Inhibition of Cytochrome P450 2B6 Activity by Voriconazole Profiled Using Efavirenz Disposition in Healthy Volunteers
Inhibition of Cytochrome P450 2B6 Activity by Voriconazole Profiled Using Efavirenz Disposition in Healthy Volunteers
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DOI：
10.1128/aac.01000-16
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发表时间：
2016-11-01
影响因子：
4.9
通讯作者：
Galinsky, Raymond E.
中科院分区：
文献类型：
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作者：
Desta, Zeruesenay;Metzger, Ingrid F.;Galinsky, Raymond E.
细胞色素P450 2B 6（CYP 2B 6）代谢临床上重要的药物和其他化合物。其表达和活性在个体之间差异很大，但由于缺乏安全和选择性的体内CYP 2B 6活性探针，定量估计受到阻碍。依法韦仑是一种非核苷类HIV-1逆转录酶抑制剂，主要通过CYP 2B 6清除，而CYP 2B 6是一种在体外可被伏立康唑强烈抑制的酶。为了检测依非韦仑代谢作为CYP 2B 6活性的体内探针，我们在61名健康志愿者中定量了伏立康唑对CYP 2B 6活性的抑制作用，这些志愿者单次口服100 mg依非韦仑，同时给予和不给予伏立康唑。依法韦仑代谢物的动力学证明了形成速率限制消除。与对照组相比，伏立康唑延长了依非韦伦的消除半衰期（t（1/2）），增加了依非韦伦的最大血药浓度（C-max）和从0 h至t的药时曲线下面积（AUC（0-t））（平均变化分别为51%、36%和89%）（P < 0.0001），并具有显著的受试者间变异性（e.例如，在一个实施例中，依法韦仑AUC（0-t）的百分比变化范围为0.4%至224%。伏立康唑使依法韦仑8-羟基化降低超过60%（P < 0.0001），而对7-羟基化的影响很小。在给药后1 - 6 h测定的依非韦仑与8-羟基依非韦仑的血药浓度比，伏立康唑显著增加，并与依非韦仑AUC（0-t）相关（Pearson r = > 0.8; P < 0.0001）。本研究证明了伏立康唑-依法韦仑相互作用的机制，建立了使用低剂量依法韦仑作为一种安全和选择性的体内探针，用于表型CYP 2B 6活性，并确定了几个易于使用的指数，应加强对CYP 2B 6个体间变异性机制的理解。
Cytochrome P450 2B6 (CYP2B6) metabolizes clinically important drugs and other compounds. Its expression and activity vary widely among individuals, but quantitative estimation is hampered by the lack of safe and selective in vivo probes of CYP2B6 activity. Efavirenz, a nonnucleoside HIV-1 reverse transcriptase inhibitor, is mainly cleared by CYP2B6, an enzyme strongly inhibited in vitro by voriconazole. To test efavirenz metabolism as an in vivo probe of CYP2B6 activity, we quantified the inhibition of CYP2B6 activity by voriconazole in 61 healthy volunteers administered a single 100-mg oral dose of efavirenz with and without voriconazole administration. The kinetics of efavirenz metabolites demonstrated formation rate-limited elimination. Compared to control, voriconazole prolonged the elimination half-life (t(1/2)) and increased both the maximum concentration of drug in serum (C-max) and the area under the concentration-time curve from 0 h to t (AUC(0-t)) of efavirenz (mean change of 51%, 36%, and 89%, respectively) (P < 0.0001) with marked intersubject variability (e. g., the percent change in efavirenz AUC(0-t) ranged from 0.4% to similar to 224%). Voriconazole decreased efavirenz 8-hydroxylation by greater than 60% (P < 0.0001), whereas its effect on 7-hydroxylation was marginal. The plasma concentration ratio of efavirenz to 8-hydroxyefavirenz, determined 1 to 6 h after dosing, was significantly increased by voriconazole and correlated with the efavirenz AUC(0-t) (Pearson r = > 0.8; P < 0.0001). This study demonstrates the mechanisms of voriconazole-efavirenz interaction, establishes the use of a low dose of efavirenz as a safe and selective in vivo probe for phenotyping CYP2B6 activity, and identifies several easy-to-use indices that should enhance understanding of the mechanisms of CYP2B6 interindividual variability.