Comparison of acute electrophysiological effects of amiodarone and its metabolite desethylamiodarone in Langendorff perfused guinea pig hearts

Abstract

During long-term treatment with amiodarone, slowing of conduction through the atrioventricular node, a prolongation of the QT-interval, and a prolongation of the atrial and ventricular myocardial refractoriness always developed. During short-term treatment, these effects were not found, except for depression of the AV-nodal conduction. This led to the suggestion that the electrophysiological effects of amiodarone during long-term treatment might be partly the result of the accumulation of its metabolite desethylamiodarone. Therefore, we examined the electrophysiological effects of amiodarone and desethylamiodarone on conduction and refractoriness in isolated spontaneously beating guinea pig hearts perfused by the method of Langendorff. Within 1 h of perfusion, desethylamiodarone caused a more pronounced prolongation of the AV-nodal, His-bundle, and intraventricular conduction intervals than did amiodarone. Desethylamiodarone, but not amiodarone led to a prolongation of the QT-interval. The refractoriness of sinoatrial-, AV-nodal conduction, and of the atrial myocardium were significantly more prolonged by amiodarone than by desethylamiodarone. Both compounds showed a comparable strong rate-dependent effect on AV-nodal refractoriness. The ventricular refractoriness was similarily prolonged by either compound. These results show that for the class-III effects (i.e., prolongation of repolarization period) observed under chronic treatment of amiodarone the metabolite desethylamiodarone may be responsible. Desethylamiodarone also exerts more pronounced effects on the fast-channel-dependent parts of the conduction system than does amiodarone, a fact indicated by a higher prolongation of His-bundle and intraventricular conduction.

Acute effects of escalating doses of amiodarone in isolated guinea pig hearts

“…The observation that this electrical restitution is preserved with amiodarone supports the contention that amiodarone does not posses a significant liability to produce torsade de pointes. Stark et al (1991), in preparations of guinea pig hearts nearly identical to ours, found that desethylamiodarone, the active metabolite of amiodarone, was principally responsible for prolongation of QT. Because in our preparation the perfusate is not recycled and obviously there is no hepatic metabolism of the parent compound, amiodarone alone must be responsible for prolongation of both QT and QTc intervals.…”

“…The observation that this electrical restitution is preserved with amiodarone supports the contention that amiodarone does not posses a significant liability to produce torsade de pointes. Stark et al . (1991), in preparations of guinea pig hearts nearly identical to ours, found that desethylamiodarone, the active metabolite of amiodarone, was principally responsible for prolongation of QT.…”

“…(1995) found prolongation of RR, QRS and QT comparable with those in our study. In yet another study on isolated perfused guinea pig hearts exposed to 10 –5 M concentration of amiodarone, Stark et al . (1991) found prolongation of RR and PQ intervals, but no lengthening of QT.…”

The metabolism of amiodarone by various CYP isoenzymes of human and rat, and the inhibitory influence of ketoconazole

“…Similar to the parent drug, DEA possesses antiarrhythmic activity of its own. Indeed, because it takes less time to exert its effect, DEA has been proposed to be a more advantageous treatment option than AM itself (12). On the negative side, DEA has been found to be more toxic towards thyroid and lung tissues than AM (13,14).…”

The effect of CYP1A induction on amiodarone disposition in the rat

“…These products include mono‐ N ‐desethylamiodarone (DEA), di‐ N ‐desethylamiodarone and deiodinated desethylamiodarone, each of which is present in the blood and/or plasma of human and animal models 7, 9, 10. Of these, DEA is especially important due to its pharmacological and toxicological activities and the presence of high circulating plasma and tissue levels in humans, which may exceed the concentrations of the parent drug itself 3, 11–14. Similar to AM, strong correlations have been observed between DEA plasma and/or myocardial concentrations and electrocardiographic parameters 15, 16.…”