Amiodarone toxicity. II. Desethylamiodarone-induced phospholipidosis and ultrastructural changes during repeated administration in rats.
The contribution of desethylamiodarone (DEA), principal metabolite of the antiarrhythmic drug amiodarone, to the major side effects of amiodarone is unclear. The effects of repeated DEA administration to 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) were administered 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 levels were significantly higher with Dose II compared to Dose I in the lung, liver, kidney, spleen, heart, and serum while the tissue to serum ratios were similar with both doses for all tissues except the heart. DEA administration caused a significant elevation in the lipid phosphorus levels of liver, lung, and alveolar macrophages compared to control levels. A strong positive correlation (p less than 0.01) was found between tissue DEA levels and lipid phosphorus for the above tissues. Electron microscopy revealed the presence of lipid inclusion bodies in liver, lung, and alveolar macrophages of DEA-treated rats. A dose-dependent increase in the percentage of vacuolar surface area was found in the lung and alveolar macrophages. The tissue ultrastructural changes after repeated DEA dosing were qualitatively similar to our previous findings with amiodarone. Increased lung and liver phospholipid levels with repeated DEA doses may result from a potent inhibitory action of DEA on tissue phospholipase A as has been observed by others in in vitro studies.
Kannan
R
R
Department of Cardiology, City of Hope National Medical Center, Duarte, California 91010.
Sarma
J S
JS
Guha
M
M
Venkataraman
K
K
D000638:Amiodarone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008264:Macrophages / Q000187:drug effects; D008297:Male; D010741:Phospholipases A / Q000378:metabolism; D010743:Phospholipids / Q000097:blood / Q000378:metabolism*; D051381:Rats; D011919:Rats, Inbred Strains; D014018:Tissue Distribution
D010743:Phospholipids; D010741:Phospholipases A; C036116:desethylamiodarone; D000638:Amiodarone