COMPARISON OF THE IN-VIVO PULMONARY TOXICITY OF AMIODARONE AND DES-OXO-AMIODARONE IN THE HAMSTER

Amiodarone (AM) is an effective antidysrhythmic agent, the use of whic h is limited because of the drug's potential for causing life-threaten ing pulmonary fibrosis. Oxidative stress involving keto oxygen-derived free radical formation has been postulated to be responsible for init iating AM-induced pulmonary toxicity (AIPT). We have investigated whet her des-oxo-amiodarone (DOAM), which has a methylene group in place of the keto oxygen group of AM, causes pulmonary fibrosis in an experime ntal animal. Hamsters were given a single intratracheal instillation o f AM HCl or DOAM HCl (1.83 mu mol). At 21 days postdosing, animals tre ated with either AM or DOAM had increased lung wet weight, hydroxyprol ine content, and histological disease index compared to control. Both AM and DOAM treatments caused marked septal thickening and fibrosis, a nd an influx of inflammatory cells into alveolar and interstitial spac es. AM caused a greater degree of alveolar macrophage infiltration tha n did DOAM, which contributed to the higher lung disease index for AM treatment. Interestingly, a greater quantity of DOAM than AM remained in the lungs and bronchoalveolar lavage fluid 1 and 5 hr after treatme nt. Thus, DOAM possesses fibrogenic properties similar to AM but based on the greater quantity of DOAM in the lung, it appears to be a less potent inducer of pulmonary toxicity. If oxidative stress has a role t o play in AIPT, the results indicate that the keto oxygen is not the m ajor determinant of AM-induced pulmonary fibrosis. (C) 1994 Academic P ress, Inc.