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

Details

Serval ID
serval:BIB_4B30049F72DE
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
In Vivo Profiling and Distribution of Known and Novel Phase I and Phase II Metabolites of Efavirenz in Plasma, Urine, and Cerebrospinal Fluid.
Journal
Drug Metabolism and Disposition: the Biological Fate of Chemicals
Author(s)
Aouri M., Barcelo C., Ternon B., Cavassini M., Anagnostopoulos A., Yerly S., Hugues H., Vernazza P., Günthard H.F., Buclin T., Telenti A., Rotger M., Decosterd L.A.
Working group(s)
Swiss HIV Cohort Study
Contributor(s)
Aubert V., Battegay M., Bernasconi E., Böni J., Braun DL., Bucher HC., Burton-Jeangros C., Calmy A., Cavassini M., Dollenmaier G., Egger M., Elzi L., Fehr J., Fellay J., Furrer H., Fux CA., Gorgievski M., Günthard H., Haerry D., Hasse B., Hirsch HH., Hoffmann M., Hösli I., Kahlert C., Kaiser L., Keiser O., Klimkait T., Kouyos R., Kovari H., Ledergerber B., Martinetti G., Martinez de Tejada B., Marzolini C., Metzner K., Müller N., Nadal D., Nicca D., Pantaleo G., Rauch A., Regenass S., Rudin C., Schöni-Affolter F., Schmid P., Speck R., Stöckle M., Tarr P., Trkola A., Vernazza P., Weber R., Yerly S.
ISSN
1521-009X (Electronic)
ISSN-L
0090-9556
Publication state
Published
Issued date
2016
Volume
44
Number
1
Pages
151-161
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
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.
Keywords
Anti-HIV Agents/adverse effects, Anti-HIV Agents/blood, Anti-HIV Agents/</QualifierName> <QualifierName MajorTopicYN="N" UI="Q000652">, Benzoxazines/adverse effects, Benzoxazines/blood, Benzoxazines/</QualifierName> <QualifierName MajorTopicYN="N" UI="Q000652">, Cytochrome P-450 CYP2A6/genetics, Cytochrome P-450 CYP2A6/metabolism, Cytochrome P-450 CYP2B6/genetics, Cytochrome P-450 CYP2B6/metabolism, Cytochrome P-450 CYP3A/genetics, Cytochrome P-450 CYP3A/metabolism, Genotype, Glucuronides/blood, Glucuronides/cerebrospinal fluid, HIV Infections/diagnosis, HIV Infections/drug therapy, Humans, Hydroxylation, Metabolic Detoxication, Phase I, Metabolic Detoxication, Phase II, Metabolomics/methods, Neurotoxicity Syndromes/etiology, Neurotoxicity Syndromes/genetics, Phenotype, Reverse Transcriptase Inhibitors/adverse effects, Reverse Transcriptase Inhibitors/blood, Reverse Transcriptase Inhibitors/</QualifierName> <QualifierName MajorTopicYN="N" UI="Q000652">, Risk Assessment, Sulfates/blood, Sulfates/cerebrospinal fluid, Tandem Mass Spectrometry
Pubmed
Web of science
Open Access
Yes
Create date
08/01/2016 11:16
Last modification date
20/08/2019 14:59
Usage data