Amiodarone induced phospholipidosis. Biochemical, morphological and functional changes in the lungs of rats chronically treated with amiodarone.
Amiodarone, an antiarrhythmic drug, causes pulmonary fibrosis in some patients during chronic treatment but the mechanism is unknown. We studied the effects of amiodarone on pulmonary biochemistry, morphology and function at doses of 25 and 50 mg/kg/12 hr given to rats by gavage for four weeks. Plasma and pulmonary phospholipids were significantly augmented, 13% and 88% respectively, in the group given amiodarone 50 mg/kg/12 hr compared to pair-fed controls. Typical phospholipidosis-like light and electron microscopic alterations were seen in the lung, their severity related to the extent of biochemical changes induced by amiodarone. Pulmonary function tests revealed mild but not significant changes in O2 and CO2 alveolar exchange efficiency and lung compliance (P-V curve) of treated animals in comparison to pair fed controls. Plasma average concentrations of amiodarone and its main metabolite, desethylamiodarone, after four weeks were 2.46 +/- 0.18 and 0.73 +/- 0.13 micrograms/ml, respectively, in the 50 mg/kg/12 hr group. In the same group amiodarone and desethylamiodarone concentrations in lung were 163 +/- 26 and 569 +/- 153 times higher than those in plasma. A highly significant correlation was found between amiodarone concentrations in plasma and lung and phospholipid content in the lung. A subgroup of animals received amiodarone 50 mg/kg/12 hr for 8 weeks. The pulmonary phospholipidosis-like lesions were similar to those observed after one month of treatment, no fibrosis was evident on light microscopic examination.
Riva
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Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
Marchi
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Pesenti
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Bizzi
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Cini
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Veneroni
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Tavbani
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Boeri
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Bertani
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T
Latini
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D000638:Amiodarone / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D008064:Lipidoses / Q000139:chemically induced*; D008168:Lung / Q000187:drug effects* / Q000473:pathology / Q000648:ultrastructure; D008170:Lung Compliance / Q000187:drug effects; D008297:Male; D010743:Phospholipids / Q000378:metabolism*; D011659:Pulmonary Gas Exchange / Q000187:drug effects; D051381:Rats; D014018:Tissue Distribution
D010743:Phospholipids; C036116:desethylamiodarone; D000638:Amiodarone