In vitro assessment of sex influence on the intestinal P-glycoprotein activity in rats

BALLENT M.; LIFSCHITZ A.; VIRKEL G.; SALLOVITZ J.; MATÉ L.; LANUSSE C

Rosario

Congreso; XLI Reunión anual de la Asociación Argentina de Farmacología Experimental (SAFE); 2009

Sociedad Argentina de farmacología Experimental

Sex-based differences in P-glycoprotein (P-gp) activity has been suggested. The aim of the present work was to characterize in vitro the sex influence on the intestinal P-gp-mediated transport of drugs using both the everted gut sac and the Ussing chamber technique in the rat. In Experiment 1, intestinal sacs (ileum) of male and female Wistar rats were incubated with ivermectin (IVM) (0.5 µM) either alone or with PSC833 (10 µM) as a P-gp modulator. For Experiment 2, the flat sheets of intestinal mucosa of both sex were mounted into Ussing chambers. Rhodamine 123 (Rho 123) (5 µM) was added to mucosal (M) and serosal (S) sides, either alone or with PSC833 (10 µM). Samples were analyzed by HPLC (IVM) and spectrofluorometer (Rho 123). The intestinal accumulation of IVM and the effective permeability (Peff) of Rho 123 were calculated. A higher accumulation (IVM)/absorption (Rho 123) was observed in female compared to male intestine. At 60 min, the IVM accumulation in the intestinal sacs was 2-fold higher in female than male. The secretion of Rho 123 was 87% higher in male than female. The response to P-gp modulation with PSC833 was higher in male than female suggesting a greater P-gp activity and/or expression in male animals. In conclusion, substantial sex-related differences were observed with both methods. Further works are needed to clarify the mechanisms involved in this phenomenon, which may have a considerable clinical relevance.