A dynamic mathematical model of bile acid clearance in HepaRG cells

Abstract

A dynamic model based on ordinary differential equations that describes uptake, basolateral and canalicular export of taurocholic acid 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 taurocholic acid clearance and bile canaliculi dynamics. By use of the HepaRG cell line, the simultaneous taurocholic acid clearance associated to basolateral uptake, canalicular and sinusoidal efflux, was predicted. The mathematical model accurately reproduced the dose-dependent inhibition of taurocholic acid clearance in the presence and absence of the prototypical cholestatic drugs cyclosporine A and chlorpromazine. Rapid inhibition of taurocholic acid clearance and recovery were found to be major characteristics of cyclosporine A. Conversely, the action of chlorpromazine was described by slow onset of inhibition relative to inhibition of taurocholic acid clearance by cyclosporine A. The established mathematical model, validated by the use of these two 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.