A Dynamic Mathematical Model of Bile Acid Clearance in HepaRG Cells

Toxicol Sci. 2018 Jan 1;161(1):48-57. doi: 10.1093/toxsci/kfx199.

Abstract

A dynamic model based on ordinary differential equations that describes uptake, basolateral and canalicular export of taurocholic acid (TCA) in human HepaRG cells is presented. The highly reproducible inter-assay experimental data were used to reliably estimate model parameters. Primary human hepatocytes were similarly evaluated to establish a mathematical model, but with notably higher inter-assay differences in TCA clearance and bile canaliculi dynamics. By use of the HepaRG cell line, the simultaneous TCA clearance associated to basolateral uptake, canalicular and sinusoidal efflux, was predicted. The mathematical model accurately reproduced the dose-dependent inhibition of TCA clearance in the presence and absence of the prototypical cholestatic drugs cyclosporine A (CsA) and chlorpromazine. Rapid inhibition of TCA clearance and recovery were found to be major characteristics of CsA. Conversely, the action of chlorpromazine was described by slow onset of inhibition relative to inhibition of TCA clearance by CsA. The established mathematical model, validated by the use of these 2 prototypical cholestatic drugs and the integration of bile canalicular dynamics, provides an important development for the further study of human hepatobiliary function, through simultaneous temporal and vectorial membrane transport of bile acids in drug-induced cholestasis.

Keywords: HepaRG cells; chlorpromazine; cyclosporine A; human hepatocytes; mathematical model; taurocholic acid.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bile Acids and Salts / metabolism*
  • Biological Transport
  • Cell Line
  • Chlorpromazine / metabolism
  • Chlorpromazine / pharmacology
  • Cyclosporine / metabolism
  • Cyclosporine / pharmacology
  • Hepatobiliary Elimination
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism*
  • Humans
  • Kinetics
  • Models, Theoretical*
  • Primary Cell Culture

Substances

  • Bile Acids and Salts
  • Cyclosporine
  • Chlorpromazine