Compartmental distribution and antiviral effect of efavirenz metabolites

Abstract

Efavirenz (EFV), one of the most widely prescribed drugs used to treat HIV, is extensively metabolized by the cytochromes P450 to a number of oxygenated products; however, the pharmacologic activity and distribution of these metabolites in anatomic compartments relevant to HIV infection beyond blood plasma have yet to be explored. The systemic distribution of EFV oxidative metabolites was examined in blood plasma (BP), seminal plasma (SP), and cerebrospinal fluid (CSF) from subjects on an EFV‐based regimen. The 8‐hydroxy EFV metabolite was detected in BP, SP and CSF, with median concentrations of 314.5ng/ml, 358.5ng/ml, and 3.37ng/ml, respectively. In contrast, 7‐hydroxy and 8,14‐hydroxy EFV were only detected in BP and SP with median concentrations of 8.84ng/ml and 10.23ng/ml, and 5.63ng/ml and 5.43ng/ml, respectively. Interestingly, protein‐free concentrations of metabolites were only detectable in SP, where a novel dihdyroxylated metabolite of EFV was also detected. The metabolite concentrations in 34 paired BP and CSF patient samples were not strongly correlated with viral RNA concentrations indicating that the metabolites of EFV are pharmacologically inactive. These results suggest there may be important compartmental differences in EFV metabolite distribution, and the male genital tract may be a novel compartment in understanding local drug distribution and efficacy of oxidative metabolites.