Compartmentalization and Antiviral Effect of Efavirenz Metabolites in Blood Plasma, Seminal Plasma, and Cerebrospinal Fluid

Abstract

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.

In Vivo Profiling and Distribution of Known and Novel Phase I and Phase II Metabolites of Efavirenz in Plasma, Urine, and Cerebrospinal Fluid

“…Overall, the majority of the studies so far have been restricted to the phase I metabolites (Cho et al, 2011;Avery et al, 2013) even though, as we will show, these metabolites are present in vivo at much lower levels than phase II metabolites.…”

“…1G). The 8,14-di-OH-EFV has been barely detected in plasma (Avery et al, 2013). Mixed sulfate-glutathione diconjugates of EFV have also been detected in humans (Mutlib et al, 1999a).…”

Population Pharmacokinetic Model Linking Plasma and Peripheral Blood Mononuclear Cell Concentrations of Efavirenz and Its Metabolite, 8-Hydroxy-Efavirenz, in HIV Patients

“…Even though the scope of the present study was not to elucidate the mechanistic details, it is assumed that either intracellular protein or tissue binding might limit the back transfer of EFV and 8OHEFV from PBMCs to the plasma compartment. EFV is known to be highly bound to plasma proteins (Ͼ99%) and tissue structures (28,29) and 8OHEFV has been reported to have protein binding similar to that of EFV (30). However, further in vitro-supported studies are warranted.…”

KAE609 (Cipargamin), a New Spiroindolone Agent for the Treatment of Malaria: Evaluation of the Absorption, Distribution, Metabolism, and Excretion of a Single Oral 300-mg Dose of [14C]KAE609 in Healthy Male Subjects

“…Although it is not a common practice to collect semen in human ADME studies, detection of drugs and their metabolites in semen has been reported previously, particularly in patients with HIV (Ette et al, 1988; Taylor and Pereira, 2001;Avery et al, 2013). Semen was evaluated since subjects in prior studies had reported semen discoloration after taking KAE609 at higher doses.…”