Inhibition of rhodamine 123 secretion by cyclosporin A as a model of P-glycoprotein mediated transport in liver

Anticancer Res. Mar-Apr 1994;14(2A):581-5.

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

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Affinity Labels
  • Animals
  • Antimetabolites, Antineoplastic / metabolism*
  • Azides / metabolism
  • Bile / drug effects
  • Bile / metabolism
  • Blotting, Western
  • Carrier Proteins / analysis
  • Carrier Proteins / isolation & purification
  • Carrier Proteins / metabolism*
  • Cyclosporine / pharmacology*
  • Dihydropyridines / metabolism
  • Drug Resistance*
  • In Vitro Techniques
  • Kinetics
  • Liver / drug effects
  • Liver / metabolism*
  • Male
  • Membrane Glycoproteins / analysis
  • Membrane Glycoproteins / isolation & purification
  • Membrane Glycoproteins / metabolism*
  • Perfusion
  • Rats
  • Rats, Inbred Strains
  • Rats, Mutant Strains
  • Rhodamine 123
  • Rhodamines / metabolism*
  • Rhodamines / pharmacology
  • Time Factors
  • Verapamil / pharmacology

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Affinity Labels
  • Antimetabolites, Antineoplastic
  • Azides
  • Carrier Proteins
  • Dihydropyridines
  • Membrane Glycoproteins
  • Rhodamines
  • Rhodamine 123
  • azidopine
  • Cyclosporine
  • Verapamil