigated the metabolism of gemfibrozil (Gem), clofibric acid (CA), fenofibric acid (FA) and bezafibrate (Beza) by cytochrome P450s (P450s) and UDP-glycosyltransferases (UGTs) using a substrate depletion approach. We also compared the metabolic characteristics of rat liver microsomes (RLM) and human liver microsomes (HLM). The intrinsic clearance rates mediated by P450s, UGTs and both were 172 ± 22, 643 ± 26, 798 ± 103 μL min -1 mg -1, respectively, for Gem and 43 ± 11, 88 ± 12, 119 ± 15 μL min -1 mg -1, respectively, for CA in RLM. The fractions metabolized by P450s and UGTs in RLM were 22% and 81% for Gem, 36% and 74% for CA. The P450- and UGT-mediated depletion rates for Gem were 303 and 1607 nmol min -1 mg -1 in RLM versus 86 and 243 nmol min -1 mg -1 in HLM. The corresponding rates for CA were 1.1 and 1.7 nmol min -1 mg -1 in RLM versus 0.025 and 0.038 nmol min -1 mg -1 in HLM. Accordingly, both P450s and UGTs substantially contribute to the clearance of Gem and CA, with UGTs playing a greater role. To avoid under-estimating the impact of these pathways, it is necessary to measure NADPH- and UDPGA-dependent metabolism. Although the fractions of these two pathways in RLM and HLM were similar, the depletion rate of Gem and CA in RLM was higher than that in HLM. The metabolism of FA and Beza by P450s and UGTs was too low to calculate intrinsic clearance in both RLM and HLM. These results indicate that fibrates are metabolized via similar pathways in rats and humans, and it is applicable to use RLM to predict the clearance of fibrates in human. © 2012 Science China Press and Springer-Verlag Berlin Heidelberg.