Current insights in the complexities underlying drug-induced cholestasis

Area of Science:

• Pharmacology
• Hepatology
• Toxicology

Background:

• Drug-induced cholestasis (DIC) is a significant hurdle in drug development, leading to attrition and market withdrawals.
• DIC involves impaired bile secretion and pathological accumulation of bile acids and salts.
• Predicting cholestatic potential early is difficult due to the complex, multifactorial nature of DIC.

Purpose of the Study:

• To review the primary molecular mechanisms underlying drug-induced cholestasis.
• To provide an overview and critical assessment of current liver models used for predicting drug cholestatic potential.
• To emphasize the importance of understanding DIC mechanisms for safer drug development.

Main Methods:

• Literature review of molecular mechanisms of DIC.
• Analysis of various *in vitro* and *in vivo* liver models for predicting drug cholestasis.
• Critical appraisal of the strengths and limitations of different predictive models.

Main Results:

• Key DIC mechanisms include alterations in hepatobiliary transporters and hepatocellular morphology.
• Membrane-based *in vitro* models excel at investigating specific mechanisms like transporter inhibition.
• Liver slices offer a more comprehensive *in vivo*-like representation by encompassing multiple biological processes.

Conclusions:

• A thorough understanding of DIC molecular mechanisms is essential for accurate prediction.
• Different liver models possess unique advantages for evaluating specific aspects of cholestatic potential.
• Appropriate selection and application of liver models are vital for mitigating drug development risks associated with DIC.