TY - JOUR T1 - Possible Involvement of P-Glycoprotein in Biliary Excretion of CPT-11 in Rats JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 440 LP - 441 VL - 27 IS - 4 AU - Xiao-Yan Chu AU - Yukio Kato AU - Yuichi Sugiyama Y1 - 1999/04/01 UR - http://dmd.aspetjournals.org/content/27/4/440.abstract N2 - 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. The American Society for Pharmacology and Experimental Therapeutics ER -