Mechanisms of drug-induced liver injury: the role of hepatic transport proteins Public Deposited

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  • March 20, 2019
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  • Yang, Kyunghee
    • Affiliation: Eshelman School of Pharmacy
Abstract
  • The objectives of this research were to investigate mechanisms of drug-induced liver injury (DILI) that involve drug-bile acid (BA) interactions at hepatic transporters, and develop a novel strategy to reliably predict human DILI. Troglitazone (TGZ), an antidiabetic withdrawn from the market due to severe DILI, was employed as a model hepatotoxic drug. Pharmacokinetic modeling of taurocholic acid (TCA, a model BA) disposition data from human and rat sandwich-cultured hepatocytes (SCH) revealed that species differences exist in TCA hepatocellular efflux pathways; in human SCH, TCA biliary excretion predominated, whereas biliary and basolateral excretion contributed equally to TCA efflux in rat SCH. This finding explains, in part, why rats are less susceptible to DILI compared to humans after administration of drugs that inhibit BA biliary excretion. The present study also revealed for the first time that TGZ sulfate (TS), a major TGZ metabolite, inhibits BA basolateral efflux in addition to biliary excretion. These findings support the hypothesis that TS is an important mediator of altered hepatic BA disposition; increased hepatic TS exposure due to impaired canalicular transport function might predispose a subset of patients to hepatotoxicity. A novel in vitro model system, rat SCH lacking selected canalicular transporters [breast cancer resistance protein (Bcrp) and multidrug resistance-associated protein 2 (Mrp2)] was established to test this hypothesis; biliary excretion of hepatically-generated TS was not significantly altered, suggesting that alternate transporters can excrete TS into bile, and loss of Bcrp and/or Mrp2 function would not necessarily be risk factors for increased hepatocellular TS accumulation in rats. To translate experimental data to in vivo humans, a mechanistic model that incorporated TGZ/TS disposition, BA physiology/pathophysiology, hepatocyte life cycle, and liver injury biomarkers was developed; intracellular BA concentrations and toxicity measured in SCH were used to link BA homeostasis and hepatotoxicity. This mechanistic model adequately predicted the incidence, delayed presentation, and species differences in TGZ hepatotoxicity. This dissertation research revealed a number of important and novel findings that improve our understanding about mechanisms underlying BA-mediated DILI, and establish a framework to integrate biological information and experimental data to evaluate DILI mechanisms and predict hepatotoxic potential of chemical entities.
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  • In Copyright
Advisor
  • Brouwer, Kim L. R.
Degree
  • Doctor of Philosophy
Graduation year
  • 2014
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