Hepatic Transporter Function in Liver Disease: Impact on Hepatobiliary Disposition and Pharmacokinetics Public Deposited

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  • March 21, 2019
  • Slizgi, Jason
    • Affiliation: Eshelman School of Pharmacy, Division of Pharmacotherapy and Experimental Therapeutics
  • The objective of this doctoral dissertation research was to understand how hepatic transporter function in liver disease affects hepatobiliary disposition and pharmacokinetics of endogenous and exogenous compounds. In particular, this dissertation focused on two forms of liver disease: non-alcoholic steatohepatitis (NASH) and autosomal dominant polycystic kidney disease (ADPKD). A multi-experimental, translational approach including transporter over-expressing membrane vesicles, sandwich-cultured human hepatocytes, isolated perfused rat livers, metabolomic profiling, imaging, and an in vivo study in humans was employed. Based on reported changes in in vitro expression of organic anion transporting polypeptide (OATP), multidrug resistance-associated protein (MRP) 2 and MRP3 in liver tissue from patients with NASH, we tested the hypothesis that the disposition of 99mTechnetium-mebrofenin (MEB), and OATP, MRP2, and MRP3 probe, was altered in this patient population. Systemic and hepatic concentrations of MEB were increased in patients with NASH compared to age- and sex-matched healthy volunteers, consistent with impaired uptake and biliary excretion, and enhanced basolateral efflux of MEB. Tolvaptan and two metabolites, DM-4103 and DM-4107, were shown to be inhibitors of the major human hepatic bile acid transporters Na+-taurocholate cotransporting polypeptide (NTCP), bile salt export pump (BSEP), and MRP2, MRP3, and MRP4, which may contribute to tolvaptan-associated liver injury in patients with ADPKD. Although impaired bile acid transport by tolvaptan and/or its metabolites may negatively impact bile acid homeostasis, the fact that liver injury has been observed only in patients with ADPKD suggests that other mechanism(s) and/or patient susceptibility factors may contribute to drug-induced liver injury (DILI) in this patient population. Metabolomic profiling of bile acids in polycystic kidney (PCK) rats, a rodent model of human ADPKD, revealed significantly increased concentrations of total bile acids and bile acids associated with hepatotoxicity in the serum and liver when compared to wild-type rats. Total serum bile acids positively correlated with measures of liver impairment (i.e. liver weight, total liver bile acids, total liver bile acids associated with hepatotoxic, and cystic volume) suggesting that serum bile acids may be useful biomarkers for liver impairment in ADPKD. Increased bile acids concentrations in the liver due to ADPKD, independent of tolvaptan therapy, suggests that it is plausible that this patient population may be susceptible bile acid-mediated hepatotoxicity. Further mechanistic studies revealed, for the first time, decreased biliary excretion of 5(6)-carboxy-2’,7’-dichlorofluorescein (CDF), a fluorescent Oatp, Mrp2, and Mrp3 probe, in PCK rats using the isolated perfused rat liver model. In total, these data suggest that drug- and disease-specific factors may play a role in the potential for bile acid-mediated hepatotoxicity associated with tolvaptan use in patients with ADPKD. This research has resulted in novel contributions that provide important insight into the impact of liver disease on hepatic transporter function. This information will significantly enhance our ability to understand and predict altered hepatic transporter function, which will improve the safety and effectiveness of drugs.
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  • In Copyright
  • Brock, William
  • Brouwer, Kim L. R.
  • Barritt, A. Sidney
  • Dupuis, Robert
  • Thakker, Dhiren
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2017

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