Gender-related differences on P-glycoprotein-mediated drug intestinal transport in rats

Abstract

Evidence of sex-related differences on drug pharmacokinetics and pharmacodynamics are markedly increasing. The aim of this study was to characterize the influence of gender on P-glycoprotein (P-gp)-mediated drug intestinal transport using two ex-vivo methodological approaches. To study the comparative tissue uptake of ivermectin, intestinal sacs (distal jejunum/ileum) of male and female Wistar rats were incubated with ivermectin (0.5 µm) (a P-gp substrate) in the presence or absence of PSC833 (10 µm) (a P-gp inhibitor). Additionally, sex-based differences in the bidirectional transport of Rhodamine 123 (Rho 123; 5 µm) incubated either alone or with PSC833 (10 µm) were examined in diffusion chambers. The ivermectin accumulation in the everted gut sacs was higher in female compared with male intestine. The presence of PSC833 increased ivermectin accumulation profiles both in male and female rats. However, a greater response to transport modulation was observed in male compared with female animals. Similar results were obtained for Rho 123, where a higher absorption was measured in the intestine of females. PSC833 decreased Rho 123 intestinal secretion in animals of both sexes with a greater inhibition in male. Substantial sex-related differences were observed on the ivermectin and Rho 123 active intestinal transport. Likewise, the PSC833-mediated modulation had a differential impact between male and female animals. Further work is needed to clarify the mechanisms underlying this phenomenon, which may have considerable pharmacological and clinical relevance.