title: Evidence for a non-MDR1 component in digoxin secretion by human intestinal Caco-2 epithelial layers.
abstract: Caco-2 epithelial layers were used as a model to re-evaluate the mechanism(s) by which intestinal digoxin absorption is limited by its active secretion back into the lumen. It is widely recognised that intestinal secretion of digoxin is mediated by the ATP-binding cassette (ABC) transporter Multidrug Resistance 1, MDR1. In MDR1-transfected Madin-Darby canine kidney, MDCKII, cell monolayers, digoxin secretion was reduced by the MDR1 inhibitor cyclosporin A, whereas no inhibition was seen in the presence of MK-571, 3-([(3-(2-[7-chloro-2-quinolinyl]ethyl)phenyl]-[(3-dimethylamino-3-oxoprphyl)-thio)-methyl]-thio) propanoic acid, a Multidrug Related Protein (MRP) inhibitor. In contrast, digoxin secretion by Caco-2 epithelia was significantly inhibited by both cyclosporin A and MK-571, suggesting that an additional non-MDR1 component may contribute to this transport. Since digoxin secretion by MRP2-transfected MDCKII monolayers was increased by only 1.2-fold relative to controls, it is likely that the contribution of MRP2 to digoxin secretion by Caco-2 cells is negligible. An additional MK-571-sensitive secretory pathway for digoxin, together with MDR1, is likely to mediate digoxin secretion in Caco-2 epithelia.
authors.affiliation: Department of Physiological Sciences, University of Newcastle upon Tyne, Medical School, NE2 4HH, Newcastle upon Tyne, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Lowes
authors.forename: Megan E
authors.initials: ME
authors.lastname: Cavet
authors.forename: Nicholas L
authors.initials: NL
authors.lastname: Simmons
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D018938:Caco-2 Cells / Q000187:drug effects* / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D004077:Digoxin / Q000378:metabolism* / Q000493:pharmacokinetics; D006801:Humans; D007700:Kinetics; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000502:physiology; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D014162:Transfection; D014747:Vinblastine / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000911:Antibodies, Monoclonal; D016572:Cyclosporine; D004077:Digoxin; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011422:Propionates; D011804:Quinolines; D014747:Vinblastine; C000715087:ABCC2 protein, human; C059141:verlukast