title: Cytotoxic interaction between amiodarone and desethylamiodarone in human peripheral lung epithelial cells.
abstract: The potent and efficacious anti-dysrhythmic agent amiodarone (AM) can cause potentially life-threatening lung damage (amiodarone-induced pulmonary toxicity; AIPT), which is characterized by cell death in the lungs, followed by inflammation and fibrosis. AM's major metabolite, desethylamiodarone (DEA), has a greater toxic potency than AM and it has been suggested that DEA may act synergistically with AM to cause lung toxicity. The objective of this study was to determine the type of cytotoxic interaction between AM and DEA in HPL1A human peripheral lung epithelial cells. Cytotoxicity was measured by lactate dehydrogenase release. AM and DEA caused concentration-dependent cytotoxicity in HPL1A cells. The concentration of drug causing 50% cell death (LC50) and the Hill slope factor, which represents steepness of the concentration-cell death curve, were significantly different between AM and DEA (12.4μM and 1.98; 5.07μM and 5.43, for AM and DEA, respectively) indicating that they may induce cytotoxicity through different mechanisms. A combined concentration of 7.13μM AM plus DEA, equivalent to 41% of each compound's individual LC50 value, resulted in 50% cell death. Isobolographic analysis revealed this effect to be additive, although the combined concentrations were only slightly higher than the concentrations that defined the threshold of synergy (threshold of synergy=4.21±1.98μM AM plus 1.73±1.05μM DEA; experimental data point=5.06±0.47μM AM plus 2.07±0.47μM DEA). The cytotoxic interaction between AM and DEA may be clinically relevant in the development of AIPT.
authors.affiliation: Pharmacology and Toxicology Graduate Program, Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada K7L 3N6.
authors.forename: Fiona C
authors.initials: FC
authors.lastname: Roth
authors.forename: Jeanne E
authors.initials: JE
authors.lastname: Mulder
authors.forename: James F
authors.initials: JF
authors.lastname: Brien
authors.forename: Takashi
authors.initials: T
authors.lastname: Takahashi
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Massey
mesh_terms: D000638:Amiodarone / Q000031:analogs & derivatives* / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004357:Drug Synergism; D004847:Epithelial Cells / Q000187:drug effects*; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008168:Lung / Q000187:drug effects; D015394:Molecular Structure; D018675:Toxicity Tests
chemical_list: D007770:L-Lactate Dehydrogenase; C036116:desethylamiodarone; D000638:Amiodarone
keywords: AIPT; AM; Amiodarone; Amiodarone-induced pulmonary toxicity; DEA; Desethylamiodarone; Drug interaction; Isobologram; LC(50); LDH; amiodarone; amiodarone-induced pulmonary toxicity; concentration causing 50% cell death; desethylamiodarone; lactate dehydrogenase