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Vol. 27, Issue 4, 440-441, April 1999

SHORT COMMUNICATION
Possible Involvement of P-Glycoprotein in Biliary Excretion of CPT-11 in Rats

Xiao-Yan Chu, Yukio Kato, and Yuichi Sugiyama

Graduate School of Pharmaceutical
Sciences,
University of Tokyo,
Bunkyo-ku,
Tokyo, Japan

In our previous work, we found that the biliary excretion of the carboxylate form of irinotecan, CPT-11, on rat bile canalicular membrane consists of two components, the low-affinity one being canalicular multispecific organic anion transporter (cMOAT). In the present study, we have investigated the high-affinity component by studying the uptake in canalicular membrane vesicles. The ATP-dependent uptake of the carboxylate form of CPT-11 was inhibited significantly by several substrates and/or modulators of P-glycoprotein, including PSC-833, verapamil, and cyclosporin A, at a substrate concentration of 5 µM, at which the high-affinity component is involved predominantly in CPT-11 transport. When the concentration of the carboxylate form of CPT-11 was 250 µM, at which the low-affinity component (cMOAT) is involved predominantly in its transport, the inhibitory effect of the above compounds was reduced greatly. Similarly, there was also much lower inhibition of the ATP-dependent uptake of S-(2,4-dinitrophenyl)-glutathione, a substrate of cMOAT, by the above compounds. Taurocholic acid, a substrate of canalicular bile acid transporter, failed to inhibit the uptake of CPT-11 at the substrate concentration of both 5 and 250 µM. These results suggest that P-glycoprotein may act as the high-affinity component in the biliary excretion of the carboxylate form of CPT-11 in rats.

Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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