Ex vivo mouse model for the early detection of drug-induced cholestasis

Ruby E.H. Karsten, Nikolaas V.J.W. Krijnen, Maciej Grajewski, Elisabeth Verpoorte, Peter Olinga

Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands

Poster

SLAS Europe 2019

BelTox, Brussels 2019

Drug-induced cholestasis (DIC), an adverse drug reaction, has a complex disease mechanism with no good model for early detection in drug development.

We are developing an ex vivo mouse model based on precision-cut liver slices (mPCLS) to study DIC.  We incubate PCLS for 48h with glibenclamide (a cholestatic drug). Cholestasis is ascertained by comparing control slices to slices treated with drug, with and without an optimized bile acid (BA) mix. We studied mPCLS viability and gene expression of BA transporters.

Non-toxic glibenclamide concentrations led to greater gene expression of basolateral and canalicular bile export transporters, the latter with a higher increase in the presence of BA mix. This study is the first that relates gene expression data to early DIC development in mPCLS. Once optimized, mPCLS will be incubated in a microfluidic device to monitor DIC onset in real time. We will use this model to elucidate disease mechanisms and perform drug toxicity screening.

1.            de Graaf IAM, Olinga P, de Jager MH, Merema MT, de Kanter R, van de Kerkhof EG, e.a. Preparation and incubation of precision-cut liver and intestinal slices for application in drug metabolism and toxicity studies. Nat Protoc. september 2010;5(9):1540–51.

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