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Evidence for a non-MDR1 component in digoxin secretion by human intestinal Caco-2 epithelial layers

Lookup NU author(s): Professor Nicholas Simmons

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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. © 2002 Elsevier Science B.V. All rights reserved.


Publication metadata

Author(s): Lowes S, Cavet ME, Simmons NL

Publication type: Article

Publication status: Published

Journal: European Journal of Pharmacology

Year: 2003

Volume: 458

Issue: 1-2

Pages: 49-56

ISSN (print): 0014-2999

ISSN (electronic): 1879-0712

Publisher: Elsevier

URL: http://dx.doi.org/10.1016/S0014-2999(02)02764-4

DOI: 10.1016/S0014-2999(02)02764-4

PubMed id: 12498906


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