Sex differences in hepatic and intestinal contributions to nevirapine biotransformation in rats

P. F. Pinheiro, A. T. Marinho, A. M.M. Antunes, M. M. Marques, S. A. Pereira, J. P. Miranda

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

Abstract

Abstract The understanding of the intestine contribution to drug biotransformation improved significantly in recent years. However, the sources of inter-individual variability in intestinal drug biotransformation, namely sex-differences, are still elusive. Nevirapine (NVP) is an orally taken anti-HIV drug associated with severe idiosyncratic reactions elicited by toxic metabolites, with women at increased risk. As such, NVP is a good model to assess sex-dimorphic metabolism. The aim of this study was to perform a comparative profiling of NVP biotransformation in rat intestine and liver and evaluate whether or not it is organ- and sex-dependent. Therefore, nevirapine-containing solutions were perfused through the intestine, in a specially designed chamber, or incubated with liver slices, from male and female Wistar rats. The levels of NVP and its Phase I metabolites were quantified by HPLC-UV. Liver incubation experiments yielded the metabolites 2-, 3-, 8-, and 12-OH-NVP, being 12-OH-NVP and 2-OH-NVP the major metabolites in males and females, respectively. Inter-sex differences in the metabolic profile were also detected in the intestine perfusion experiments. Herein, the metabolites 3- and 12-OH-NVP were only found in male rats, whereas 2-OH-NVP levels were higher in females, both in extraluminal (p < 0.01) and intraluminal media. The metabolite 8-OH-NVP was not detected in the intraluminal media from either males or females. In this study, important inter-sex differences were detected in both organs, providing further clues to the sex-dimorphic profile of NVP toxicity. Moreover, an extra-hepatic contribution to NVP biotransformation was observed, strengthening the relevance of the intestinal contribution in the biotransformation of orally taken-drugs.

Original languageEnglish
Article number7323
Pages (from-to)115-121
Number of pages7
JournalChemico-Biological Interactions
Volume233
DOIs
Publication statusPublished - 25 May 2015

Keywords

  • Extra-hepatic biotransformation
  • Gastro-intestinal first-pass effect
  • Nevirapine biotransformation
  • Sex differences

Fingerprint

Dive into the research topics of 'Sex differences in hepatic and intestinal contributions to nevirapine biotransformation in rats'. Together they form a unique fingerprint.

Cite this