Developing In Vitro Models to Define the Role of Direct Mitochondrial Toxicity in Frequently Reported Drug-Induced...

Area of Science:

• Pharmacology
• Toxicology
• Mitochondrial Biology

Background:

• Rhabdomyolysis is a serious adverse drug reaction.
• The United States Food and Drug Administration Adverse Event Reporting System (FAERS) contains extensive data on adverse events.
• Identifying common mechanisms for drug-induced rhabdomyolysis is crucial for patient safety.

Purpose of the Study:

• To identify drugs frequently associated with rhabdomyolysis using FAERS data.
• To investigate mitochondrial toxicity as a potential common mechanism for drug-induced rhabdomyolysis.
• To validate findings in human-relevant cell models.

Main Methods:

• Analysis of FAERS data (2004-2020) to identify 14 frequently reported drugs linked to rhabdomyolysis.
• In vitro screening for mitochondrial toxicity using an acute metabolic switch assay in murine L6 cells.
• Detailed mechanistic investigation of mitotoxic drugs using real-time respirometry (Seahorse Technology).
• Validation of findings in primary human skeletal muscle-derived cells (HSKMDC).

Main Results:

• 14 drugs were identified as frequently reported in rhabdomyolysis cases.
• Fenofibrate, risperidone, pregabalin, propofol, and simvastatin lactone showed preliminary signs of mitochondrial toxicity.
• Real-time respirometry confirmed mitochondrial dysfunction as the mechanism for these drugs.
• Human skeletal muscle cells confirmed the mitotoxic potential, with more pronounced effects observed.

Conclusions:

• The L6 cell model serves as a cost-effective initial screen for potential human myotoxicants.
• Mitochondrial dysfunction is a shared mechanism underlying myotoxicity for several drugs.
• Findings emphasize the importance of considering mitochondrial toxicity in drug safety evaluations for rhabdomyolysis.