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

Publication

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

Journal Paper/Review - Nov 9, 2015

Aouri Manel, Rotger Margalida, Telenti Amalio, Buclin Thierry, Günthard Huldrych F, Vernazza Pietro, Henry Hugues, Yerly Sabine, Anagnostopoulos Alexia, Cavassini Matthias, Ternon Beatrice, Barcelo Catalina, Decosterd Laurent A

Citation

Aouri M, Rotger M, Telenti A, Buclin T, Günthard H, Vernazza P, Henry H, Yerly S, Anagnostopoulos A, Cavassini M, Ternon B, Barcelo C, Decosterd L. In Vivo Profiling and Distribution of Known and Novel Phase I and Phase II Metabolites of Efavirenz in Plasma, Urine and Cerebro-Spinal Fluid. Drug Metab Dispos 2015

Type

Journal Paper/Review (English)

Journal

Drug Metab Dispos 2015

Publication Date

Nov 9, 2015

Issn Electronic

1521-009X

Brief description/objective

UNASSIGNED
Efavirenz (EFV) is principally metabolized by CYP2B6 to 8-hydroxy-efavirenz (8OH-EFV) and to a lesser extent by CYP2A6 to 7-hydroxy-efavirenz (7OH-EFV). Most metabolites profile analyses have been so far restricted to 8OH-EFV, 7OH-EFV and EFV-N-gln even though these metabolites represent a minor percentage of EFV metabolites present in vivo. We have performed a quantitative phase I and II metabolites profiles analyses by tandem mass spectrometry of plasma, CSF and urine samples in 71 HIV patients under efavirenz, prior to and after enzymatic (glucuronidase and sulfatase) hydrolysis. We have shown that phase II metabolites constitute the major part of the known circulating efavirenz species in humans. The 8OH-EFV-Glucuronide, and 8OH-EFV-sulfate (identified for the first time) in humans were found 64- and 7-fold higher than the parent 8OH-EFV, respectively. In individuals (n = 67) genotyped for CYP2B6, 2A6 and CYP3A metabolic pathways, the 8OH-EFV/EFV ratios in plasma were an index of CYP2B6 phenotypic activity (p < 0.0001) which was also reflected by phase II metabolites 8OH-EFV-gln/EFV and 8OH-EFV-sulfate/EFV ratios. Neither EFV nor 8OH-EFV, nor any other considered metabolites in plasma were associated with an increased risk of CNS toxicity. In CSF, 8OH-EFV levels were not influenced by CYP2B6 genotypes and did not predict CNS toxicity. The phase II metabolites 8OH-EFV - gln, 8OH-EFV-sulfate and 7OH-EFV - gln were present in CSF at 2- to 9-fold higher concentrations than 8OH-EFV. The potential contribution of these previously unreported EFV metabolites in CSF to the neuropsychological effects of efavirenz need to be further examined in larger cohort studies.