Skip to Main content Skip to Navigation
Journal articles

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 (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.
Document type :
Journal articles
Complete list of metadatas

Cited literature [29 references]  Display  Hide  Download

https://hal-univ-rennes1.archives-ouvertes.fr/hal-01696669
Contributor : Laurent Jonchère <>
Submitted on : Wednesday, January 31, 2018 - 3:10:38 PM
Last modification on : Wednesday, May 16, 2018 - 11:23:31 AM
Long-term archiving on: : Saturday, May 26, 2018 - 12:09:17 AM

File

Sharanek - A dynamic mathemati...
Files produced by the author(s)

Identifiers

Citation

D. Kaschek, A. Sharanek, A. Guillouzo, J. Timmer, R.J. Weaver. A dynamic mathematical model of bile acid clearance in HepaRG cells. Toxicological Sciences, Oxford University Press (OUP), 2018, 161 (1), pp.48-57. ⟨10.1093/toxsci/kfx199⟩. ⟨hal-01696669⟩

Share

Metrics

Record views

261

Files downloads

249