Ishida Kazuya, Taira Shigehiro, Morishita Hiroki, Kayano Yuichiro, Taguchi Masato, Hashimoto Yukiya
Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Sugitani, Toyama, Japan.
Biol Pharm Bull. 2008 Jun;31(6):1297-300. doi: 10.1248/bpb.31.1297.
The aim of the present study was to investigate the mechanism for the stereoselective presystemic clearance of carvedilol. We examined the oxidation and glucuronidation of carvedilol in human liver microsomes (HLM) and human intestinal microsomes (HIM). The oxidation of carvedilol in HLM and HIM was evaluated in the presence of NADPH, whereas glucuronidation was evaluated in the presence of UDP-glucuronic acid. Oxidation of S-carvedilol in HLM and HIM was greater than that of R-carvedilol. In addition, the oxidation of R-carvedilol in HLM was inhibited by quinidine, whereas that of S-carvedilol was inhibited by both quinidine and furafylline. On the other hand, R- and S-carvedilol oxidation in HIM was inhibited by ketoconazole. Glucuronidation of S-carvedilol in HLM and HIM was also higher than that of R-carvedilol. These results suggested that cytochrome P450 (CYP) 2D6 and CYP1A2 are involved in the stereoselective oxidation of carvedilol in the liver, that CYP3A4 is involved in intestinal oxidation, and that glucuronidation in the liver and intestine is at least partly responsible for stereoselective presystemic clearance.
本研究的目的是探究卡维地洛立体选择性首过清除的机制。我们检测了卡维地洛在人肝微粒体（HLM）和人肠微粒体（HIM）中的氧化和葡萄糖醛酸化反应。在存在NADPH的情况下评估卡维地洛在HLM和HIM中的氧化反应，而在存在尿苷二磷酸葡萄糖醛酸的情况下评估葡萄糖醛酸化反应。HLM和HIM中S-卡维地洛的氧化反应大于R-卡维地洛。此外，HLM中R-卡维地洛的氧化反应受奎尼丁抑制，而S-卡维地洛的氧化反应受奎尼丁和呋拉茶碱两者抑制。另一方面，HIM中R-和S-卡维地洛的氧化反应受酮康唑抑制。HLM和HIM中S-卡维地洛的葡萄糖醛酸化反应也高于R-卡维地洛。这些结果表明，细胞色素P450（CYP）2D6和CYP1A2参与了肝脏中卡维地洛的立体选择性氧化反应，CYP3A4参与了肠道氧化反应，并且肝脏和肠道中的葡萄糖醛酸化反应至少部分地导致了立体选择性首过清除。
