title: Effects of metabolites and analogs of amiodarone on alveolar macrophages: structure-activity relationship.
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.
authors.affiliation: Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena.
authors.forename: Daniela
authors.initials: D
authors.lastname: Quaglino
authors.forename: Huy Riem
authors.initials: HR
authors.lastname: Ha
authors.forename: Elena
authors.initials: E
authors.lastname: Duner
authors.forename: Daniela
authors.initials: D
authors.lastname: Bruttomesso
authors.forename: Laurent
authors.initials: L
authors.lastname: Bigler
authors.forename: Ferenc
authors.initials: F
authors.lastname: Follath
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Realdi
authors.forename: Andrea
authors.initials: A
authors.lastname: Pettenazzo
authors.forename: Aldo
authors.initials: A
authors.lastname: Baritussio
mesh_terms: D000638:Amiodarone / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001572:Benzofurans / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D000077764:Dronedarone; D007457:Iodine Radioisotopes; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000648:ultrastructure; D008854:Microscopy, Electron; D037662:Pulmonary Surfactant-Associated Protein A / Q000493:pharmacokinetics; D011817:Rabbits; D013329:Structure-Activity Relationship; D014132:Trachea
chemical_list: D000889:Anti-Arrhythmia Agents; D001572:Benzofurans; D007457:Iodine Radioisotopes; C446946:KB 130015; D037662:Pulmonary Surfactant-Associated Protein A; D000077764:Dronedarone; D000638:Amiodarone