triiodothyronine--reverse and desethylamiodarone

The basis for the unique effectiveness of long-term amiodarone treatment on cardiac arrhythmias is incompletely understood. The present study investigated the pharmacogenomic profile of amiodarone on genes encoding ion-channel subunits.. Adult male mice were treated for 6 weeks with vehicle or oral amiodarone at 30, 90, or 180 mg x kg(-1) x d(-1). Plasma and myocardial levels of amiodarone and N-desethylamiodarone increased dose-dependently, reaching therapeutic ranges observed in human. Plasma triiodothyronine levels decreased, whereas reverse triiodothyronine levels increased in amiodarone-treated animals. In ECG recordings, amiodarone dose-dependently prolonged the RR, PR, QRS, and corrected QT intervals. Specific microarrays containing probes for the complete ion-channel repertoire (IonChips) and real-time reverse transcription-polymerase chain reaction experiments demonstrated that amiodarone induced a dose-dependent remodeling in multiple ion-channel subunits. Genes encoding Na+ (SCN4A, SCN5A, SCN1B), connexin (GJA1), Ca2+ (CaCNA1C), and K+ channels (KCNA5, KCNB1, KCND2) were downregulated. In patch-clamp experiments, lower expression of K+ and Na+ channel genes was associated with decreased I(to,f), I(K,slow), and I(Na) currents. Inversely, other K+ channel alpha- and beta-subunits, such as KCNA4, KCNK1, KCNAB1, and KCNE3, were upregulated.. Long-term amiodarone treatment induces a dose-dependent remodeling of ion-channel expression that is correlated with the cardiac electrophysiologic effects of the drug. This profile cannot be attributed solely to the amiodarone-induced cardiac hypothyroidism syndrome. Thus, in addition to the direct effect of the drug on membrane proteins, part of the therapeutic action of long-term amiodarone treatment is likely related to its effect on ion-channel transcripts.

Topics: Amiodarone; Animals; Anti-Arrhythmia Agents; Gene Expression Regulation; Ion Channels; Male; Mice; Mice, Inbred C57BL; Myocardium; Patch-Clamp Techniques; RNA, Messenger; Transcription, Genetic; Triiodothyronine; Triiodothyronine, Reverse

The effects of amiodarone, an iodinated antiarrhythmic drug, on thyroid hormone metabolism are known. It is not known whether the main metabolite, desethylamiodarone, is responsible. We investigated the influence of both compounds on the intracellular rT3, T4, and T3 concentrations in tissues of the rat, the source of T3 (plasma-derived vs. produced locally from T4) and T3 and T4 production by the thyroid. Special attention is paid to the heart. We found that both amiodarone and desethylamiodarone cause a decrease in intracellular T3 in all tissues (P less than 0.001), in most tissues an increase in T4 and a greater increase in the rT3 concentration. Both compounds inhibit both deiodination (P less than 0.0001) and T3 production by the thyroid (P less than 0.0001); T4 production was enhanced (P less than 0.05). In the heart a hypothyroid-like state, caused by decreased plasma-derived T3 (P less than 0.0001), was found. But a pool of T3 produced locally from T4 was present (21% of the total T3, P less than 0.01), which has never been demonstrated under normal conditions. This pool might play a role in the mechanism of action of the drugs. Differences between the drugs were organ-specific, but the effects of desethylamiodarone were as strong as or stronger than those of amiodarone. We conclude that desethylamiodarone was responsible for the changes, although the possibility of a common metabolite, generated later, has not been excluded.

Topics: Adipose Tissue, Brown; Amiodarone; Animals; Brain; Heart; Liver; Male; Myocardium; Organ Specificity; Pituitary Gland; Prostate; Rats; Rats, Inbred Strains; Testis; Thyroid Gland; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

Desethylamiodarone is the principal metabolite of amiodarone. Amiodarone is a class III antiarrhythmic agent, which acts by lengthening repolarization in the myocardium, an effect that is identical to that produced by hypothyroidism. Amiodarone is known to alter thyroid hormone metabolism, and it has been suggested that the mechanism underlying its antiarrhythmic action is the induction of a myocardial but not generalized hypothyroidism. Since the serum levels of desethylamiodarone reach those of the parent compound during chronic amiodarone therapy, it has been suggested that at least part of amiodarone's pharmacological effects may be attributable to the additive effects of the metabolite. Therefore, we investigated the effects of desethylamiodarone on thyroid hormone metabolism and compared them with those of amiodarone in rats. We have shown that chronic treatment with desethylamiodarone decreased serum T3, markedly increased serum reverse T3 with no significant change in serum T4. These effects are similar to those of amiodarone. The data suggest that the chronic effects of amiodarone on thyroid hormone metabolism may be due at least in part to the actions of desethylamiodarone.

Topics: Amiodarone; Animals; Benzofurans; Chemical Phenomena; Chemistry; Male; Rats; Rats, Inbred F344; Thyroid Hormones; Thyroxine; Triiodothyronine; Triiodothyronine, Reverse

The interrelationships between serum levels of amiodarone, desethylamiodarone, and reverse T3, and changes in the corrected QT interval (delta QTc) were examined in 22 patients during long-term treatment with amiodarone. At 1, 3, and 6 months of follow-up, the correlation coefficient between serum levels of amiodarone or desethylamiodarone and reverse T3 ranged from 0.01 to -0.2 (p greater than 0.4). At the same time intervals, the correlation coefficient between both amiodarone and desethylamiodarone levels and delta QTc ranged from 0.1 to -0.1 (p greater than 0.6), and the correlation coefficient between reverse T3 and delta QTc also ranged between 0.1 to -0.1 (p greater than 0.5). Substituting percent delta QTc for delta QTc also did not reveal a significant correlation. These data demonstrate that serum levels of reverse T3 cannot be used as a substitute for serum levels of amiodarone in monitoring patients being treated with amiodarone. The absence of a correlation between serum reverse T3 levels and delta QTc suggests that the delay in repolarization which occurs during amiodarone therapy is not secondary to an amiodarone-induced abnormality in thyroid hormone metabolism.

Topics: Adult; Aged; Amiodarone; Arrhythmias, Cardiac; Benzofurans; Electrocardiography; Female; Follow-Up Studies; Humans; Male; Middle Aged; Time Factors; Triiodothyronine, Reverse