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Research ArticleArticle

Hepatocyte Concentrations of Imaging Compounds Associated with Transporter Inhibition: Evidence in Perfused Rat Livers

Pierre Bonnaventure, Fabien Cusin and Catherine M. Pastor
Drug Metabolism and Disposition April 2019, 47 (4) 412-418; DOI: https://doi.org/10.1124/dmd.118.084624
Pierre Bonnaventure
Department of Radiology, Hôpitaux Universitaires de Genève, Geneva, Switzerland (P.B., F.C., C.M.P.); and Laboratory of Imaging Biomarkers, Centre of Research on Inflammation, Unité Mixte de Recherche 1149, Institut National de la santé et de la Recherche Médicale and University Paris Diderot, Paris, France (C.M.P.)
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Fabien Cusin
Department of Radiology, Hôpitaux Universitaires de Genève, Geneva, Switzerland (P.B., F.C., C.M.P.); and Laboratory of Imaging Biomarkers, Centre of Research on Inflammation, Unité Mixte de Recherche 1149, Institut National de la santé et de la Recherche Médicale and University Paris Diderot, Paris, France (C.M.P.)
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Catherine M. Pastor
Department of Radiology, Hôpitaux Universitaires de Genève, Geneva, Switzerland (P.B., F.C., C.M.P.); and Laboratory of Imaging Biomarkers, Centre of Research on Inflammation, Unité Mixte de Recherche 1149, Institut National de la santé et de la Recherche Médicale and University Paris Diderot, Paris, France (C.M.P.)
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Abstract

In the liver, several approaches are used to investigate and predict the complex issue of drug-induced transporter inhibition. These approaches include in vitro assays and pharmacokinetic models that predict how inhibitors modify the systemic and liver concentrations of the victim drugs. Imaging is another approach that shows how inhibitors might alter liver concentrations stronger than systemic concentrations. In perfused rat livers associated with a gamma counter that measures liver concentrations continuously, we previously showed how fluxes across transporters generate the hepatocyte concentrations of two clinical imaging compounds, one with a low extraction ratio [gadobenate dimeglumine (BOPTA)] and one with a high extraction ratio [mebrofenin (MEB)]. BOPTA and MEB are transported by rat organic anion transporting polypeptide and multiple resistance-associated protein 2, which are both inhibited by rifampicin. The aim of the study is to measure how rifampicin modifies the hepatocyte concentrations and membrane clearances of BOPTA and MEB and to determine whether these compounds might be used to investigate transporter-mediated drug-drug interactions in clinical studies. We show that rifampicin coperfusion greatly decreases BOPTA hepatocyte concentrations, but increases those of MEB. Rifampicin strongly decreases BOPTA hepatic clearance. In contrast, rifampicin decreases moderately MEB hepatic clearance and blocks the biliary intrinsic clearance, increasing MEB hepatocyte concentrations. In conclusion, low concentrations prevent the quantification of BOPTA biliary intrinsic clearance, while MEB is a promising imaging probe substrate to evidence transporter-mediated drug-drug interactions when inhibitors act on influx and efflux transporters.

Footnotes

    • Received September 21, 2018.
    • Accepted January 18, 2019.
  • This work was supported by the Swiss National Foundation [Grant 126030].

  • https://doi.org/10.1124/dmd.118.084624.

  • Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 47 (4)
Drug Metabolism and Disposition
Vol. 47, Issue 4
1 Apr 2019
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Research ArticleArticle

Drug Hepatocyte Concentrations and Transporter Inhibition

Pierre Bonnaventure, Fabien Cusin and Catherine M. Pastor
Drug Metabolism and Disposition April 1, 2019, 47 (4) 412-418; DOI: https://doi.org/10.1124/dmd.118.084624

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Research ArticleArticle

Drug Hepatocyte Concentrations and Transporter Inhibition

Pierre Bonnaventure, Fabien Cusin and Catherine M. Pastor
Drug Metabolism and Disposition April 1, 2019, 47 (4) 412-418; DOI: https://doi.org/10.1124/dmd.118.084624
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