POSSIBLE INVOLVEMENT OF MULTIPLE P-GLYCOPROTEIN-MEDIATED EFFLUX SYSTEMS IN THE TRANSPORT OF VERAPAMIL AND OTHER ORGANIC CATIONS ACROSS RAT INTESTINE

We investigated the intestinal transport of verapamil, chlorpromazine, and propantheline, particularly their P-glycoprotein-mediated secreti on. Methods, Permeation of rat intestinal segments in vitro was determ ined using diffusion cells. Results. Verapamil permeation in the seros al-to-mucosal direction was much greater than in the mucosal-to-serosa l direction using duodenal,jejunal, and colonic membranes. The concent ration dependence of jejunal permeation in the absorptive and secretor y directions was consistent with saturability of a secretory transport system. Using a monoclonal antibody to inhibit P-glycoprotein-mediate d secretion caused a significant enhancement of verapamil absorption t hrough the jejunum. In contrast, the rat ileum did not preferentially transport verapamil in the secretory direction, and the P-glycoprotein antibody had no effect on ileal absorption. Chlorpromazine and propan theline enhanced the mucosal-to-serosal permeation of verapamil throug h the jejunum, most likely due to competitive inhibition of the P-glyc oprotein-mediated secretory process. Vinblastine, tetraethylammonium, and guanidine did not affect verapamil permeation. Propantheline was a lso a substrate for P-glycoprotein-mediated secretory transport, but i n contrast to verapamil, propantheline secretory transport was express ed in rat ileum. Conclusions. These results suggest that these cationi c compounds are transported by plural P-glycoprotein-mediated efflux s ystems with different substrate specificities depending on the intesti nal site.