Disease-related determinants of susceptibility to drug-induced idiosyncratic hepatotoxicity

Area of Science:

• Pharmacology
• Toxicology
• Mitochondrial Medicine

Background:

• Idiosyncratic adverse drug reactions (ADRs), particularly hepatotoxicity, pose significant challenges in pharmaceutical development.
• Patient-specific factors (genetic/acquired) and underlying disease states contribute to drug toxicity.
• Certain diseases, including viral infections, inflammatory conditions, neurodegenerative diseases, and type II diabetes, are associated with mitochondrial abnormalities.

Purpose of the Study:

• To review diseases linked to mitochondrial dysfunction that are treated with drugs potentially causing mitochondrial toxicity.
• To explore how co-occurring mitochondrial events in disease and drug treatment can exacerbate toxicity.
• To emphasize the importance of animal models for mechanistic studies and drug candidate selection.

Main Methods:

• Literature review focusing on diseases with mitochondrial implications and associated drug toxicities.
• Analysis of mechanistic links between therapeutic agents and mitochondrial dysfunction.
• Discussion on the role of animal models in understanding drug-induced mitochondrial toxicity.

Main Results:

• Identified therapeutic indications frequently associated with mitochondrial abnormalities.
• Highlighted drugs mechanistically linked to mitochondrial toxicity, creating superimposed effects.
• Emphasized the critical need for enhanced use of animal models in research.

Conclusions:

• Co-occurrence of disease-related mitochondrial dysfunction and drug-induced mitochondrial toxicity is a significant concern.
• Improved preclinical models are essential for predicting and mitigating drug-induced toxicity in susceptible patient populations.
• Further research integrating disease mechanisms and drug toxicology is crucial for safer drug development.