Pharmacodynamic studies of amiodarone and its active N-desethyl metabolite.
Electrophysiologic effects of the N-desethyl metabolite of amiodarone have been postulated to explain differences between the effects of acute and chronic amiodarone administration. To compare the effects of amiodarone and desethylamiodarone, 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. Desethylamiodarone 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 amiodarone (but not of desethylamiodarone) 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 desethylamiodarone as compared to amiodarone. These experiments suggest that desethylamiodarone has potentially important electrophysiologic effects, differing in some respects from those of the parent compound. The accumulation of desethylamiodarone in patients chronically treated with amiodarone may result in significant electrophysiologic changes.
D000273:Adipose Tissue / Q000378:metabolism; D000638:Amiodarone / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009206:Myocardium / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D001572:Benzofurans; C036116:desethylamiodarone; D000638:Amiodarone