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 which is limited because of the drug's potential for causing life-threatening pulmonary fibrosis. Oxidative stress involving keto oxygen-derived free radical formation has been postulated to be responsible for initiating AM-induced pulmonary toxicity (AIPT). We have investigated whether des-oxo-amiodarone (DOAM), which has a methylene group in place of the keto oxygen group of AM, causes pulmonary fibrosis in an experimental animal. Hamsters were given a single intratracheal instillation of AM HCl or DOAM HCl (1.83 mumol). At 21 days postdosing, animals treated with either AM or DOAM had increased lung wet weight, hydroxyproline content, and histological disease index compared to control. Both AM and DOAM treatments caused marked septal thickening and fibrosis, and an influx of inflammatory cells into alveolar and interstitial spaces. AM caused a greater degree of alveolar macrophage infiltration than 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 treatment. Thus, DOAM possess 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 to play in AIPT, the results indicate that the keto oxygen is not the major determinant of AM-induced pulmonary fibrosis.
Rafeiro
E
E
Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada.
Leeder
R G
RG
Brien
J F
JF
Kabalka
G W
GW
Chatla
N
N
Massey
T E
TE
D000638:Amiodarone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D006224:Cricetinae; D006909:Hydroxyproline / Q000378:metabolism; D008168:Lung / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008647:Mesocricetus; D009929:Organ Size / Q000187:drug effects; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000473:pathology
C058304:desoxoamiodrone; D000638:Amiodarone; D006909:Hydroxyproline