New approach methodologies (NAMs) to understand and predict drug-induced effects on bile acid homeostasis and cholestasis

Summary

Various chemicals, including some drugs, might lead to a disturbance of the bile acid pool in the human body. A disturbance in the bile acid pool is related to various adverse health reactions, such as inflammatory bowel disease or the liver disease cholestasis. Therefore, this thesis aimed to develop and apply reliable human cell based models and physiologically based kinetic (PBK) models to better understand and predict drug-induced disruption of bile acid homeostasis on bile acid homeostasis. To this end, (i) the capacity of three different hepatic cell models to emulate human liver functionality to synthesize and secrete bile acids were compared, (ii) intestinal bile acid absorption was studied using a cell based assay for the intestinal epithelium and (iii) PBK models were developed to predict drug-induced alterations in the bile acid pool in liver, intestine and blood stream. The current work shows that it is feasible to apply non-animal methods to predict drug-induced effects on the bile acid pool and thereby the current work contributes to the 3Rs (reduction, refinement, replacement) of experimental animal studies.