Influence of peroxisome proliferator-activated receptor-alpha (PPARα) activity on adverse effects associated with amiodarone exposure in mice

Although amiodarone is the most effective antiarrhythmic agent currently available, concerns regarding adverse effects, including liver, lung and thyroid toxicity, often limit its use. Previously, we reported that amiodarone-induced hepatic steatosis in mice was associated with an upregulation of target genes modulated by peroxisome proliferator-activated receptor-alpha (PPARα). Because amiodarone does not directly stimulate PPARα, target gene induction may reflect a compensatory reaction countering some adverse effects of amiodarone. To test this, we examined co-treatment with the PPARα agonist, fenofibrate, and amiodarone in both PPARα(+/+) and PPARα(-/-) mice. Amiodarone treated PPARα(-/-) mice exhibited significantly greater weight loss and higher serum aspartate aminotransferase (AST) compared to PPARα(+/+) mice. Fenofibrate co-treatment reduced weight loss in amiodarone treated PPARα(-/-) mice, but not PPARα(+/+) mice. Fenofibrate stimulation of PPARα reduced serum amiodarone concentrations in normal mice. Serum amiodarone concentrations were higher in mice without PPARα expression given at 40-80 mg/kg amiodarone doses. These results are consistent with a protective influence of PPARα in reducing amiodarone-induced hepatic toxicity. In addition to PPARα-dependent effects, fenofibrate also demonstrated PPARα-independent actions that suggest a complex interaction modulating both hepatic lipid metabolism and amiodarone disposition. Further studies of the beneficial effect of fenofibrate and the interplay between lipid metabolism and amiodarone pharmacokinetics are required.