Laboratory of Pharmacokinetics, Department of Biopharmaceutical Sciences and Pharmacy, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Biol Pharm Bull. 2012;35(2):151-63. doi: 10.1248/bpb.35.151.
Carvedilol is administered orally as a racemic mixture of R(+)- and S(-)-enantiomers for treatment of angina pectoris, hypertension and chronic heart failure. We have reported that enzyme kinetic parameters for carvedilol glucuronidation by human liver microsomes (HLM) differed greatly depending on the substrate form, namely, racemic carvedilol and each enantiomer. These phenomena were thought to be caused by mutual inhibition between carvedilol enantiomers during racemate glucuronidation. The aim of this study was to clarify the mechanism of these phenomena in HLM and human intestinal microsomes (HIM) and its relevance to uridine 5'-diphosphate (UDP)-glucuronosyl transferase (UGT) 1A1, UGT2B4 and UGT2B7, which mainly metabolize carvedilol directly in phase II enzymes. HLM apparently preferred metabolizing (S)-carvedilol to (R)-carvedilol in the racemate, but true activities of HLM for both glucuronidation were approximately equal. By determination of the inhibitory effects of (S)-carvedilol on (R)-carvedilol glucuronidation and vice versa, it was shown that (R)-carvedilol glucuronidation was more easily inhibited than was (S)-carvedilol glucuronidation. UGT2B7 was responsible for (S)-carvedilol glucuronidation in HLM. Ratios of contribution to (R)-carvedilol glucuronidation were approximately equal among UGT1A1, UGT2B4 and UGT2B7. However, enzyme kinetic parameters were different between the two lots of HLM used in this study, depending on the contribution ratio of UGT2B4, in which (R)-glucuronidation was much more easily inhibited by (S)-carvedilol than was (S)-glucuronidation by (R)-carvedilol. Meanwhile, HIM preferred metabolizing (R)-carvedilol, and this tendency was not different between the kinds of substrate form.
卡维地洛以消旋混合物的形式（R(+)-和 S(-)-对映异构体）口服给药，用于治疗心绞痛、高血压和慢性心力衰竭。我们曾报道过，人肝微粒体（HLM）中卡维地洛葡萄糖醛酸化的酶动力学参数因底物形式而异，即消旋卡维地洛和每个对映异构体。这些现象被认为是由于在消旋体葡萄糖醛酸化过程中卡维地洛对映异构体之间的相互抑制所致。本研究的目的是阐明这些现象在 HLM 和人肠微粒体（HIM）中的机制及其与主要在 II 相酶中直接代谢卡维地洛的尿苷 5'-二磷酸（UDP）-葡萄糖醛酸基转移酶（UGT）1A1、UGT2B4 和 UGT2B7 的相关性。HLM 显然更喜欢代谢消旋体中的（S）-卡维地洛，而不是（R）-卡维地洛，但 HLM 对两者葡萄糖醛酸化的真正活性大致相等。通过测定（S）-卡维地洛对（R）-卡维地洛葡萄糖醛酸化的抑制作用及其相反作用，表明（R）-卡维地洛葡萄糖醛酸化比（S）-卡维地洛葡萄糖醛酸化更容易受到抑制。UGT2B7 负责 HLM 中的（S）-卡维地洛葡萄糖醛酸化。UGT1A1、UGT2B4 和 UGT2B7 对（R）-卡维地洛葡萄糖醛酸化的贡献比例大致相等。然而，本研究中使用的两种 HLM 的酶动力学参数不同，这取决于 UGT2B4 的贡献比例，其中（R）-葡萄糖醛酸化比（S）-葡萄糖醛酸化更容易受到（S）-卡维地洛的抑制。同时，HIM 更喜欢代谢（R）-卡维地洛，而这一趋势在底物形式之间没有区别。
