Abstract
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.
Footnotes
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Send reprint requests to: Yuichi Sugiyama, Ph.D., Professor and Chair, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan. E-mail: sugiyama{at}seizai.f.u-tokyo.ac.jp
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This study was supported, in part, by a Grant-in-Aid for Scientific Research provided by the Ministry of Education, Science, and Culture of Japan; a grant for Cancer Research from the Ministry of Health and Welfare of Japan; and CREST (Core Research for Evolutional Science and Technology) of Japan Science and Technology Corporation (to J.S.T.).
- Abbreviations used are::
- CPT-11
- 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxy camptothecin
- CMVs
- canalicular membrane vesicles
- P-gp
- P-glycoprotein
- cMOAT
- canalicular multispecific organic anion transporter
- DNP-SG
- S-(2,4-dinitrophenyl) glutathione
- CsA
- cyclosporin A
- Received July 21, 1998.
- Accepted January 18, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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