TY - JOUR
T1 - Sex differences in hepatic and intestinal contributions to nevirapine biotransformation in rats
AU - Pinheiro, P. F.
AU - Marinho, A. T.
AU - Antunes, A. M.M.
AU - Marques, M. M.
AU - Pereira, S. A.
AU - Miranda, J. P.
N1 - Funding Information:
This work was supported by Fundação para a Ciência e a Tecnologia ( FCT , Portugal), through research Grants (PTDC/QUI-QUI/113910/2009, EXPL/DTP-FTO/0204/2012, RECI/QEQ-MED/0330/2012, SFRH/BD/92191/2013 to ATM, and Ciencia2008 to JPM) and strategic funding to iMed.ULisboa (Pest-OE/SAU/UI4013/2011) and to Centro de Química Estrutural (PEst-OE/QUI/UI0100/2013, UID/QUI/00100/2013).
Publisher Copyright:
© 2015 Elsevier Ireland Ltd. All rights reserved.
PY - 2015/5/25
Y1 - 2015/5/25
N2 - 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.
AB - 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.
KW - Extra-hepatic biotransformation
KW - Gastro-intestinal first-pass effect
KW - Nevirapine biotransformation
KW - Sex differences
UR - http://www.scopus.com/inward/record.url?scp=84926657811&partnerID=8YFLogxK
U2 - 10.1016/j.cbi.2015.03.024
DO - 10.1016/j.cbi.2015.03.024
M3 - Article
C2 - 25818046
AN - SCOPUS:84926657811
SN - 0009-2797
VL - 233
SP - 115
EP - 121
JO - Chemico-Biological Interactions
JF - Chemico-Biological Interactions
M1 - 7323
ER -