Hanatani T, Fukuda T, Ikeda M, Imaoka S, Hiroi T, Funae Y, Azuma J
Clinical Evaluation of Medicines and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Japan.
Pharmacogenomics J. 2001;1(4):288-92. doi: 10.1038/sj.tpj.6500063.
Candesartan cilexetil is an angiotensin II receptor antagonist, and candesartan, its active metabolite, is metabolized by CYP2C9. However, the effect of CYP2C93 on candesartan metabolism is not established. We characterized the kinetics of candesartan by CYP2C91/1 and CYP2C91/3 in human liver microsomes. The difference between the two was not significant. Subsequently, CYP2C91 and CYP2C93 (Leu359) were expressed in yeast, and the kinetics of candesartan were determined. The wild-type showed the lower Km (345 vs 439 microM; 3/4) and higher Vmax/Km (1/3) than the Leu359 variant. Also, we investigated potential interaction between candesartan and warfarin with both the wild-type and the Leu359 variant. Candesartan had no effect on S-warfarin 7-hydroxylation. In contrast, S-warfarin inhibited candesartan metabolism by the wild-type (K = 17microM) greater than by the Leu359 variant (Ki = 36 microM). These findings suggest that CYP2C93 may change not only the metabolic activity but also the inhibitory susceptibility compared with CYP2C9*1.
坎地沙坦酯是一种血管紧张素II受体拮抗剂，其活性代谢产物坎地沙坦由CYP2C9代谢。然而，CYP2C93对坎地沙坦代谢的影响尚未明确。我们在人肝微粒体中研究了CYP2C91/1和CYP2C91/3对坎地沙坦的代谢动力学。两者之间的差异不显著。随后，在酵母中表达了CYP2C91和CYP2C93（Leu359），并测定了坎地沙坦的代谢动力学。野生型显示出比Leu359变体更低的Km（345对439 microM；3/4）和更高的Vmax/Km（1/3）。此外，我们研究了野生型和Leu359变体中坎地沙坦与华法林之间的潜在相互作用。坎地沙坦对S-华法林7-羟化无影响。相反，S-华法林对野生型坎地沙坦代谢的抑制作用（K = 17 microM）大于对Leu359变体的抑制作用（Ki = 36 microM）。这些发现表明，与CYP2C91相比，CYP2C9*3不仅可能改变代谢活性，还可能改变抑制敏感性。
