Pulmonary accumulation of amiodarone and N-desethylamiodarone. Relationship to the development of pulmonary toxicity.

To investigate the relationship between the amount of amiodarone and the major metabolite N-desethylamiodarone found in the lung with the development of toxicity, Fischer 344 and Wistar rats were given 175 mg/kg/day of drug by gavage. After 1, 3, 6, and 12 wk of drug feeding, both stains were examined for histologic evidence of pulmonary inflammation and for changes in lavage cell counts and differentials. The amounts of amiodarone and N-desethylamiodarone in the lungs were determined using high performance liquid chromatography. We found that in drug-fed Wistar rats the lavage differentials were unchanged, lavage cell counts were decreased compared with those in control rats, and the lungs appeared normal except for some foamy macrophages. Wistar rats also had low levels of amiodarone and metabolite in both lung tissue and cells. In contrast, Fischer rats had an increase in lavage lymphocytes, neutrophils, and macrophages compared with that in control rats and abnormal lung histologies. Also, there was much more drug and metabolite in the lungs than the amounts found in Wistar rats. Because Fischer rats had more metabolite than amiodarone in the lung and the reverse was true in Wistar rats, the in vitro cytotoxicity of amiodarone and N-desethylamiodarone were compared. We found that N-desethylamiodarone was significantly more cytotoxic than amiodarone to both fibroblasts and endothelial cells. We conclude that there is a relationship between the amounts of drug and metabolite in the lung and the development of pulmonary inflammation, and that N-desethylamiodarone may be more cytotoxic than amiodarone.