title: Influence of peroxisome proliferator-activated receptor-alpha (PPARα) activity on adverse effects associated with amiodarone exposure in mice.
abstract: 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.
authors.affiliation: Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Ernst
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Sinal
authors.forename: P Timothy
authors.initials: PT
authors.lastname: Pollak
mesh_terms: D000638:Amiodarone / Q000097:blood / Q000633:toxicity*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000097:blood / Q000633:toxicity*; D001219:Aspartate Aminotransferases / Q000097:blood / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D011345:Fenofibrate / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015431:Weight Loss / Q000187:drug effects
chemical_list: D000889:Anti-Arrhythmia Agents; D008055:Lipids; D047493:PPAR alpha; D014157:Transcription Factors; D001219:Aspartate Aminotransferases; D000638:Amiodarone; D011345:Fenofibrate