It is known that males and females respond differently to medicines and that differences\nin drug behaviour are due to inter-individual variability and sex specificity. In this work, we have\nexamined the influence of pharmaceutical excipients on drug bioavailability in males and females.\nUsing a rat model, we report that a portfolio of polyoxyethylated solubilising excipients (polyethylene\nglycol 2000, Cremophor RH 40, Poloxamer 188 and Tween 80) increase ranitidine bioavailability in\nmales but not in females. The in vivo sex and excipient effects were reflected in vitro in intestinal\npermeability experiments using an Ussing chamber system. The mechanism of such an effect\non drug bioavailability is suggested to be due to the interaction between the excipients and\nthe efflux membrane transporter P-glycoprotein (P-gp), whose expression in terms of gene and\nprotein levels were inhibited by the solubilising agents in male but not in female rats. In contrast,\nthe non-polyoxyethylated excipient, Span 20, significantly increased ranitidine bioavailability in both\nmales and females in a non-sex-dependent manner. These findings have significant implications for\nthe use of polyoxyethylated solubilising excipients in drug formulation in light of their sex-specific\nmodulation on the bioavailability of drugs that are P-gp substrates. As such, pharmaceutical research\nis required to retract from a â??one size fits allâ?? approach and to, instead, evaluate the potential impact\nof the interplay between excipients and sex on drug effect to ensure effective pharmacotherapy.
Loading....