Abstract
PSC 833, a nonimmunosuppressive cyclosporin, is a potent inhibitor of the efflux of antitumor drugs mediated by P-glycoprotein and thus has been introduced in clinical trials as an agent to overcome multidrug resistance. The purpose of this study was to evaluate the dose-dependent pharmacokinetics of PSC 833 and its effects on the biliary excretion of endogenous substrates in rats. The major elimination route for PSC 833 is metabolism, followed by excretion into bile. The biliary clearance of PSC 833 was reduced in a dose-dependent manner, whereas no urinary excretion of PSC 833 was detectable. The tissue/blood concentration ratios for PSC 833 in the liver, kidney, intestine, and spleen were reduced in a dose-dependent manner, suggesting the presence of a saturable uptake process and/or saturable binding in these tissues. The dose-dependent increase in the tissue/blood concentration ratio in the brain suggests the presence of efflux transporters on the blood-brain barrier. PSC 833 reduced the bile flow rate by decreasing the biliary excretion of bile acids and reduced and oxidized glutathione, in a dose-dependent manner. The mechanism for the dose-dependent disposition of PSC 833 and its effects on the biliary excretion of endogenous substrates could be related to interactions with transporters.
Footnotes
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Send reprint requests to: Dr. Yuichi Sugiyama, Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7–3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
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This work was supported in part by a grant-in-aid from the Ministry of Education, Science, Sports, and Culture of Japan and by the Core Research for Evolutional Sciences and Technology of Japan Science and Technology Corp.
- Abbreviations used are::
- CsA
- cyclosporin A
- MDR
- multidrug resistance
- P-gp
- P-glycoprotein
- P450
- cytochrome P450
- cMOAT
- canalicular multispecific organic anion transporter
- Kp
- tissue/blood concentration ratio
- GSH
- reduced glutathione
- GSSG
- oxidized glutathione
- CMV
- canalicular membrane vesicles
- Received January 30, 1998.
- Accepted July 2, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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