Chronic amiodarone ingestion induces pulmonary toxicity in rats

Patients who receive amiodarone may develop interstitial pulmonary disease. The objective of the present study was to develop an experimental model of interstitial pulmonary disease in rats based on the chronic oral administration of amiodarone diluted in water ad libitum. A total of 97 three-month old male Wistar rats weighing 133-167 g (control and intoxicated) were studied after daily administration of amiodarone (about 50 mg/kg) for 3 weeks and 3, 6, and 13 months. We carried out conventional histopathologic evaluation, morphometric studies of the alveolar wall, transmission electron microscopy, measurement of pulmonary volumes and forced expiratory flows, and computed respiratory system resistance and elastance during spontaneous breath cycles. Chronic ingestion of amiodarone by rats produced pulmonary disease that started as a phospholipidosis, as early as 3 weeks after the use of the drug. After 6, and mainly after 13 months, a focal inflammatory reaction with reactive alveolar epithelium was observed. Signals of a concomitant repair process were also present, but fibrosis was visible only by electron microscopy. The physiologic dysfunction could be identified after 13 months; expiratory flow (ml/sec) limitation and an increased respiratory system elastance (cmH2O/ml) were the main functional changes, respectively 10.8 (forced expiratory mean flow between 0-25% of forced vital capacity) and 5.36 in treated animals vs 13.3 and 3.65 in controls, reported as mean +/- SD for 6 animals in each group. A body of evidence suggests that amiodarone may cause changes in lung phospholipid metabolism that may be responsible for a part of the functional derangement observed in this study.