Yoon Yune-Jung, Kim Kwon-Bok, Kim Hyunmi, Seo Kyung-Ah, Kim Ho-Sook, Cha In-June, Kim Eun-Young, Liu Kwang-Hyeon, Shin Jae-Gook
Department of Pharmacology and PharmacoGenomics Research Center, Inje University College of Medicine, 633-165, Gaegum-Dong, Busanjin-Gu, Busan 614-735, South Korea.
Drug Metab Dispos. 2007 Sep;35(9):1518-24. doi: 10.1124/dmd.106.013607. Epub 2007 May 30.
Benidipine is a dihydropyridine calcium antagonist that has been used clinically as an antihypertensive and antianginal agent. It is used clinically as a racemate, containing the (-)-alpha and (+)-alpha isomers of benidipine. This study was performed to elucidate the metabolism of benidipine and its enantiomers in human liver microsomes (HLMs) and to characterize the cytochrome P450 (P450) enzymes that are involved in the metabolism of benidipine. Human liver microsomal incubation of benidipine in the presence of NADPH resulted in the formation of two metabolites, N-desbenzylbenidipine and dehydrobenidipine. The intrinsic clearance (CL(int)) of the formation of N-desbenzylbenidipine and dehydrobenidipine metabolites from (-)-alpha isomer was similar to those from the (+)-alpha isomer (1.9 +/- 0.1 versus 2.3 +/- 2.3 microl/min/pmol P450 and 0.5 +/- 0.2 versus 0.6 +/- 0.6 microl/min/pmol P450, respectively). Correlation analysis between the known P450 enzyme activities and the rate of the formation of benidipine metabolites in the 15 HLMs showed that benidipine metabolism is correlated with CYP3A activity. The P450 isoform-selective inhibition study in liver microsomes and the incubation study of cDNA-expressed enzymes also showed that theN-debenzylation and dehydrogenation of benidipine are mainly mediated by CYP3A4 and CYP3A5. The total CL(int) values of CYP3A4-mediated metabolite formation from (-)-alpha isomer were similar to those from (+)-alpha isomer (17.7 versus 14.4 microl/min/pmol P450, respectively). The total CL(int) values of CYP3A5-mediated metabolite formation from (-)-alpha isomer were also similar to those from (+)-alpha isomer (8.3 versus 11.0 microl/min/pmol P450, respectively). These findings suggest that CYP3A4 and CYP3A5 isoforms are major enzymes contributing to the disposition of benidipine, but stereoselective disposition of benidipine in vivo may be influenced not by stereoselective metabolism but by other factors.
贝尼地平是一种二氢吡啶类钙拮抗剂，临床上用作抗高血压和抗心绞痛药物。临床上使用的是外消旋体，包含贝尼地平的（-）-α和（+）-α异构体。本研究旨在阐明贝尼地平及其对映体在人肝微粒体（HLM）中的代谢情况，并鉴定参与贝尼地平代谢的细胞色素P450（P450）酶。在存在NADPH的情况下，对贝尼地平进行人肝微粒体孵育，结果形成了两种代谢产物，N-去苄基贝尼地平与脱氢贝尼地平。（-）-α异构体形成N-去苄基贝尼地平与脱氢贝尼地平代谢产物的内在清除率（CL(int)）与（+）-α异构体相似（分别为1.9±0.1对2.3±2.3微升/分钟/皮摩尔P450以及0.5±0.2对0.6±0.6微升/分钟/皮摩尔P450）。对15份HLM中已知的P450酶活性与贝尼地平代谢产物形成速率之间进行的相关性分析表明，贝尼地平代谢与CYP3A活性相关。肝微粒体中的P450同工酶选择性抑制研究以及cDNA表达酶的孵育研究还表明，贝尼地平的N-去苄基化和脱氢主要由CYP3A4和CYP3A5介导。CYP3A4介导的（-）-α异构体代谢产物形成的总CL(int)值与（+）-α异构体相似（分别为17.7对14.4微升/分钟/皮摩尔P450）。CYP3A5介导的（-）-α异构体代谢产物形成的总CL(int)值也与（+）-α异构体相似（分别为8.3对11.0微升/分钟/皮摩尔P450）。这些发现表明，CYP3A4和CYP3A5同工酶是促成贝尼地平处置的主要酶，但贝尼地平在体内的立体选择性处置可能不受立体选择性代谢影响，而是受其他因素影响。
