Effect of antifungal drugs on cytochrome P450 (CYP) 1A2, CYP2D6, and CYP2E1 activities in human liver microsomes
Effect of antifungal drugs on cytochrome P450 (CYP) 1A2, CYP2D6, and CYP2E1 activities in human liver microsomes
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DOI：
10.1248/bpb.28.1813
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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;Inoue-Yamamoto, S;Takagi, A
比较了氟康唑、伊曲康唑、米卡芬净、咪康唑和伏立康唑等5种抗真菌药物对人肝微粒体细胞色素P450(CYP)1A2介导的7-乙氧基间苯二酚O-脱乙基化、细胞色素P2D6介导的去甲基异喹4-羟基化和细胞色素P450(CYP)1A2介导的氯唑沙宗6-羟化的影响。此外，还评估了预孵育的效果，以探讨基于机制的抑制。咪康唑对细胞色素P1A2和细胞色素P450 2D6活性的IC50值分别为2.90和6.46 mU M，10 mU M的咪康唑对细胞色素P450 2的活性有轻微的抑制作用。另一方面，其他抗真菌药物既不抑制也不刺激所有的代谢活动。对任何一种抗真菌药物均未观察到预孵育15min对其代谢活性抑制作用的刺激作用，提示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的抑制作用最强的药物。
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 mu M, respectively, and miconazole at 10 mu M 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.