Gaining Mechanistic Insight in Drug Induced Cholestasis: What Can We Learn from Bile Acid Profiling in Human Hepatocytes?

Date: June 22 2022
Presenter(s): Pieter Annaert, PharmD., PhD

Summary of the presentation:

Preclinical prediction of drug induced cholestasis liability remains a major drug development challenge. In recent years, several in vitro models have been developed and applied to achieve a better risk assessment regarding the drug induced cholestasis potential of novel drug candidates. Vesicle-based models allowing high throughput assessment of interaction with the activity of the bile salt export pump (BSEP, ABCB11) have become a standard assay when screening drug candidates. In addition, holistic models for detecting compounds with a cholestatic signature have emerged. Several hepatocyte-based models have been developed relying on a toxicity/viability endpoint (e.g. urea production or ATP content) after incubations of test compounds in the absence or presence of bile acid mixtures. Meanwhile, it has become clear that the network of mechanisms underlying drug-induced cholestasis remains elusive and extends far beyond BSEP inhibition alone. In this context, our research group has invested in the generation of in vitro data regarding the disposition of bile acids in sandwich-cultured cultured human hepatocytes, including the disturbance by the signature cholestatic drug bosentan. The aim of this webinar is to first provide an overview of the state-of-the-art regarding bile acid profiling in cultured hepatocytes. Secondly, this webinar will address how altered bile acid profiles may provide future opportunities for developing improved in vitro models for understanding and predicting drug-induced cholestasis.

Selected references:

Chatterjee, S., Richert, L., Augustijns, P. & Annaert, P. Hepatocyte-based in vitro model for assessment of drug-induced cholestasis. Toxicol Appl Pharm 274, 124–136 (2014).

Brantegem, P. V., Deferm, N., Qi, B., Vocht, T. D. & Annaert, P. Experimental Cholestasis Research. Methods Mol Biology 1981, 55–73 (2019).

Deferm, N. et al. Current insights in the complexities underlying drug-induced cholestasis. Crit Rev Toxicol 49, 1–29 (2019).

Brantegem, P. V., Chatterjee, S., Bruyn, T. D., Annaert, P. & Deferm, N. Drug-induced cholestasis assay in primary hepatocytes. Methodsx 7, 101080 (2020).

Oorts, M. et al. Bosentan alters endo- and exogenous bile salt disposition in sandwich-cultured human hepatocytes. J Pharmacol Exp Ther 379, JPET-AR-2021-000695 (2021).

About the presenter:

ANNAERT Pieter, PharmD., PhD.

Professor of Pharmacokinetics, Chair of the Department of Pharmaceutical and Pharmacological Sciences, KU Leuven


Pieter Annaert is a pharmacist by training and obtained his PhD in pharmaceutical Sciences at KU Leuven in 1998. He conducted 2 years of postdoctoral research in the field of in vitro hepatic drug disposition at the University of North Carolina at Chapel Hill. After some years at Janssen Pharmaceutica, in the division of preclinical pharmacokinetics, he moved to KU Leuven in 2005, where he currently is full professor at the Drug Delivery and Disposition Lab. Since 2020 he is the chair of the KU Leuven Department of Pharmaceutical and Pharmacological Sciences. In 2017 he co-founded the CRO BioNotus, specialized in bioanalysis, pharmacometrics and Discovery ADMET.

His research interests are in the field of Mechanistic Pharmacokinetics. This includes the development and application of in vitro models of the liver, as well as physiology based pharmacokinetic modelling and simulation. In addition, his team has particular interest in predicting and understanding perinatal pharmacology and drug-induced cholestasis.