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

摘要

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 (PPARalpha). Because amiodarone does not directly stimulate PPARalpha, target gene induction may reflect a compensatory reaction countering some adverse effects of amiodarone. To test this, we examined co-treatment with the PPARalpha agonist, fenofibrate, and amiodarone in both PPARalpha(+/+) and PPARalpha(-/-) mice. Amiodarone treated PPARalpha(-/-) mice exhibited significantly greater weight loss and higher serum aspartate aminotransferase (AST) compared to PPARalpha(+/+) mice. Fenofibrate co-treatment reduced weight loss in amiodarone treated PPARalpha(-/-) mice, but not PPARalpha(+/+) mice. Fenofibrate stimulation of PPARalpha reduced serum amiodarone concentrations in normal mice. Serum amiodarone concentrations were higher in mice without PPARalpha expression given at 40-80 mg/kg amiodarone doses. These results are consistent with a protective influence of PPARalpha in reducing amiodarone-induced hepatic toxicity. In addition to PPARalpha-dependent effects, fenofibrate also demonstrated PPARalpha-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.