Enantioselectivity of inhibition of cytochrome P450 3A4 (CYP3A4) by ketoconazole: Testosterone and methadone as substrates

被引:64
作者
Dilmaghanian, S
Gerber, JG
Filler, SG
Sanchez, A
Gal, J
机构
[1] Univ Colorado, Hlth Sci Ctr, Div Clin Pharmacol & Toxicol, Denver, CO 80262 USA
[2] Univ Calif Los Angeles, Harbor Res & Educ Inst, Dept Med, Torrance, CA USA
关键词
stereoselective; ketoconazole; enantiomers; CYP3A4; inhibition; azoles; drug interactions; antifungal; fungal CYP51;
D O I
10.1002/chir.10294
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Racemic ketoconazole (KTZ) was the first orally active azole antifungal agent used in clinical practice and has become widely used in the treatment of mucosal fungal infections associated with AIDS inummosuppression and cancer chemotherapy. However, the use of KTZ has been limited because of adverse drug-drug interactions. KTZ blocks ergosterol biosynthesis by inhibiting the fungal cytochrome P450 (CYP51). M is also a potent inhibitor of human cytochrome P450 3A4 (CYP3A4) enzyme, the major drug-metabolizing CYP isozyme in the human liver. We examined the enantioselective differences of KTZ in the inhibition of human CYP3A4 and in antifungal action. Dextro- and levo-KTZ exhibited modest enantioselective differences with respect to CYP3A4 inhibition of testosterone and methadone metabolism. For both substrates levo-KTZ was approximately a 2-fold more potent inhibitor. We examined the enantioselective differences in the in vitro activity of KTZ against medically relevant species of Candida and Aspergillus, as well as Cryptococcus neoformans. Overall, levo-M was 2-4-fold more active than dextro-KTZ. Therefore, levo-KTZ is a more potent inhibitor of CYP3A4 and has stronger in vitro antifungal activity. (C) 2004 Wiley-Liss, Inc.
引用
收藏
页码:79 / 85
页数:7
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