Amiodarone Toxicity: II. Desethylamiodarone-Induced Phospholipidosis and Ultrastructural Changes during Repeated Administration in Rats

The contribution of desethylamiodarone (DEA), principal metaboliteof the antiarrhythmic drug amiodarone, to the major side effectsof amiodarone is unclear. The effects of repeated DEA administrationto rats on tissue drug accumulation, ultrastructural changes,and phospholipid concentrations were studied. Two groups (n= 8/group) of male Sprague-Dawley rats (250 g body wt) wereadministered a 5% aqueous solution of DEA (Dose I, 40 mg/kg/day,Dose II, 60 mg/kg/day) intraperitoneally for 21–23 days,while a third group (control, n = 8) received saline. DEA levelswere significantly higher with Dose II compared to Dose I inthe lung, liver, kidney, spleen, heart, and serum while thetissue to serum ratios were similar with both doses for alltissues except the heart. DEA administration caused a significantelevation in the lipid phosphorus levels of liver, lung, andalveolar macrophages compared to control levels. A strong positivecorrelation (p < 0.01) was found between tissue DEA levelsand lipid phosphorus for the above tissues. Electron microscopyrevealed the presence of lipid inclusion bodies in liver, lung,and alveolar macrophages of DEA-treated rats. A dose-dependentincrease in the percentage of vacuolar surface area was foundin the lung and alveolar macrophages. The tissue ultrastructuralchanges after repeated DEA dosing were qualitatively similarto our previous findings with amiodarone. Increased lung andliver phospholipid levels with repeated DEA doses may resultfrom a potent inhibitory action of DEA on tissue phospholipaseA as has been observed by others in in vitro studies.