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Research ArticleArticle

Evidence of Drug-Drug Interactions through Uptake and Efflux Transport Systems in Rat Hepatocytes: Implications for Cellular Concentrations of Competing Drugs

Youssef Daali, Philippe Millet, Pierre Dayer and Catherine M. Pastor
Drug Metabolism and Disposition August 2013, 41 (8) 1548-1556; DOI: https://doi.org/10.1124/dmd.113.051870
Youssef Daali
Service de Pharmacologie et Toxicologie Clinique (Y.D., P.D.), Unité de Neurophysiologie Clinique et Neuroimagerie (P.M.), Laboratoire de Physiopathologie Hépatique et Imagerie Moléculaire, Hôpitaux Universitaires de Genève, Geneva, Switzerland; and INSERM U 773, Département de Radiologie, Hôpital Universitaire de Beaujon, Clichy, France (C.M.P.)
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Philippe Millet
Service de Pharmacologie et Toxicologie Clinique (Y.D., P.D.), Unité de Neurophysiologie Clinique et Neuroimagerie (P.M.), Laboratoire de Physiopathologie Hépatique et Imagerie Moléculaire, Hôpitaux Universitaires de Genève, Geneva, Switzerland; and INSERM U 773, Département de Radiologie, Hôpital Universitaire de Beaujon, Clichy, France (C.M.P.)
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Pierre Dayer
Service de Pharmacologie et Toxicologie Clinique (Y.D., P.D.), Unité de Neurophysiologie Clinique et Neuroimagerie (P.M.), Laboratoire de Physiopathologie Hépatique et Imagerie Moléculaire, Hôpitaux Universitaires de Genève, Geneva, Switzerland; and INSERM U 773, Département de Radiologie, Hôpital Universitaire de Beaujon, Clichy, France (C.M.P.)
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Catherine M. Pastor
Service de Pharmacologie et Toxicologie Clinique (Y.D., P.D.), Unité de Neurophysiologie Clinique et Neuroimagerie (P.M.), Laboratoire de Physiopathologie Hépatique et Imagerie Moléculaire, Hôpitaux Universitaires de Genève, Geneva, Switzerland; and INSERM U 773, Département de Radiologie, Hôpital Universitaire de Beaujon, Clichy, France (C.M.P.)
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Abstract

For drugs with hepatobiliary transport across hepatocytes, the interplay between uptake and efflux transporters determines hepatic concentrations of drugs, but the evolution over time of these concentrations is difficult to measure in humans other than with magnetic resonance imaging contrast agents in the liver. Gadobenate dimeglumine (BOPTA) is a contrast agent used in liver magnetic resonance imaging that enters into human hepatocytes through organic anion transporting polypeptides (OATP) and exits unchanged into bile through the multiple resistance-associated protein 2 (MRP2). Rifampicin (RIF) is transported by the same membrane proteins and may compete with BOPTA for hepatic uptake. Simultaneous drug-drug interactions through uptake and efflux transport systems in hepatocytes according to the cellular concentrations of competing drugs were never investigated. In perfused rat liver preparations, we demonstrate how the drug-drug interactions through transporters determine cellular concentrations of the competing drugs BOPTA and RIF, and we show that the cellular concentrations by modulating transport through membranes regulate the rat Oatp-Mrp2 interplay. Moreover, drug interactions through transporters change greatly over time.

Footnotes

    • Received March 8, 2013.
    • Accepted May 24, 2013.
  • This work was supported by the Fonds National Suisse de la Recherche Scientifique [Grant 310030-126030]; and the Boninchi Foundation of Geneva, Switzerland [Grant ME9117].

  • dx.doi.org/10.1124/dmd.113.051870.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (8)
Drug Metabolism and Disposition
Vol. 41, Issue 8
1 Aug 2013
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Research ArticleArticle

Drug-Drug Interactions within Hepatocytes

Youssef Daali, Philippe Millet, Pierre Dayer and Catherine M. Pastor
Drug Metabolism and Disposition August 1, 2013, 41 (8) 1548-1556; DOI: https://doi.org/10.1124/dmd.113.051870

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Research ArticleArticle

Drug-Drug Interactions within Hepatocytes

Youssef Daali, Philippe Millet, Pierre Dayer and Catherine M. Pastor
Drug Metabolism and Disposition August 1, 2013, 41 (8) 1548-1556; DOI: https://doi.org/10.1124/dmd.113.051870
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