Bile canalicular cationic dye secretion as a model for P-glycoprotein mediated transport

Eur J Pharmacol. 1994 Apr 4;270(2-3):213-20. doi: 10.1016/0926-6917(94)90065-5.


This study explores properties of P-glycoprotein dependent membrane transport in rat liver with the use of acridine orange as the substrate. We studied the biliary secretion of the dye, its binding to canalicular membrane P-glycoprotein, and effects of the inhibitor cyclosporin A: acridine orange is excreted into bile together with less hydrophobic and glucuronidated metabolites. Cyclosporin A inhibited both the secretion of acridine orange and of its metabolites. In TR- animals, a rat strain that is deficient of the canalicular multi-specific organic anion transport system, non-metabolized acridine orange is the predominant species in bile and its secretion is also inhibited by cyclosporin A. Binding of acridine orange to liver P-glycoprotein was analyzed by photoaffinity labeling with azidopine, a substrate of P-glycoprotein dependent transport in multi-drug resistant tumor cells. Labeling of the immunoprecipitated P-glycoprotein was inhibited by acridine orange, verapamil, and by cyclosporin A. The results show that biliary secretion of acridine orange is highly analogous to P-glycoprotein mediated membrane drug transport in tumor cells that exhibit multi-drug resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Acridine Orange / pharmacokinetics*
  • Affinity Labels
  • Animals
  • Azides / pharmacokinetics
  • Bile Canaliculi / metabolism*
  • Blotting, Western
  • Carrier Proteins / metabolism*
  • Cell Membrane / metabolism
  • Cyclosporine / pharmacology
  • Dihydropyridines / pharmacokinetics
  • In Vitro Techniques
  • Liver / metabolism
  • Male
  • Membrane Glycoproteins / metabolism*
  • Models, Biological
  • Perfusion
  • Precipitin Tests
  • Rats
  • Rats, Inbred Strains
  • Verapamil / pharmacology


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Affinity Labels
  • Azides
  • Carrier Proteins
  • Dihydropyridines
  • Membrane Glycoproteins
  • azidopine
  • Cyclosporine
  • Verapamil
  • Acridine Orange