Scientific article
Open access

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

Published inDrug Metabolism and Disposition, vol. 44, no. 1, p. 151-161
Publication date2016

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
Citation (ISO format)
AOURI, Manel et al. In Vivo Profiling and Distribution of Known and Novel Phase I and Phase II Metabolites of Efavirenz in Plasma, Urine, and Cerebrospinal Fluid. In: Drug Metabolism and Disposition, 2016, vol. 44, n° 1, p. 151–161. doi: 10.1124/dmd.115.065839
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Article (Published version)
ISSN of the journal0090-9556

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