Abstract
The interaction between P-glycoprotein modulators and P-glycoprotein mediated transport was investigated using rhodamine 123 in the isolated perfused rat liver of a mutant (TR-) rat strain. TR- rats, deficient in the canalicular multispecific anion transport system, are unable to extrude organic anions (glucuronides) and therefore excrete solely unconjugated rhodamine 123 via P-glycoprotein. Cyclosporin A, a modulator of multidrug resistance in tumor cells, inhibited the biliary secretion of rhodamine 123 dose dependently in a non-competitive manner. Both cyclosporin A and rhodamine inhibited photoaffinity labeling of immunoprecipitated P-glycoprotein with azidopine, indicating binding to hepatic P-glycoprotein. Our results indicate that monitoring the biliary rhodamine 123 secretion in the isolated perfused liver of TR- rats offers a new system for testing modulators of P-glycoprotein like cyclosporin A.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Affinity Labels
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Animals
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Antimetabolites, Antineoplastic / metabolism*
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Azides / metabolism
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Bile / drug effects
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Bile / metabolism
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Blotting, Western
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Carrier Proteins / analysis
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Carrier Proteins / isolation & purification
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Carrier Proteins / metabolism*
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Cyclosporine / pharmacology*
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Dihydropyridines / metabolism
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Drug Resistance*
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In Vitro Techniques
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Kinetics
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Liver / drug effects
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Liver / metabolism*
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Male
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Membrane Glycoproteins / analysis
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Membrane Glycoproteins / isolation & purification
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Membrane Glycoproteins / metabolism*
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Perfusion
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Rats
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Rats, Inbred Strains
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Rats, Mutant Strains
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Rhodamine 123
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Rhodamines / metabolism*
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Rhodamines / pharmacology
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Time Factors
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Verapamil / pharmacology
Substances
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ATP Binding Cassette Transporter, Subfamily B, Member 1
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Affinity Labels
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Antimetabolites, Antineoplastic
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Azides
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Carrier Proteins
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Dihydropyridines
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Membrane Glycoproteins
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Rhodamines
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Rhodamine 123
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azidopine
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Cyclosporine
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Verapamil