Document Detail

Interaction of amiodarone and desethylamiodarone with solubilized nuclear thyroid hormone receptors.
MedLine Citation:
PMID:  3558985     Owner:  NLM     Status:  MEDLINE    
The mechanisms of action of the potent antiarrhythmic drug amiodarone are unknown. However, amiodarone and its abundant metabolite, desethylamiodarone, bear a striking structural resemblance to thyroid hormones. In addition, certain cardiac electrophysiologic effects of amiodarone treatment are similar to those of hypothyroidism. These facts suggest that amiodarone or desethylamiodarone could be acting, in part, by blocking thyroid hormone action. Because thyroid hormones are known to act through nuclear receptor proteins, the binding of amiodarone and desethylamiodarone was measured to nuclear extracts derived from human lymphocytes, bovine atrium and ventricle and rat liver. The capacity of increasing concentrations of amiodarone and desethylamiodarone nuclear extracts to block receptor binding of radiolabeled triiodothyronine (T3) in a standard in vitro competition assay was tested. Nuclear extracts demonstrated only minimal binding to amiodarone. However, all receptor preparations had substantial affinities (KD) for the desethyl analog: lymphocyte, 8.6 microM; atrium, 35.0 microM; ventricle, 26.9 microM and liver, 8.6 microM. Desethylamiodarone accumulates in very large quantities in parenchymatous organs during long-term amiodarone treatment. Taking its usual therapeutic serum level (about 4 microM or 2.7 micrograms/ml) as an estimate of intranuclear concentration, desethylamiodarone would partially saturate nuclear thyroid hormone receptors in several different tissues, including the heart. Thus, amiodarone treatment may exert some of its electrophysiologic effects by metabolic conversion to desethylamiodarone. This metabolite may then exclude thyroid hormone from nuclear receptor sites within the myocardium.
K R Latham; D F Sellitti; R E Goldstein
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, Non-P.H.S.    
Journal Detail:
Title:  Journal of the American College of Cardiology     Volume:  9     ISSN:  0735-1097     ISO Abbreviation:  J. Am. Coll. Cardiol.     Publication Date:  1987 Apr 
Date Detail:
Created Date:  1987-04-27     Completed Date:  1987-04-27     Revised Date:  2008-11-21    
Medline Journal Info:
Nlm Unique ID:  8301365     Medline TA:  J Am Coll Cardiol     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  872-6     Citation Subset:  AIM; IM    
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MeSH Terms
Amiodarone / analogs & derivatives*,  metabolism*
Binding, Competitive
Chemical Phenomena
Drug Interactions
Liver / metabolism
Lymphocytes / metabolism
Myocardium / metabolism
Receptors, Thyroid Hormone / metabolism*
Structure-Activity Relationship
Triiodothyronine / antagonists & inhibitors
Reg. No./Substance:
0/Receptors, Thyroid Hormone; 1951-25-3/Amiodarone; 6893-02-3/Triiodothyronine; 83409-32-9/desethylamiodarone

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