Relative contribution of absorptive and secretory transporters to the intestinal absorption of fexofenadine in rats

It has been shown that fexofenadine, a selective non-sedating histamine H1-receptor antagonist, is a substrate for P-glycoprotein (P-gp) and an organic anion transporting peptide (OATP). This study was undertaken to investigate the relative contribution of these absorptive and secretory transporters to the intestinal absorption of fexofenadine in rats. When 0.1 mM fexofenadine was introduced into duodenal, jejunal, and ileal loops, its disappearance was around 10% over 30 min. Cyclosporine A, but not ketoconazole, probenecid or mitoxantron, significantly increased fexofenadine disappearance in the ileal loops. The serosal-to-mucosal permeation of fexofenadine across the rat ileal segments was approximately 18-fold greater than its mucosal-to-serosal permeation. The secretory orientation of the ileal permeation of fexofenadine was weakened significantly in the presence of cyclosporine A, moderately in the presence of ketoconazole, but was unchanged in the presence of probenecid. When fexofenadine (0.1 or 0.5 mM) was administered to rats intraluminally, plasma concentrations increased linearly up to 120 min. The magnitude of the increase in plasma fexofenadine concentrations in the presence of cyclosporine A was more remarkable at 0.5 mM than at 0.1 mM. The results obtained in this study suggest that the intestinal absorption of fexofenadine is relatively small in rats even if OATP functions as an absorptive transporter for fexofenadine. Low absorption of fexofenadine in rats is attributed to potent secretory transport mediated by P-gp.