Inhibition of MDR3 Activity in Human Hepatocytes by Drugs Associated with Liver Injury

Chemical Research in Toxicology
Kan HeThomas F Woolf

Abstract

MDR3 dysfunction is associated with liver diseases. We report here a novel MDR3 activity assay involving in situ biosynthesis in primary hepatocytes of deuterium (d9)-labeled PC and LC-MS/MS determination of transported extracellular PC-d9. Several drugs associated with DILI such as chlorpromazine, imipramine, itraconazole, haloperidol, ketoconazole, sequinavir, clotrimazole, ritonavir, and troglitazone inhibit MDR3 activity. MDR3 inhibition may play an important role in drug-induced cholestasis and vanishing bile duct syndrome. Several lines of evidence demonstrate that the reported assay is physiologically relevant and can be used to assess the potential of chemical entities and their metabolites to modulate MDR3 activity and/or PC biosynthesis in hepatocytes.

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Citations

May 22, 2016·Toxicological Sciences : an Official Journal of the Society of Toxicology·Laia TolosaRamiro Jover
Nov 20, 2016·Clinical Pharmacology and Therapeutics·M Mosedale, P B Watkins
Apr 4, 2017·Toxicological Sciences : an Official Journal of the Society of Toxicology·Robert W YuchaMingxiang Liao
Apr 8, 2017·Journal of Pharmaceutical Sciences·Bruno Stieger, Zainab M Mahdi
Jun 12, 2018·Expert Opinion on Drug Metabolism & Toxicology·Petar D PetrovRamiro Jover
Feb 15, 2019·Clinical and Translational Science·Paul B Watkins
Oct 8, 2019·Critical Reviews in Toxicology·Neel DefermPieter Annaert
Dec 19, 2016·Chemical Research in Toxicology·Jinping GanW Griffith Humphreys

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