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© 1989 Oxford University Press

research-article

Tissue Drug Accumulation and Ultrastructural Changes during Amiodarone Administration in Rats

R. KANNAN, J. S. M. SARMA, M. GUHA and K. VENKATARAMAN

Department of Cardiology, City of Hope National Medical Center 1500 East Duarte Road. Duarte. California 91010

Received December 19, 1988; accepted June 8, 1989

Pulmonary and hepatotoxicity arc the two major side effects of chronic amiodarone therapy. We studied the accumulation of amiodarone and its principal metabolite, desethylamiodarone, in lung and liver of rats treated ip for 21 to 23 days with either 40 or 80 mg/kg/day amiodarone. The ultrastructural changes in liver, lung, and alveolar macro-phages in saline controls and in rats on the two amiodarone dosage regimens were investigated. There was a dose-dependent increase in amiodarone and desethylamiodarone levels in serum and in tissues. The desethylamiodarone/amiodarone ratios in liver and lung, but not in serum, increased significantly with increasing dose. Serum also contained another metabolite, mono-deiodinated desethylamiodarone. Increase in vacuolization and presence of whorled lamellar inclusion bodies in alveolar macrophages occurred with an increase in dose and higher lung amiodarone and desethylamiodarone levels. Electron microscopy of the liver of amiodarone-treated rats revealed the presence of large inclusion bodies partially filled with amorphous material in the cytoplasm. The quantitative relationship of the above changes to organ toxicity and to phospholipidosis that accompanies amiodarone administration remains to be established.


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