Activity Variations of CYP2B6 Determine the Metabolic Stratification of Efavirenz

埃法维伦兹 CYP2B6型 最大值 微粒体 药理学 化学 体内 代谢物 IC50型 生物 药代动力学 体外 人类免疫缺陷病毒(HIV) 生物化学 生物技术 免疫学 抗逆转录病毒疗法 CYP1A2 病毒载量
作者
Xinyue Li,Qian Liu,Xiaoyu Xu,Jing Wang,Yun-shan Zhong,Le-Hao Jin,Jing Yuan,Jianchang Qian,Xiao-Dan Zhang
出处
期刊:Chemical Research in Toxicology [American Chemical Society]
卷期号:37 (11): 1867-1875
标识
DOI:10.1021/acs.chemrestox.4c00230
摘要

Purpose: To investigate the effects of hepatic enzyme activity variations and CYP2B6 gene polymorphisms on the in vivo and in vitro metabolism of efavirenz. Main methods: In vitro enzyme systems using rat and human liver microsomes (RLM/HLM) were established, with in vivo studies conducted on Sprague–Dawley rats. Metabolite detection was performed via LC-MS/MS. Human recombinant CYP2B6 microsomes were prepared using a baculovirus-insect cell system and ultracentrifugation, with efavirenz serving as the substrate to study enzyme kinetics. Results: Isavuconazole exhibited an IC50 of 21.14 ± 0.57 μM in RLM, indicating a mixed competitive and noncompetitive mechanism, and an IC50 of 40.44 ± 4.23 μM in HLM, suggesting an anticompetitive mechanism. In rats, coadministration of efavirenz and isavuconazole significantly increased the AUC, Tmax, and Cmax of efavirenz. Co-administration of efavirenz and rifampicin significantly elevated the AUC, Tmax, and Cmax of 8-OH-efavirenz. The activity of CYP2B6.4, 6, and 7 increased significantly compared to CYP2B6.1, with relative clearance ranging from 158.34% to 212.72%. Conversely, the activity of CYP2B6.3, 8, 10, 11, 13–15, 18–21, 23–27, 31–33, and 37 was markedly reduced, ranging from 4.30% to 79.89%. Conclusion: Variations in liver enzyme activity and CYP2B6 genetic polymorphisms can significantly alter the metabolism of efavirenz. It provides laboratory-based data for the precise application of efavirenz and other CYP2B6 substrate drugs.
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