Metabolism of fibrates by cytochrome P450s and UDP-glycosyltransferases in rat and human liver microsomes |
| |
Authors: | YanMi Zhou AiMing Liu Hui Xie Gary Q Cheng RenKe Dai |
| |
Institution: | [1]School of Bioscience and Bioengineering, South China University of Technology, Guangzhou 510006, China [2]Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China [3]Medical School of Ningbo University, Ningbo 315211, China [4]South China Center for Innovative Pharmaceuticals, Guangzhou 510006, China |
| |
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. |
| |
Keywords: | cytochrome P450 UDP-glycosyltransferase fibrates metabolism microsomes |
本文献已被 CNKI 维普 SpringerLink 等数据库收录! |
|