Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Drug Metab Dispos. 2013 Feb;41(2):422-9. doi: 10.1124/dmd.112.049601. Epub 2012 Nov 19.
Efavirenz (EFV) is one of the most commonly prescribed antiretrovirals for use in the treatment of human immunodeficiency virus (HIV) infection. EFV is extensively metabolized by cytochrome P450 to a number of oxygenated products; however, the pharmacologic activity and distribution of these metabolites in anatomic compartments have yet to be explored. The systemic distribution of EFV oxidative metabolites was examined in blood plasma, seminal plasma, and cerebrospinal fluid from subjects on an EFV-based regimen. The 8-hydroxy EFV metabolite was detected in blood plasma, seminal plasma, and cerebrospinal fluid, with median concentrations of 314.5 ng/ml, 358.5 ng/ml, and 3.37 ng/ml, respectively. In contrast, 7-hydroxy and 8,14-hydroxy EFV were only detected in blood plasma and seminal plasma with median concentrations of 8.84 ng/ml and 10.23 ng/ml, and 5.63 ng/ml and 5.43 ng/ml, respectively. Interestingly, protein-free concentrations of metabolites were only detectable in seminal plasma, where a novel dihdyroxylated metabolite of EFV was also detected. This accumulation of protein-free EFV metabolites was demonstrated to be the result of differential protein binding in seminal plasma compared with that of blood plasma. In addition, the oxidative metabolites of EFV did not present with any significant pharmacologic activity toward HIV-1 as measured using an HIV green fluorescent protein single-round infectivity assay. This study is the first to report the physiologic distribution of metabolites of an antiretroviral into biologic compartments that the virus is known to distribute and to examine their anti-HIV activity. These data suggest that the male genital tract may be a novel compartment that should be considered in the evaluation of drug metabolite exposure.
依非韦伦（EFV）是最常用于治疗人类免疫缺陷病毒（HIV）感染的抗逆转录病毒药物之一。EFV 广泛被细胞色素 P450 代谢为许多含氧产物；然而，这些代谢物在解剖隔室中的药理活性和分布尚未得到探索。本研究在接受 EFV 方案治疗的受试者的血浆、精液和脑脊液中检测了 EFV 氧化代谢物的全身分布。在血浆、精液和脑脊液中均检测到 8-羟基 EFV 代谢物，其中位数浓度分别为 314.5ng/ml、358.5ng/ml 和 3.37ng/ml。相比之下，7-羟基和 8,14-羟基 EFV 仅在血浆和精液中被检测到，其中位数浓度分别为 8.84ng/ml 和 10.23ng/ml，以及 5.63ng/ml 和 5.43ng/ml。有趣的是，仅在精液中可检测到无蛋白结合的代谢物，还检测到 EFV 的一种新型二羟化代谢物。这种 EFV 无蛋白结合代谢物的积累被证明是由于与血浆相比，在精液中存在差异的蛋白结合。此外，用 HIV 绿色荧光蛋白单轮感染测定法测量，EFV 的氧化代谢物对 HIV-1 没有表现出任何显著的药理活性。本研究首次报道了抗病毒药物代谢物在已知病毒分布的生物隔室中的生理分布，并研究了它们的抗 HIV 活性。这些数据表明，男性生殖道可能是一个新的隔室，在评估药物代谢物暴露时应加以考虑。
