Amiodarone Inhibits the Conversion of Thyroxine to Triiodothyronine in Isolated Rat Hepatocytes

Abstract

Previous studies have shown decreased T3 and increased T4 and rT3 serum levels in subjects treated with amiodarone. We studied the acute effect of amiodarone on the in vitro conversion of T4 to T3 in suspensions of isolated rat hepatocytes. Iodine and melperone, another class III antiarrhythmic drug, were included in the study as controls. Amiodarone (60 microM) totally blocked the formation of T3 from T4, whereas concentrations of 6 and 0.6 microM reduced T3 formation to 13.7 +/- 10.6% and 63.9 +/- 15.9% (+/- SD), respectively, compared with untreated controls. The drug solvent did not affect the conversion rate. Iodide (120 microM) had an inhibitory effect of approximately 10% compared with the controls, whereas melperone did not affect this in vitro conversion. Amiodarone (60 microM) caused a slight but significant reduction of the cellular uptake of [125I]T4 after 10 min of incubation, whereas the 60 min values were unaltered. Our study indicates that amiodarone inhibits the 5'-monodeiodination of T4 to T3 in a dose-related manner. It is suggested that the antiarrhythmic activity of the drug is related to its inhibitory effect on the conversion of T4 to T3.

Amiodarone: A Common Source of Iodine-Induced Thyrotoxicosis

“…These changes are accompanied dur ing the first 3 months of therapy by an increase in both the basal and TRH-stimulated serum TSH concentrations [23][24][25][26]. This can be explained by: (1) decreased con version of T4 to T 3 in peripheral tissues [23][24][25][26][27][28][29], including the pituitary [30,31]; (2) de creased entrance of T4 and T3 into cells [32,33]; (3) impaired cellular response to T 3 [34], However, after prolonged amiodarone treat ment, serum TSH concentrations normalize and the response to TRH may be absent or blunted in euthyroid patients [25,35], Amiodarone can cause both hyperthy roidism or hypothyroidism [15,[35][36][37][38][39][40][41][42][43][44][45][46][47][48][49], pos sibly by altering intrathyroidal autorcgulatory mechanisms. The occurrence of AIIT ranges from less than 1 % to 20% of patients chronically treated, probably depending on environmental iodine intake.…”

Structure–activity relationships of antiarrhythmic agents: crystal structure of amiodarone hydrochloride and two derivatives, and their conformational comparison with thyroxine

“…Amiodarone is a potent antiarrhythmic agent which acts by lengthening repolarization in the myocardium. It has been shown to have many diverse effects on thyroid-hormone metabolism, transport and action causing reduced peripheral conversion of thyroxine (Ta) to 3,5,3'-triiodothyronine (T3) owing to impaired hepatic deiodinase activity (Sogol, Hershman, Reed & Dillmann, 1983;Aanderud, Sundsfjord & Aarbakke, 1984;Kannan, Ookhtens, Chopra & Singh, 1984). In addition, there is a reduction in heart rate and cardiac Ca2+-activated myosin ATPase activity.…”

Effects of amiodarone on 5′-deiodination of thyroxine to tri-iodothyronine in rat myocardium

“…It follows that inhibition INTRODUCTION Amiodarone (AMD) has proved to be a potent antiarrhythmic compound, even though its mechanism of action remains unknown. Since AMD blocks the deiodination of thyroxine (T4) to tri-iodothyronine (T3) and since the major portion of the extrathyroidal T3 pool is derived from the deiodinating activity (Schwarz, Surks & Oppenheimer, 1971 ;Larsen, Silva & Kaplan, 1981) it has been suggested that the decreased supply of T3 to the myocardium could mediate the antiarrhythmic action of AMD (Aanderud, Sundsfjord & Aarbakke, 1984). This contention found support in the observation that AMD produced a generalized hypometabolic effect, electrophysiological patterns as in hypothyroidism (Singh & Vaughan Williams, 1970), bradycardia (Melmed, Nademanee, Reed et al 1981), decreased oxygen consumption and prolongation of the duration of atrial and ventricular action potentials (Singh et al 1970).…”