Iwaki Masahiro, Niwa Toshiro, Bandoh Saya, Itoh Megumi, Hirose Hitomi, Kawase Atsushi, Komura Hiroshi
Faculty of Pharmacy, Department of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan.
Faculty of Pharmacy, Department of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-osaka, Osaka 577-8502, Japan; School of Pharmacy, Shujitsu University, 1-6-1 Nishigawara, Naka-ku, Okayama 703-8516, Japan.
Drug Metab Pharmacokinet. 2016 Dec;31(6):425-432. doi: 10.1016/j.dmpk.2016.08.007. Epub 2016 Sep 2.
To evaluate the relative contribution of cytochrome P450 (CYP) isoforms responsible for carvedilol (CAR) oxidation, enantioselective metabolism of CAR was investigated in human liver microsomes (HLMs) and recombinant human CYPs by using the substrate depletion assay. CYP2D6 exhibited the highest contribution to the metabolism of R-CAR, followed by CYP3A4, CYP1A2, and CYP2C9, whereas the metabolism of the S-enantiomer was mainly mediated by CYP1A2, followed by CYP2D6 and CYP3A4. In HLMs, metabolism of R- and S-CAR was markedly inhibited by quinidine; R-CAR metabolism (57-61% decrease) was more inhibited than S-CAR metabolism (37-43% decrease), and furafylline and ketoconazole almost equally inhibited metabolism of both enantiomers by 25-32% and 30-50%, respectively. The absence of CYP2D6 in a mixture of five major recombinant CYP isoforms at the approximate ratio as in HLMs resulted in a 42% and 25% decrease in the metabolic activities for R- and S-CAR, respectively. Moreover, the absence of CYP1A2 in the mixture resulted in a 16% and 39% decrease in the metabolic activities for R- and S-CAR, respectively. Our results suggest the stereoselective metabolism of CAR is determined by not only the activity of CYP2D6 but also of CYP1A2 and CYP3A4.
为评估负责卡维地洛（CAR）氧化的细胞色素P450（CYP）同工型的相对贡献，采用底物消耗法在人肝微粒体（HLMs）和重组人CYPs中研究了CAR的对映体选择性代谢。CYP2D6对R-CAR代谢的贡献最大，其次是CYP3A4、CYP1A2和CYP2C9，而S-对映体的代谢主要由CYP1A2介导，其次是CYP2D6和CYP3A4。在HLMs中，奎尼丁显著抑制R-和S-CAR的代谢；R-CAR代谢（降低57 - 61%）比S-CAR代谢（降低37 - 43%）受到的抑制更明显，呋拉茶碱和酮康唑分别使两种对映体的代谢受到25 - 32%和30 - 50%的几乎同等程度的抑制。在五种主要重组CYP同工型的混合物中，以与HLMs中大致相同的比例缺失CYP2D6，导致R-和S-CAR的代谢活性分别降低42%和25%。此外，混合物中缺失CYP1A2导致R-和S-CAR的代谢活性分别降低16%和39%。我们的结果表明，CAR的立体选择性代谢不仅由CYP2D6的活性决定，还由CYP1A2和CYP3A4的活性决定。
