title: Sex differences in hepatic and intestinal contributions to nevirapine biotransformation in rats.
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.
authors.affiliation: Research Institute for Medicines (iMed.Ulisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal; Centro de Química Estrutural (CQE), Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal.
authors.forename: P F
authors.initials: PF
authors.lastname: Pinheiro
authors.affiliation: Chronic Diseases Research Center (CEDOC), NOVA Medical School, Universidade Nova, Campo Mártires da Pátria, 130, 1169-056 Lisboa, Portugal.
authors.forename: A T
authors.initials: AT
authors.lastname: Marinho
authors.affiliation: Centro de Química Estrutural (CQE), Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal.
authors.forename: A M M
authors.initials: AM
authors.lastname: Antunes
authors.affiliation: Centro de Química Estrutural (CQE), Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisboa, Portugal.
authors.forename: M M
authors.initials: MM
authors.lastname: Marques
authors.affiliation: Chronic Diseases Research Center (CEDOC), NOVA Medical School, Universidade Nova, Campo Mártires da Pátria, 130, 1169-056 Lisboa, Portugal.
authors.forename: S A
authors.initials: SA
authors.lastname: Pereira
authors.affiliation: Research Institute for Medicines (iMed.Ulisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal. Electronic address: jmiranda@ff.ul.pt.
authors.forename: J P
authors.initials: JP
authors.lastname: Miranda
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000378:metabolism*; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D005260:Female; D007413:Intestinal Mucosa / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D019829:Nevirapine / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012727:Sex Characteristics
chemical_list: D019380:Anti-HIV Agents; D019829:Nevirapine
keywords: Extra-hepatic biotransformation; Gastro-intestinal first-pass effect; Nevirapine biotransformation; Sex differences