Webinar Announcement - Join us on 22 June, Wednesday!
May 27, 2022
Date: Wednesday, 22 June, 2022
Timing:
8:00 am (PT)
11:00 am (ET)
4:00 pm (GMT)
5:00 pm (CET)
6:00 pm (IST)
12:00 pm (Beijing)
01:00 am (Tokyo, Seoul)
Click here to register!
Presenter:
Pieter Annaert, PharmD., PhD.
Professor of Pharmacokinetics
Chair of the Department of Pharmaceutical and Pharmacological Sciences
KU Leuven
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).
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