Iwaki Masahiro, Niwa Toshiro, Nakamura Yukiko, Kawase Atsushi, Komura Hiroshi
Department of Pharmacy, Faculty of Pharmacy, Kindai University.
School of Pharmacy, Shujitsu University.
J Toxicol Sci. 2018;43(1):59-63. doi: 10.2131/jts.43.59.
The relative contribution of cytochrome P450 (CYP) isoforms responsible for carvedilol (CAR) oxidation in rats were evaluated in order to compare with that of reported human CYPs responsible for the metabolism of CAR enantiomers. The depletion of CAR enantiomers by recombinant CYPs and the effects of CYP-selective inhibitors on the depletion catalyzed by rat liver microsomes (RLM) was determined. Quinine (rat CYP2D inhibitor) markedly inhibited the metabolism of both R- and S-CAR by RLM. The metabolism of S-CAR was inhibited more than that of R-CAR by furafylline, (a CYP1A2 inhibitor, 53.5% vs 11.3%), α-naphthoflavone (a CYP1A2 inhibitor, 64.5% vs 33.6%), and ketoconazole (a CYP3A inhibitor, 87.1% vs 51.2%). Among the CYPs examined, CYP2D2 showed the highest metabolic activities against both the enantiomers. R-CAR was mainly metabolized by CYP2D2 and CYP3A2. CYP2C11 and CYP3A1, in addition to CYP2D2 and CYP3A2 showed higher metabolic activities against S-CAR than that against R-CAR. These results suggest that CYP2D2 predominantly catalyzed R-CAR metabolism, whereas CYP2D2 and CYP3A1/2 catalyzed S-CAR metabolism in rats.
为了与报道的负责卡维地洛（CAR）对映体代谢的人细胞色素P450（CYP）进行比较，评估了大鼠体内负责CAR氧化的CYP同工型的相对贡献。测定了重组CYP对CAR对映体的消耗以及CYP选择性抑制剂对大鼠肝微粒体（RLM）催化的消耗的影响。奎宁（大鼠CYP2D抑制剂）显著抑制RLM对R-和S-CAR的代谢。呋拉茶碱（一种CYP1A2抑制剂，53.5%对11.3%）、α-萘黄酮（一种CYP1A2抑制剂，64.5%对33.6%）和酮康唑（一种CYP3A抑制剂，87.1%对51.2%）对S-CAR代谢的抑制作用比对R-CAR的抑制作用更强。在所检测的CYP中，CYP2D2对两种对映体均表现出最高的代谢活性。R-CAR主要由CYP2D2和CYP3A2代谢。除CYP2D2和CYP3A2外，CYP2C11和CYP3A1对S-CAR的代谢活性比对R-CAR的代谢活性更高。这些结果表明，在大鼠中，CYP2D2主要催化R-CAR的代谢，而CYP2D2和CYP3A1/2催化S-CAR的代谢。
