Effect of antifungal drugs on cytochrome P450 (CYP) 2C9, CYP2C19, and CYP3A4 activities in human liver microsomes
Effect of antifungal drugs on cytochrome P450 (CYP) 2C9, CYP2C19, and CYP3A4 activities in human liver microsomes
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DOI：
10.1248/bpb.28.1805
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发表时间：
2005-09-01
影响因子：
2
通讯作者：
Takagi, A
中科院分区：
文献类型：
--
作者：
Niwa, T;Shiraga, T;Takagi, A
比较了氟康唑、伊曲康唑、米卡芬净、咪康唑和伏立康唑五种抗真菌药物对人肝微粒体中细胞色素 P450 (CYP) 2C9 介导的甲苯磺丁脲羟基化、CYP209 介导的 S-美芬妥英 4'-羟基化和 CYP3A4 介导的硝苯地平氧化活性的影响。此外，还评估了预孵育的效果，以研究基于机制的抑制。咪康唑针对甲苯磺丁脲羟基化的IC50值最低（2.0μM），其次是伏立康唑（8.4μM）和氟康唑（30.3μM）。类似地，针对S-美芬妥英4'-羟基化的IC50值最低的是咪康唑(0.33μM)，其次是伏立康唑(8.7μM)和氟康唑(12.3μM)。另一方面，浓度为10或25μM的米卡芬净既不抑制也不刺激甲苯磺丁脲羟基化和S-美芬妥英4'-羟基化，并且伊曲康唑针对这些的IC50值大于10μM。这些结果表明，咪康唑是CYP2C9和CYP2C19最强的抑制剂，其次是伏立康唑和氟康唑，而米卡芬净则相反。通过抑制代谢，不会与 CYP2C9 或 CYP2CI9 代谢的其他药物引起临床上显着的相互作用。伏立康唑抗硝苯地平氧化的IC50值与氟康唑和米卡芬净相当，高于伊曲康唑和咪康唑。任何抗真菌药物均未观察到 15 分钟预孵育对 CYP2C9、CYP2C19 或 CYP3A4 介导反应的抑制作用，表明这些药物不是基于机制的抑制剂。
The effects of five antifungal drugs, fluconazole, itraconazole, micafungin, miconazole, and voriconazole, on cytochrome P450 (CYP) 2C9-mediated tolbutamide hydroxylation, CYP209-mediated S-mephenytoin 4'-hydroxylation, and CYP3A4-mediated nifedipine oxidation activities in human liver microsomes were compared. In addition, the effects of preincubation were estimated to investigate the mechanism-based inhibition. The IC50 value against tolbutamide hydroxylation was the lowest for miconazole (2.0 mu M), followed by voriconazole (8.4 mu M) and fluconazole (30.3 mu M). Similarly, the IC50 value against S-mephenytoin 4'-hydroxylation was the lowest for miconazole (0.33 mu M), followed by voriconazole (8.7 mu M) and fluconazole (12.3 mu M). On the other hand, micafungin at a concentration of 10 or 25 mu M neither inhibited nor stimulated tolbutamide hydroxylation and S-mephenytoin 4'-hydroxylation, and the IC50 values for itraconazole against these were greater than 10 mu M. These results suggest that miconazole is the strongest inhibitor of CYP2C9 and CYP2C19, followed by voriconazole and fluconazole, whereas micafungin would not cause clinically significant interactions with other drugs that are metabolized by CYP2C9 or CYP2CI9 via the inhibition of metabolism. The IC50 value of voriconazole against nifedipine oxidation was comparable with that of fluconazole and micafungin and higher than that of itraconazole and miconazole. The stimulation of the inhibition of CYP2C9-, CYP2C19-, or CYP3A4-mediated reactions by 15-min preincubation was not observed for any of the antifungal drugs, suggesting that these drugs are not mechanism-based inhibitors.