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Effects of metabolites and analogs of amiodarone on alveolar macrophages: structure-activity relationship.
- Source :
-
American journal of physiology. Lung cellular and molecular physiology [Am J Physiol Lung Cell Mol Physiol] 2004 Aug; Vol. 287 (2), pp. L438-47. Date of Electronic Publication: 2004 Apr 09. - Publication Year :
- 2004
-
Abstract
- Amiodarone, an antiarrhythmic drug toxic toward the lung, is metabolized through sequential modifications of the diethylaminoethoxy group to mono-N-desethylamiodarone (MDEA), di-N-desethylamiodarone (DDEA), and amiodarone-EtOH (B2-O-EtOH), whose effects on lung cells are unclear. To clarify this, we exposed rabbit alveolar macrophages to analogs with different modifications of the diethylaminoethoxy group and then searched for biochemical signs of cell damage, formation of vacuoles and inclusion bodies, and interference with the degradation of surfactant protein A, used as a tracer of the endocytic pathway. The substances studied included MDEA, DDEA, and B2-O-EtOH, analogs with different modifications of the diethylaminoethoxy group, fragments of the amiodarone molecule, and the antiarrhythmic agents dronedarone (SR-33589) and KB-130015. We found the following: 1). MDEA, DDEA, and B2-O-EtOH rank in order of decreasing toxicity toward alveolar macrophages, indicating that dealkylation and deamination of the diethylaminoethoxy group represent important mechanisms of detoxification; 2). dronedarone has greater, and KB-130015 has smaller, toxicity than amiodarone toward alveolar macrophages; and 3). the benzofuran moiety, which is toxic to liver cells, is not directly toxic toward alveolar macrophages.
- Subjects :
- Amiodarone metabolism
Animals
Anti-Arrhythmia Agents metabolism
Benzofurans chemistry
Benzofurans metabolism
Benzofurans pharmacology
Cell Survival drug effects
Dronedarone
Iodine Radioisotopes
Macrophages, Alveolar ultrastructure
Microscopy, Electron
Pulmonary Surfactant-Associated Protein A pharmacokinetics
Rabbits
Structure-Activity Relationship
Trachea
Amiodarone analogs & derivatives
Amiodarone chemistry
Amiodarone pharmacology
Anti-Arrhythmia Agents chemistry
Anti-Arrhythmia Agents pharmacology
Macrophages, Alveolar drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1040-0605
- Volume :
- 287
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Lung cellular and molecular physiology
- Publication Type :
- Academic Journal
- Accession number :
- 15075249
- Full Text :
- https://doi.org/10.1152/ajplung.00434.2003