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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Possible involvement of multiple P-glycoprotein-mediated efflux systems in the transport of verapamil and other organic cations across rat intestine.

PURPOSE. We investigated the intestinal transport of verapamil, chlorpromazine, and propantheline, particularly their P-glycoprotein-mediated secretion. METHODS. Permeation of rat intestinal segments in vitro was determined using diffusion cells. RESULTS. Verapamil permeation in the serosal-to-mucosal direction was much greater than in the mucosal-to-serosal direction using duodenal, jejunal, and colonic membranes. The concentration dependence of jejunal permeation in the absorptive and secretory directions was consistent with saturability of a secretory transport system. Using a monoclonal antibody to inhibit P-glycoprotein-mediated secretion caused a significant enhancement of verapamil absorption through 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 propantheline enhanced the mucosal-to-serosal permeation of verapamil through the jejunum, most likely due to competitive inhibition of the P-glycoprotein-mediated secretory process. Vinblastine, tetraethylammonium, and guanidine did not affect verapamil permeation. Propantheline was also a substrate for P-glycoprotein-mediated secretory transport, but in contrast to verapamil, propantheline secretory transport was expressed in rat ileum. CONCLUSIONS. These results suggest that these cationic compounds are transported by plural P-glycoprotein-mediated efflux systems with different substrate specificities depending on the intestinal site.[1]


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