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1Department of Biomedical Sciences, University of Modena and Reggio Emilia, 41100 Modena 3Clinica Medica I, Department of Medical and Surgical Sciences 4Malattie del Metabolismo, Department of Clinical Medicine 6Department of Pediatrics, University of Padua, 35128 Padua, Italy 2Cardiovascular Therapy Research Laboratory, Department of Internal Medicine, University Hospital of Zurich, 8091 Zurich 5Institute of Organic Chemistry, University of Zurich, 8057 Zurich, Switzerland
Submitted 5 December 2003 ; accepted in final form 25 March 2004
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.
dronedarone; KB-130015
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