Possible involvement of multiple P-glycoprotein-mediated efflux systems in the transport of verapamil and other organic cations across rat intestine.
OBJECTIVE
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.
Saitoh
H
H
DuPont Merck Pharmaceutical Co., Wilmington, DE 19880-0400, USA.
Aungst
B J
BJ
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D001693:Biological Transport, Active / Q000187:drug effects; D002437:Cefazolin / Q000493:pharmacokinetics; D002746:Chlorpromazine / Q000493:pharmacokinetics / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D007422:Intestines / Q000187:drug effects; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism; D008297:Male; D011413:Propantheline / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013806:Theophylline / Q000493:pharmacokinetics; D014700:Verapamil / Q000493:pharmacokinetics*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001647:Bile Acids and Salts; D011413:Propantheline; D013806:Theophylline; D014700:Verapamil; D002437:Cefazolin; D002746:Chlorpromazine