School of Pharmacy, Shujitsu University, 1-6-1 Nishigawara, Naka-ku, Okayama 703-8516, Japan.
J Pharm Pharm Sci. 2016 Oct-Dec;19(4):423-429. doi: 10.18433/J31S53.
The metabolic activities of aminopyrine N-demethylation and tolbutamide methylhydroxylation by the human hepatic cytochrome P450 (P450 or CYP) 2C subfamily were compared and the effects of azole antifungal agent on the drug-metabolizing activity of CYP2C8 were investigated.
Aminopyrine N-demethylation and tolbutamide methylhydroxylation by CYP2C8, CYP2C9, and CYP2C19 were determined by the previous reported methods. The effects of five azole antifungal agents, fluconazole, itraconazole, ketoconazole, miconazole, and voriconazole, on the aminopyrine N-demethylation activity by CYP2C8 were investigated.
With regard to aminopyrine N-demethylation, CYP2C19 had the lowest Michaelis constant (Km) and CYP2C8 had the highest maximal velocity (Vmax) among the CYP2C subfamily members. The Vmax/Km values for CYP2C8 were the highest, followed by CYP2C19. For tolbutamide methylhydroxylation, the Km and Vmax for CYP2C19 were three and six times higher than the corresponding values for CYP2C9, and the Vmax/Km value for CYP2C19 was twice that for CYP2C9, whereas hydroxylated tolbutamide formed by CYP2C8 was not detected. Fluconazole, itraconazole, and voriconazole at a concentration of 2 or 10 µM neither inhibited nor stimulated CYP2C8-mediated aminopyrine N-demethylation activity at substrate concentrations around the Km (5 mM). However, ketoconazole and miconazole noncompetitively inhibited CYP2C8-mediated aminopyrine N-demethylation with the inhibitory constant values of 1.98 and 0.86 µM, respectively.
These results suggest that ketoconazole and miconazole might inhibit CYP2C8 clinically. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.
比较人肝细胞色素 P450（CYP 或 CYP）2C 亚家族中甲氧苯并芘 N-去甲基化和甲苯磺丁脲甲基羟化的代谢活性，并研究唑类抗真菌药物对 CYP2C8 药物代谢活性的影响。
采用先前报道的方法测定 CYP2C8、CYP2C9 和 CYP2C19 的甲氧基苯并芘 N-去甲基化和甲苯磺丁脲甲基羟化。研究了氟康唑、伊曲康唑、酮康唑、咪康唑和伏立康唑 5 种唑类抗真菌药物对 CYP2C8 中甲氧苯并芘 N-去甲基化活性的影响。
在甲氧基苯并芘 N-去甲基化方面，CYP2C19 的米氏常数（Km）最低，CYP2C8 的最大速度（Vmax）最高，CYP2C 亚家族成员中。CYP2C8 的 Vmax/Km 值最高，其次是 CYP2C19。对于甲苯磺丁脲甲基羟化，CYP2C19 的 Km 和 Vmax 分别是 CYP2C9 的 3 倍和 6 倍，CYP2C19 的 Vmax/Km 值是 CYP2C9 的两倍，而 CYP2C8 形成的羟化甲苯磺丁脲则未检测到。氟康唑、伊曲康唑和伏立康唑在 2 或 10 μM 浓度下，在接近 Km（5 mM）的底物浓度下，既不抑制也不刺激 CYP2C8 介导的甲氧基苯并芘 N-去甲基化活性。然而，酮康唑和咪康唑非竞争性抑制 CYP2C8 介导的甲氧基苯并芘 N-去甲基化，抑制常数值分别为 1.98 和 0.86 μM。
这些结果表明，酮康唑和咪康唑在临床上可能会抑制 CYP2C8。本文接受发表后评审。注册读者（见“读者须知”）可在本期内容页面上点击摘要进行评论。
