Hepatic toxicity of dronedarone in mice: Role of mitochondrial β-oxidation

•Dronedarone is not hepatotoxic to mice up to 200 mg/kg/day.•At 400 mg/kg/day dronedarone decreases food intake and inhibits hepatic fatty acid metabolism.•Impaired hepatic fatty acid metabolism is associated with increased hepatocyte apoptosis and serum transaminases.•Mice with subclinical impairment of β-oxidation are slightly more susceptible to dronaderone than wild type mice.

Dronedarone is an amiodarone-like antiarrhythmic drug associated with severe liver injury. Since dronedarone inhibits mitochondrial respiration and β-oxidation in vitro, mitochondrial toxicity may also explain dronedarone-associated hepatotoxicity in vivo. We therefore studied hepatotoxicity of dronedarone (200 mg/kg/day for 2 weeks or 400 mg/kg/day for 1 week by intragastric gavage) in heterozygous juvenile visceral steatosis (jvs+/−) and wild-type mice. Jvs+/− mice have reduced carnitine stores and are sensitive for mitochondrial β-oxidation inhibitors.Treatment with dronedarone 200 mg/kg/day had no effect on body weight, serum transaminases and bilirubin, and hepatic mitochondrial function in both wild-type and jvs+/− mice. In contrast, dronedarone 400 mg/kg/day was associated with a 10-15% drop in body weight, and a 3-5-fold increase in transaminases and bilirubin in wild-type mice and, more accentuated, in jvs+/− mice. In vivo metabolism of intraperitoneal 14C-palmitate was impaired in wild-type, and, more accentuated, in jvs+/− mice treated with 400 mg/kg/day dronedarone compared to vehicle-treated mice. Impaired β-oxidation was also found in isolated mitochondria ex vivo. A likely explanation for these findings was a reduced activity of carnitine palmitoyltransferase 1a in liver mitochondria from dronedarone-treated mice. In contrast, dronedarone did not affect the activity of the respiratory chain ex vivo.We conclude that dronedarone inhibits mitochondrial β-oxidation in and ex vivo, but not the respiratory chain. Jvs+/− mice are slightly more sensitive for the effect of dronedarone on mitochondrial β-oxidation than wild-type mice. The results suggest that inhibition of mitochondrial β-oxidation is an important mechanism of hepatotoxicity associated with dronedarone.