Dilmaghanian Shahrzad, Gerber John G, Filler Scott G, Sanchez Angela, Gal Joseph
Division of Clinical Pharmacology and Toxicology, University of Colorado Health Sciences Center, Denver, Colorado, USA.
Chirality. 2004 Feb;16(2):79-85. doi: 10.1002/chir.10294.
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 immunosuppression 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). KTZ 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-KTZ 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. Chirality 16:79-85, 2004.
消旋酮康唑（KTZ）是临床实践中使用的第一种口服活性唑类抗真菌药物，已广泛用于治疗与艾滋病免疫抑制和癌症化疗相关的黏膜真菌感染。然而，由于不良的药物相互作用，KTZ的使用受到了限制。KTZ通过抑制真菌细胞色素P450（CYP51）来阻断麦角固醇的生物合成。KTZ也是人细胞色素P450 3A4（CYP3A4）酶的强效抑制剂，该酶是人类肝脏中主要的药物代谢CYP同工酶。我们研究了KTZ在抑制人CYP3A4和抗真菌作用方面的对映体选择性差异。右旋和左旋KTZ在对睾酮和美沙酮代谢的CYP3A4抑制方面表现出适度的对映体选择性差异。对于这两种底物，左旋KTZ的抑制效力大约高2倍。我们研究了KTZ对医学上相关的念珠菌属、曲霉属以及新型隐球菌的体外活性的对映体选择性差异。总体而言，左旋KTZ的活性比右旋KTZ高2至4倍。因此，左旋KTZ是一种更强效的CYP3A4抑制剂，并且具有更强的体外抗真菌活性。《手性》16:79 - 85，2004年。
