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Front. Physiol. | doi: 10.3389/fphys.2019.01192

A physiology-based model of human bile acid metabolism for predicting bile acid tissue levels after drug administration in healthy subjects and BRIC type 2 patients

 Vanessa Baier1, 2, Henrik Cordes1, Christoph Thiel1,  José V. Castell3,  Ulf P. Neumann4,  Lars M. Blank1 and Lars Kuepfer1*
  • 1Institute of Applied Microbiology (iAMB), Aachen Biology and Biotechnology (ABBt), RWTH Aachen University, Germany
  • 2Department of Plastic Surgery, Hand and Burn Surgery, University Hospital RWTH Aachen, Germany
  • 3Unidad de Hepatología Experimental, Health Research Institute Hospital La Fe, Spain
  • 4Department of Surgery, University Hospital RWTH Aachen, Germany

Drug-induced liver injury (DILI) is a matter of concern in the course of drug development and patient safety, often leading to discontinuation of drug-development programs or early withdrawal of drugs from market. Hepatocellular toxicity or impairment of bile acid (BA) metabolism, known as cholestasis, are the two clinical forms of DILI. Whole-body physiology-based modelling allows a mechanistic investigation of the physiological processes leading to cholestasis in man. Objectives of the present study were: 1) the development of a physiology-based model of the human BA metabolism, 2) population-based model validation and characterisation, and 3) the prediction and quantification of altered BA levels in special genotype subgroups and after drug administration. The developed physiology-based bile acid (PBBA) model describes the systemic BA circulation in humans and includes mechanistically relevant active and passive processes such as the hepatic synthesis, gallbladder emptying, transition through the gastrointestinal tract, reabsorption into the liver, distribution within the whole body, and excretion via urine and faeces. The kinetics of active processes were determined for the exemplary BA glycochenodeoxycholic acid based on blood plasma concentration-time profiles. The robustness of our PBBA model was verified with population simulations of healthy individuals. In addition to plasma levels, the possibility to estimate BA concentrations in relevant tissues like the intracellular space of the liver enhance the mechanistic understanding of cholestasis. We analysed BA levels in various tissues of Benign Recurrent Intrahepatic Cholestasis type 2 (BRIC2) patients and our simulations suggest a higher susceptibility of BRIC2 patients towards cholestatic DILI due to BA accumulation in the liver. The effect of drugs on systemic BA levels were simulated for cyclosporine A (CsA). Our results confirmed the higher risk of DILI after CsA administration in healthy and BRIC2 patients. The presented PBBA model enhances our mechanistic understanding underlying cholestasis and drug-induced alterations of BA levels in blood and organs. The developed PBBA model might be applied in the future to anticipate potential risk of cholestasis in patients.

Keywords: Cholestasis, BRIC type 2, DILI (drug-induced liver injury), computational modeling, bile acids, PBPK

Received: 18 Feb 2019; Accepted: 03 Sep 2019.

Copyright: © 2019 Baier, Cordes, Thiel, Castell, Neumann, Blank and Kuepfer. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Lars Kuepfer, RWTH Aachen University, Institute of Applied Microbiology (iAMB), Aachen Biology and Biotechnology (ABBt), Aachen, Germany, lars.kuepfer@rwth-aachen.de