Antioxidant activity of amiodarone on human lipoprotein oxidation

1 Lipoprotein oxidation is crucial in atherogenic processes. Amiodarone is a lipophilic antiarrhythmic/antianginal drug which is able to influence the physicochemical status of biological lipid components. Since oxidation of lipids is affected by their physicochemical state and amiodarone binds to l ipoproteins, we hypothesized that the drug may exert an antioxidant activit y on human lipoprotein oxidation. 2 Dose-dependent effects of therapeutically achievable amiodarone concentra tions (1.5, 3, 5, 7 and 10 muM) were studied on copper-catalysed oxidation of the non-HDL fraction in vitro. Amiodarone inhibited oxidation as judged by generation of thiobarbituric acid reactive substances (TBARS), lipid hyd roperoxides (LOOH) and fluorescent products of lipoperoxidation (FPL) as we ll as from the kinetics of conjugated diene formation. This antioxidant act ivity was significant at 1.5 muM with total inhibition at 10 muM and an IC5 0 of 4 muM. The primary in vivo metabolite of amiodarone, namely desethylam iodarone, also exhibited specific antioxidant properties although it was le ss effective than amiodarone with an IC50 of 7 muM. 3 In further ill I vivo experiments, susceptibility to copper-mediated oxid ation of the non-HDL fraction was investigated before and 4 weeks after ora l amiodarone administration to humans. Following treatment, significant inh ibition of TEARS, LOOH and FPL generation was observed in comparison with b aseline levels and a placebo-treated control group, highlighting an effecti ve antioxidant capacity of amiodarone in vivo. 4 Amiodarone did not change lipoprotein vitamin E and phospholipid content ill vivo and did not show scavenging effects on oxidizing species involved in lipoprotein oxidation, such as peroxyl radicals, nor metal-binding/inact ivating properties suggesting that physicochemical modifications of lipopro tein lipids induced by the lipophilic drug may be involved in its antioxida nt activity. 5 In conclusion, amiodarone, and its primary metabolite desethylamiodarone, show previously unrecognized antioxidant activity on human lipoprotein oxi dation. This effect is also evident in vivo and at therapeutically achievab le drug concentrations. Thus, amiodarone may act as an antioxidant/antiathe rosclerotic agent in humans, although this issue warrants further clinical study.