Sex differences in hepatic and intestinal contributions to nevirapine biotransformation in rats. (25th May 2015)

• Record Type: Journal Article
• Authors: Pinheiro, P.F.; Marinho, A.T.; Antunes, A.M.M.; Marques, M.M.; Pereira, S.A.; Miranda, J.P.
• Is Part Of: Chemico-biological interactions. Volume 233(2015)
• Page Start: 115
• Page End: 121
• Publication Date: 2015-05-25
• Subjects: 2-OH-NVP 2-hydroxy-nevirapine -- 3-OH-NVP 3-hydroxy-nevirapine -- 8-OH-NVP 8-hydroxy-nevirapine -- 12-OH-NVP 12-hydroxy-nevirapine -- cART combined antiretroviral therapy -- CYP cytochrome P450 -- EGTA ethylene glycol tetraacetic acid -- Ex-Lum extraluminal -- GI gastrointestinal -- HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid -- HPLC-UV high-performance liquid chromatography with ultra-violet detection -- I-Lum intraluminal -- I.S. internal standard -- MeOH methanol -- NNRTI non-nucleoside reverse transcriptase inhibitor -- NVP nevirapine -- PBS phosphate buffered saline -- SULT sulfotransferase; Nevirapine biotransformation -- Sex differences -- Gastro-intestinal first-pass effect -- Extra-hepatic biotransformation; Biochemistry -- Periodicals; Toxicological chemistry -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biochimie -- Périodiques; Toxicologie biochimique -- Périodiques; 572
• DOI: 10.1016/j.cbi.2015.03.024
• Languages: English
• ISSNs: 0009-2797

Abstract

Highlights: There is a relevant extra-hepatic contribution to nevirapine (NVP) biotransformation. Inter-sex differences contribute to the variability in biotransformation of NVP. The major hepatic Phase I metabolite is 12-OH-NVP in males and 2-OH-NVP in females. 3- and 12-OH-NVP were found only in male intestinal perfusion solutions. 2-OH-NVP levels were higher in females, both in extraluminal and intraluminal media. 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.