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

Article Article scientifique Article In Vivo Profiling and Distribution of Known and Novel Phase I and Phase II Metabolites of Efavirenz in Plasma, Urine, and Cerebrospinal Fluid eng 2016 author Aouri Manel 653328 author Barcelo Catalina author Ternon Béatrice author Cavassini Matthias author Anagnostopoulos Alexia author Yerly Ferrillo Sabine 23752 author Hugues Henry author Vernazza Pietro author Günthard Huldrych F author Buclin Thierry 648525 author Telenti Amalio author Rotger Margalida author Decosterd Laurent A 151-161 10.1124/dmd.115.065839 26553012 0090-9556 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). So far, most metabolite profile analyses have been restricted to 8OH-EFV, 7OH-EFV, and EFV-N-glucuronide, even though these metabolites represent a minor percentage of EFV metabolites present in vivo. We have performed a quantitative phase I and II metabolite profile analysis by tandem mass spectrometry of plasma, cerebrospinal fluid (CSF), and urine samples in 71 human immunodeficiency virus patients taking 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 (gln) and 8OH-EFV-sulfate (identified for the first time) in humans were found to be 64- and 7-fold higher than the parent 8OH-EFV, respectively. In individuals (n = 67) genotyped for CYP2B6, 2A6, and CYP3A metabolic pathways, 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-glucuronide/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 central nervous system (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 known and previously unreported EFV metabolites in CSF to the neuropsychological effects of efavirenz needs to be further examined in larger cohort studies. Anti-HIV Agents/adverse effects/blood/cerebrospinal fluid/pharmacokinetics/urine Benzoxazines/adverse effects/blood/cerebrospinal fluid/pharmacokinetics/urine Cytochrome P-450 CYP2A6/genetics/metabolism Cytochrome P-450 CYP2B6/genetics/metabolism Cytochrome P-450 CYP3A/genetics/metabolism Genotype Glucuronides/blood/cerebrospinal fluid/urine HIV Infections/diagnosis/drug therapy/metabolism Humans Hydroxylation Metabolic Detoxication Phase I Metabolic Detoxication Phase II Metabolomics/methods Neurotoxicity Syndromes/etiology/genetics/metabolism Phenotype Reverse Transcriptase Inhibitors/adverse effects/blood/cerebrospinal fluid/pharmacokinetics/urine Risk Assessment Sulfates/blood/cerebrospinal fluid/urine Tandem Mass Spectrometry Dewey 616 56 Département de médecine 221 false 400 Virologie clinique 668 Drug Metabolism and Disposition 44 1 7bf266f1-5d3a-4ef0-bbbc-0a33524ab8e5 Article (Published version) Public Novel_classical_human_astroviruses_in_stool_cerebrospinal_fluid.pdf 546476 application/pdf CC0 openAccess Faculté de médecine / Section de médecine clinique / Département de médecine

Title	Published in	Year	Views	Downloads

In Vivo Profiling and Distribution of Known and Novel Phase I and Phase II Metabolites of Efavirenz in Plasma, Urine, and Cerebrospinal Fluid	Drug Metabolism and Disposition	2016	615	286
Drug interactions between voriconazole, darunavir/ritonavir and etravirine in an HIV-infected patient with Aspergillus pneumonia	AIDS	2012	683	0

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