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Possible Involvement of Multiple P-Glycoprotein-Mediated Efflux Systems in the Transport of Verapamil and Other Organic Cations Across Rat Intestine

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Abstract

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.

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  1. Hiroshi Saitoh

    Present address: Department of Pharmacy, Hokkaido University, Kita-14-jo, Nishi-5-chome, Kita-ku, Sapporo, 060, Japan

Authors and Affiliations

  1. Research and Development, The DuPont Merck Pharmaceutical Co.,, P.O. Box 80400, 19880-0400, Wilmington, DE

    Hiroshi Saitoh & Bruce J. Aungst

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  1. Hiroshi Saitoh
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Saitoh, H., Aungst, B.J. Possible Involvement of Multiple P-Glycoprotein-Mediated Efflux Systems in the Transport of Verapamil and Other Organic Cations Across Rat Intestine. Pharm Res 12, 1304–1310 (1995). https://doi.org/10.1023/A:1016217505990

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