Pharmacodynamic studies of amiodarone and its active N-desethyl metabolite
Nattel, S.
Journal of Cardiovascular Pharmacology 8(4): 771-777
1986
ISSN/ISBN: 0160-2446 PMID: 2427817 Document Number: 284001
Electrophysiologic effects of the N-deethyl metabolite of amiodarone have been postulated to explain differences between the effects of acute and chronic amiodarone administration. To compare the effects of aminodarone and deethylamidarone, each agent was administered to Sprague-Dawley rats, and the relationship between plasma drug concentrations, measured by high-pressure liquid chromatography (HPLC), and changes in electrocardiographic intervals was observed. Both drugs produced concentration-related increases in QRS, QT, and QTc intervals. Deethylamiodarone altered these variables with a potency significantly greater than that of amiodarone after both single-dose and chronic (for 1 or 4 weeks) therapy. In contrast, chronic administration of amidodarone (but not of deethylamiodarone) produced concentration-related increases in RR and PR intervals. Some of the potency differences between these agents may have been due to greater myocardial concentration of deethylamiodarone as compared to amiodarone. These experiments suggest that deethylamiodarone has potentially important electrophysiologic effects, differing in some respects from those of the parent compound. The accumulation of deethylamiodarone in patients chronically treated with amiodarone may result in significant electrophysiologic changes.