Amiodarone-induced pulmonary toxicity in rats: biochemical and pharmacological characteristics.

Treatment of humans with the antiarrhythmic drug, amiodarone (AD), may result in the development of pulmonary toxicity. To characterize this response, male Fischer 344 rats were treated with AD for 1, 3, 9, and 16 weeks. AD induces a twofold increase in the level of pulmonary phospholipid after 3 weeks of treatment. Continued administration results in only a small increase above this level. All classes of phospholipids are elevated; phosphatidylcholine displays the largest increase, both quantitatively and as a relative increase over the control level. Both AD and its principal metabolite, desethylAD, are sequestered in the lungs following AD treatment. The relative levels are similar at all time points except 16 weeks, where the relative amount of AD is decreased. After 3 weeks of AD, female 344 rats show the same increase in pulmonary phospholipid as males. While similar levels of desethyAD are sequestered in the lungs of both sexes, AD levels are much lower in female lungs. Evidence is presented to suggest that desethylAD may play an important role in the induction of the phospholipidosis. The activity of Na+,K+-ATPase in the lungs is inhibited by 75% after 9 weeks of AD while the activity of the acid hydrolase, beta-N-acetylglucosaminidase is increased significantly at this time point. All biochemical changes are reversible with values returning to control levels 2 weeks after termination of a 3-week AD treatment protocol. Measurable levels of AD and desethylAD are present in lung tissue after 5 weeks of recovery.