抗真菌药物对人肝微粒体中细胞色素P450（CYP）1A2、CYP2D6和CYP2E1活性的影响。

Effect of antifungal drugs on cytochrome P450 (CYP) 1A2, CYP2D6, and CYP2E1 activities in human liver microsomes.

作者信息

Niwa Toshiro, Inoue-Yamamoto Sachiko, Shiraga Toshifumi, Takagi Akira

机构信息

Post Marketing Product Development, Astellas Pharma Inc., Osaka, Japan.

出版信息

Biol Pharm Bull. 2005 Sep;28(9):1813-6. doi: 10.1248/bpb.28.1813.

DOI:10.1248/bpb.28.1813

PMID:16141569

Abstract

The effects of five antifungal drugs, fluconazole, itraconazole, micafungin, miconazole, and voriconazole, on cytochrome P450 (CYP) 1A2-mediated 7-ethoxyresorufin O-deethylation, CYP2D6-mediated debrisoquine 4-hydroxylation, and CYP2E1-mediated chlorzoxazone 6-hydroxylation activities in human liver microsomes were compared. In addition, the effect of preincubation was estimated in order to investigate the mechanism-based inhibition. IC50 values of miconazole against CYP1A2 and CYP2D6 activities were 2.90 and 6.46 microM, respectively, and miconazole at 10 microM concentration slightly inhibited CYP2E1 activity. On the other hand, other antifungal drugs neither inhibited nor stimulated all of the metabolic activities. The stimulation of the inhibition of the metabolic activities mediated by CYP1A2, CYP2D6, or CYP2E1 by 15-min preincubation was not observed for any of the antifungal drugs, suggesting that these antifungal drugs are not mechanism-based inhibitors. These results suggest that miconazole is the strongest inhibitor against CYP1A2, CYP2D6, and CYP2E1 among the antifungal drugs investigated.

摘要

比较了氟康唑、伊曲康唑、米卡芬净、咪康唑和伏立康唑这五种抗真菌药物对人肝微粒体中细胞色素P450（CYP）1A2介导的7-乙氧基试卤灵O-脱乙基化、CYP2D6介导的异喹胍4-羟化以及CYP2E1介导的氯唑沙宗6-羟化活性的影响。此外，为了研究基于机制的抑制作用，评估了预孵育的效果。咪康唑对CYP1A2和CYP2D6活性的IC50值分别为2.90和6.46微摩尔，10微摩尔浓度的咪康唑对CYP2E1活性有轻微抑制作用。另一方面，其他抗真菌药物既不抑制也不刺激所有代谢活性。对于任何一种抗真菌药物，均未观察到15分钟预孵育对CYP1A2、CYP2D6或CYP2E1介导的代谢活性抑制的刺激作用，这表明这些抗真菌药物不是基于机制的抑制剂。这些结果表明，在所研究的抗真菌药物中，咪康唑是对CYP1A2、CYP2D6和CYP2E1最强的抑制剂。