{"title":"CYP2B6 的活性变化决定了依非韦伦的代谢分层。","authors":"Xin-Yue Li, Qian Liu, Xiao-Yu Xu, Jing Wang, Yun-Shan Zhong, Le-Hao Jin, Jing Yuan, Jian-Chang Qian, Xiao-Dan Zhang","doi":"10.1021/acs.chemrestox.4c00230","DOIUrl":null,"url":null,"abstract":"<p><strong>Purpose: </strong>To investigate the effects of hepatic enzyme activity variations and CYP2B6 gene polymorphisms on the <i>in vivo</i> and <i>in vitro</i> metabolism of efavirenz.</p><p><strong>Main methods: </strong>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.</p><p><strong>Results: </strong>Isavuconazole exhibited an IC<sub>50</sub> of 21.14 ± 0.57 μM in RLM, indicating a mixed competitive and noncompetitive mechanism, and an IC<sub>50</sub> of 40.44 ± 4.23 μM in HLM, suggesting an anticompetitive mechanism. In rats, coadministration of efavirenz and isavuconazole significantly increased the AUC, <i>T</i><sub>max</sub>, and <i>C</i><sub>max</sub> of efavirenz. Co-administration of efavirenz and rifampicin significantly elevated the AUC, <i>T</i><sub>max</sub>, and <i>C</i><sub>max</sub> 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%.</p><p><strong>Conclusion: </strong>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.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":"1867-1875"},"PeriodicalIF":3.7000,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Activity Variations of CYP2B6 Determine the Metabolic Stratification of Efavirenz.\",\"authors\":\"Xin-Yue Li, Qian Liu, Xiao-Yu Xu, Jing Wang, Yun-Shan Zhong, Le-Hao Jin, Jing Yuan, Jian-Chang Qian, Xiao-Dan Zhang\",\"doi\":\"10.1021/acs.chemrestox.4c00230\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Purpose: </strong>To investigate the effects of hepatic enzyme activity variations and CYP2B6 gene polymorphisms on the <i>in vivo</i> and <i>in vitro</i> metabolism of efavirenz.</p><p><strong>Main methods: </strong>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.</p><p><strong>Results: </strong>Isavuconazole exhibited an IC<sub>50</sub> of 21.14 ± 0.57 μM in RLM, indicating a mixed competitive and noncompetitive mechanism, and an IC<sub>50</sub> of 40.44 ± 4.23 μM in HLM, suggesting an anticompetitive mechanism. In rats, coadministration of efavirenz and isavuconazole significantly increased the AUC, <i>T</i><sub>max</sub>, and <i>C</i><sub>max</sub> of efavirenz. Co-administration of efavirenz and rifampicin significantly elevated the AUC, <i>T</i><sub>max</sub>, and <i>C</i><sub>max</sub> 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%.</p><p><strong>Conclusion: </strong>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.</p>\",\"PeriodicalId\":31,\"journal\":{\"name\":\"Chemical Research in Toxicology\",\"volume\":\" \",\"pages\":\"1867-1875\"},\"PeriodicalIF\":3.7000,\"publicationDate\":\"2024-11-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Chemical Research in Toxicology\",\"FirstCategoryId\":\"88\",\"ListUrlMain\":\"https://doi.org/10.1021/acs.chemrestox.4c00230\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/10/14 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Chemical Research in Toxicology","FirstCategoryId":"88","ListUrlMain":"https://doi.org/10.1021/acs.chemrestox.4c00230","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/10/14 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
Activity Variations of CYP2B6 Determine the Metabolic Stratification of Efavirenz.
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.
期刊介绍：
Chemical Research in Toxicology publishes Articles, Rapid Reports, Chemical Profiles, Reviews, Perspectives, Letters to the Editor, and ToxWatch on a wide range of topics in Toxicology that inform a chemical and molecular understanding and capacity to predict biological outcomes on the basis of structures and processes. The overarching goal of activities reported in the Journal are to provide knowledge and innovative approaches needed to promote intelligent solutions for human safety and ecosystem preservation. The journal emphasizes insight concerning mechanisms of toxicity over phenomenological observations. It upholds rigorous chemical, physical and mathematical standards for characterization and application of modern techniques.
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