Pulmonary fibrosis induced in the hamster by amiodarone and desethylamiodarone.
Associated with amiodarone use is pneumonitis which may progress to life-threatening pulmonary fibrosis. Desethylamiodarone, a metabolite, whose role in the etiology of amiodarone-induced pulmonary toxicity has been unclear, also possesses antiarrhythmic activity and could potentially be used as an antiarrhythmic drug itself. We have used a single intratracheal administration of equimolar amounts of amiodarone or desethylamiodarone (1.83 mumol) to male golden Syrian hamsters to investigate the fibrogenicity of desethylamiodarone. Animals were terminated at 1, 7, 14, 21, and 28 days post-treatment, and toxicity was assessed by measurement of lung hydroxyproline content and by histological techniques. Amiodarone and desethylamiodarone significantly increased lung hydroxyproline content over vehicle control animals by 21 days (33 and 58% respectively). While amiodarone-treated lungs had hydroxyproline contents similar to control levels at 28 days, desethylamiodarone-treated lungs remained elevated (44% over control values). Quantitative histologic examination revealed that lungs from desethylamiodarone-treated animals displayed a greater toxic effect, while trichrome staining confirmed the increased deposition of interstitial collagen in these same animals. These results may be due to the higher affinity of the lung for desethylamiodarone and thus a prolonged exposure. The findings indicate that, in the hamster, both compounds are toxic by this route and that desethylamiodarone is not a nontoxic metabolite. Further, use of desethylamiodarone as an antiarrhythmic agent may not be devoid of the adverse effects associated with amiodarone.
Department of Pharmacology and Toxicology, Kingston, Ontario, Canada.
J M
JM
Daniels
J F
JF
Brien
T E
TE
Massey
D000638:Amiodarone / Q000031:analogs & derivatives* / Q000633:toxicity*; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D004195:Disease Models, Animal; D006651:Histocytochemistry; D006909:Hydroxyproline / Q000032:analysis; D008168:Lung / Q000032:analysis / Q000473:pathology; D008297:Male; D008647:Mesocricetus; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D014018:Tissue Distribution
C036116:desethylamiodarone; D000638:Amiodarone; D006909:Hydroxyproline