Predicting drug-induced cholestasis: preclinical models.

Area of Science:

• Hepatology
• Toxicology
• Drug Safety

Background:

• Drug-induced liver injury (DILI) frequently involves cholestasis, impairing bile flow.
• The idiosyncratic nature of cholestasis makes prediction challenging.
• Accurate prediction of drug-induced cholestasis (DIC) is a critical safety concern.

Purpose of the Study:

• To review the current state of preclinical models for predicting cholestatic DILI.
• To evaluate the strengths and limitations of existing animal and in vitro models.
• To highlight the need for improved models that capture the idiosyncrasy of DIC.

Main Methods:

• Review of preclinical models for cholestatic DILI prediction.
• Classification of models based on goal, complexity, availability, and applicability.
• Analysis of experimental animal models and in vitro systems.

Main Results:

• Animal models exhibit homogeneity and species-specific differences, limiting predictability.
• In vitro human models are advancing, increasingly mimicking the in vivo hepatocyte phenotype.
• Existing models struggle to fully recapitulate the idiosyncratic features of DIC.

Conclusions:

• Reliable prediction of drug-induced cholestasis requires models that capture idiosyncrasy.
• In vitro human models are emerging as the most promising approach for future DIC prediction.
• Advancements necessitate both improved predictive models and deeper mechanistic understanding.