Tissue drug accumulation and ultrastructural changes during amiodarone administration in rats

Pulmonary and hepatotoxicity are 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...

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Bibliographic Details
Published in:Fundamental and applied toxicology 1989-11, Vol.13 (4), p.793-803
Main Authors: Kannan, R., Sarma, J.S.M., Guha, M., Venkataraman, K.
Format: Article
Language:English
Subjects:
Amiodarone - analogs & derivatives
Amiodarone - metabolism
Amiodarone - pharmacokinetics
Amiodarone - toxicity
Animals
Biological and medical sciences
Chromatography, High Pressure Liquid
Drug toxicity and drugs side effects treatment
Macrophages - drug effects
Macrophages - ultrastructure
Male
Medical sciences
Pharmacology. Drug treatments
Rats
Rats, Inbred Strains
Tissue Distribution
Toxicity: digestive system
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Summary:Pulmonary and hepatotoxicity are 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 macrophages 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, monodeiodinated 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.
ISSN:0272-0590
1095-6832
DOI:10.1016/0272-0590(89)90334-5