Sagnik Chatterjee* and Pieter Annaert Pages 808 - 818 ( 11 )
Background: Drug-induced cholestasis is a risk factor in the progression of drug candidates, and poses a serious health hazard if not detected before going into a human. Intrahepatic accumulation of Bile Acids (BAs) represents a characteristic phenomenon associated with drug-induced cholestasis.
Methods: This review will discuss the current knowledge and knowledge gaps regarding drug-induced cholestasis, such as complexity of BA-mediated toxicity mechanisms, disconnect in signatures of toxicity between clinical and preclinical models, and the impact of bile acids at different ‘targets’ such as transporters, enzymes and nuclear receptors.
Results: It is important to assess drug-induced cholestasis mechanisms in a physiologically relevant holistic in vitro system. Lack of sensitive and early preclinical biomarkers relevant to the clinical situation, complicates proper detection of drug-induced cholestasis. Significant overlap in biomarker signatures between different mechanisms of Drug-induced Liver Injury (DILI) precludes identification of specific mechanisms. Unavailability of suitable animal models predictive of the toxicity observed in human add to the lack of prediction of clinical drug-induced cholestasis.
Conclusion: Recent developments regarding BA-mediated inflammation as a trigger for toxicity significantly improved understanding of mechanisms of clinical drug-induced cholestasis. Increased insight into susceptibility factors in addition to Bile Salt Export Pump (BSEP) inhibition, biomarkers and involvement of immune system decreased knowledge gaps. Increased knowledge is assisting the development of the novel in vitro models providing a holistic understanding of processes underlying drug-induced cholestasis. This review summarizes the challenges and recent developments about drug-induced cholestasis with a potential path forward for informed decision-making during the drug development process.
Bile acids, drug-induced cholestasis, drug-induced liver injury, biomarkers, in vitro models, hepatocytes, inflammation, cholestasis.
Biocon Bristol-Myers Squibb Research Center, Bangalore 560099, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, Drug Delivery and Disposition, Leuven 3000