Prediction and Evaluation of Hepatic Bile Acid Transporter-Mediated Drug Interactions Using In Vitro Tools and Pharmacokinetic Modeling Public Deposited

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  • March 19, 2019
Creator
  • Guo, Cen
    • Affiliation: Eshelman School of Pharmacy, Pharmaceutical Sciences Program
Abstract
  • The objective of this doctoral dissertation research was to develop novel strategies to predict and evaluate drug interactions with hepatic bile acid transporters. Sandwich-cultured hepatocytes (SCH) and mechanistic pharmacokinetic modeling were employed. Altered disposition of the model bile acid taurocholate (TCA) in human SCH due to inhibition of multiple transporters was predicted based on the potency of inhibitors [e.g., inhibition constant (Ki)] and kinetic parameters of TCA using pharmacokinetic modeling. The accuracy of predictions using total and unbound inhibitor concentrations was assessed. The effect of bosentan and telmisartan (model inhibitors) was predicted adequately by using intracellular unbound concentrations of the inhibitors. In subsequent studies, a simulation-based method was proposed to determine the relevant inhibitor concentration when predicting the effect of hepatic efflux transporter inhibition. For inhibitors with high plasma protein binding and/or high relative inhibition potency, using intracellular unbound rather than total inhibitor concentrations was optimal. The utility of this method was evaluated using experimental data from human SCH. To circumvent the limitations of individual transporter Ki data, a model-based approach was proposed to obtain overall Ki values against each efflux clearance pathway (i.e., biliary and basolateral efflux clearance) of TCA in rat SCH. The study design was optimized using modeling and simulation to estimate Ki values of troglitazone sulfate (the model inhibitor). Using this study design, Ki estimation in different hepatocyte lots, and limitations on the accuracy, were evaluated using simulated data. In addition to inhibition, transporter induction by Farnesoid X Receptor agonists was investigated in human SCH. Basolateral efflux and biliary clearance values for TCA, determined by pharmacokinetic modeling, were significantly increased by the Farnesoid X Receptor agonists, obeticholic acid and chenodeoxycholic acid. These studies provided direct functional evidence for transporter induction. Immunoblot analysis results suggested that organic solute transporter alpha/beta may be the primary transporter responsible for the increase in the basolateral efflux clearance of TCA. This research leveraged pharmacokinetic modeling and simulation to integrate and interpret in vitro bile acid transport data. The approaches developed and the results detailed in this dissertation will improve the accuracy of predictions and mechanistic understanding of drug-bile acid interactions.
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Advisor
  • Cao, Yanguang
  • Gonzalez, Daniel
  • Barton, Hugh
  • Watkins, Paul
  • Brouwer, Kim L. R.
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2018
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