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There is a growing body of evidence which suggests that formerly regarded “inert” pharmaceutical excipients have the potential to influence oral drug bioavailability. The solubilizing agent polyethylene glycol 400 (PEG 400), for instance, has a sex-specific effect on P-glycoprotein (P-gp)-mediated drug bioavailability. We hypothesized that such an effect could be via PEG-induced alteration of P-gp activity and/or expression to different extents in males and females. To test this hypothesis in vivo, we investigated the influence of orally administered PEG 400 on the protein content and mRNA expression of P-gp in different regions of the gastrointestinal tract in male and female rats. Fasted rats received an oral dose of PEG 400 and at different time intervals, rats were sacrificed and their intestines were collected. The P-gp protein and mRNA expression in different intestinal segments (duodenum, jejunum, ileum and colon) were measured by Western blotting and PCR, respectively. It was found that P-gp protein and mRNA levels increased along the gastrointestinal tract in control animals (i.e. without PEG administration), and was higher in males compared to the female rats. The oral administration of PEG 400 decreased the P-gp expression in the jejunum, ileum and colon of males but not in the corresponding segments in females. This sex-dependent influence of PEG 400 on P-gp levels reflects and explains the sex-related effect of PEG 400 on oral absorption of certain drugs. The data further adds to the growing literature on the importance of taking into consideration an individual's sex for optimal drug administration.