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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
pharmacology, toxicology and pharmaceutics
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, Volume 44, No. 1, Year 2016
Notification
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Description
Efavirenz (EFV) is principally metabolized by CYP2B6 to 8-hydroxyefavirenz (8OH-EFV) and to a lesser extent by CYP2A6 to 7-hydroxyefavirenz (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, 8OHEFV levels were not influenced by CYP2B6 genotypes and did not predict CNS toxicity. The phase II metabolites 8OH-EFV-gln, 8OHEFV- 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. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.
Authors & Co-Authors
Aouri, Manel
Switzerland, Lausanne
Université de Lausanne Unil
Cavassini, Matthias
Switzerland, Lausanne
Université de Lausanne Unil
Anagnostopoulos, Alexia
Switzerland, Zurich
Universität Zürich
Yerly, Sabine T.B.D.
Switzerland, Geneva
Hôpitaux Universitaires de Genève
Vernazza, Pietro Luigi
Switzerland, St Gallen
Kantonsspital St.gallen
Günthard, Huldrych F.
Switzerland, Zurich
Universität Zürich
Buclin, Thierry J.
Switzerland, Lausanne
Université de Lausanne Unil
Telenti, Amalio
Switzerland, Lausanne
Université de Lausanne Unil
United States, Rockville
J. Craig Venter Institute
Décosterd, Laurent Arthur
Switzerland, Lausanne
Université de Lausanne Unil
Aubert, Vincent
Unknown Affiliation
Battegay, Manuel
Unknown Affiliation
Bernasconi, Enos
Unknown Affiliation
Böni, Jürg
Unknown Affiliation
Braun, Dominique Laurent
Unknown Affiliation
Bucher, Heíner C.C.
Unknown Affiliation
Burton-Jeangros, Claudine
Unknown Affiliation
Calmy, Alexandra L.
Unknown Affiliation
Dollenmaier, Guenter
Unknown Affiliation
Egger, Matthias
Unknown Affiliation
Elzi, Luigia
Unknown Affiliation
Fehr, Jan Sven
Unknown Affiliation
Fellay, Jacques
Unknown Affiliation
Furrer, Hansjakob
Unknown Affiliation
Fux, Christoph Andreas
Unknown Affiliation
Gorgievski, Meri
Unknown Affiliation
Günthard, Hüldrych Fritz
Unknown Affiliation
Haerry, David Hans Ulrich
Unknown Affiliation
Hasse, Barbara Katharina
Unknown Affiliation
Hirsch, Hans H.
Unknown Affiliation
Hoffmann, Matthias
Unknown Affiliation
Hösli, Irene Mathilde
Unknown Affiliation
Kahlert, Christian R.
Unknown Affiliation
Kaiser, Laurent K.
Unknown Affiliation
Keiser, Olivia
Unknown Affiliation
Klimkait, Thomas
Unknown Affiliation
Kouyos, Roger D.
Unknown Affiliation
Kovari, Helen
Unknown Affiliation
Ledergerber, Bruno
Unknown Affiliation
Martinetti, Gladys
Unknown Affiliation
Martínez de Tejada, Begoῆa
Unknown Affiliation
Marzolini, Catia
Unknown Affiliation
Metzner, Karin Jutta
Unknown Affiliation
Müller, Nicolas J.
Unknown Affiliation
Nadal, David
Unknown Affiliation
Nicca, Dunja
Unknown Affiliation
Pantaleo, Giuseppe P.
Unknown Affiliation
Rauch, Andri
Unknown Affiliation
Regenass, Stephan
Unknown Affiliation
Rudin, Christoph
Unknown Affiliation
Schöni-Affolter, Franziska
Unknown Affiliation
Schmid, Patrick
Unknown Affiliation
Speck, Roberto F.
Unknown Affiliation
Stöckle, Marcel
Unknown Affiliation
Tarr, Philip E.
Unknown Affiliation
Trkola, Alexandra
Unknown Affiliation
Vernazza, Pietro L.
Unknown Affiliation
Weber, Rainer
Unknown Affiliation
Yerly, Sabine
Unknown Affiliation
Statistics
Citations: 24
Authors: 58
Affiliations: 5
Identifiers
Doi:
10.1124/dmd.115.065839
ISSN:
00909556
Research Areas
Noncommunicable Diseases
Study Design
Cohort Study
Study Approach
Quantitative