ELECTROPHYSIOLOGIC EFFECTS OF DESETHYLAMIODARONE, AN ACTIVE METABOLITE OF AMIODARONE - COMPARISON WITH AMIODARONE DURING CHRONIC ADMINISTRATION IN RABBITS
ELECTROPHYSIOLOGIC EFFECTS OF DESETHYLAMIODARONE, AN ACTIVE METABOLITE OF AMIODARONE - COMPARISON WITH AMIODARONE DURING CHRONIC ADMINISTRATION IN RABBITS
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DOI：
10.1016/0002-8703(88)90481-4
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发表时间：
1988-02-01
影响因子：
4.8
通讯作者：
SINGH, BN
中科院分区：
文献类型：
--
作者：
KATO, R;VENKATESH, N;SINGH, BN
在通过标准微电极技术进行的急性灌注研究中，我们之前表明，在高药物浓度下，胺碘酮及其主要代谢物去乙基胺碘酮对动作电位持续时间（APD）的延长有适度的影响，并对心肌钠通道产生速率依赖性阻断。在本研究中，比较了这两种化合物对长期服用这两种化合物的家兔的电生理效应，特别参考了复极和窦结自动性。其变化与血清、组织药物水平及甲状腺激素指标相关。1周后，两种药物对心房或窦房结电位均无显著影响；治疗3周后，胺碘酮使90%复极时心房APD增加10.5% (p < 0.05)，有效不应期（ERP）增加6.7% （p < 0.05）。去乙基胺酮的相应数字分别为13% （NS）和18% （NS）。胺碘酮组窦循环长度增加12% (NS)，代谢物组窦循环长度增加27.9% （p < 0.05）。治疗6周后，胺碘酮使复极率为90%的心室APD增加58.8% (p < 0.01)，去乙基胺碘酮使复极率为42.0%，ERP分别增加63.4% （p < 0.01）和47.4% （p < 0.01）。在使用的刺激频率下，两种化合物对Vmax都没有显著影响。胺碘酮和去乙基胺碘酮均能显著降低血清三碘甲状腺原氨酸水平，并增加逆转三碘甲状腺原氨酸水平，但对甲状腺素无影响。电生理效应和甲状腺激素指标与胺碘酮或去乙基胺碘酮的血清或组织水平均无系统关系。数据表明，慢性给药后，去乙胺酮产生电生理效应，其强度和发病潜伏期与母体化合物相当。该代谢物具有显著的电生理效应，在慢性给药过程中可能会与母体化合物的效应叠加。
During acute superfusion studies by means of the standard microelectrode technique, we previously showed that both amiodarone and its major metabolite, desethylamiodarone, had a modest effect on the lengthening of the action potential duration (APD) at high drug concentrations and produced a rate-dependent block of the sodium channel in cardiac muscle. In this study the comparative electrophysiologic effects of the two compounds in rabbits treated chronically with these compounds were determined with particular reference to repolarization and sinus node automaticity. The changes were correlated with those in serum and tissue drug levels and in thyroid hormone indices. After 1 week neither compound had a significnat effect on atrial or sinus nodal potentials; after 3 weeks, amiodarone increased the atrial APD at 90% repolarization time by 10.5% (p < 0.05) and the effective refractory period (ERP) by 6.7% (p < 0.05). The corresponding figures for desethylaminodarone were 13% (NS) and 18% (NS). The sinus cycle length was increased 12% (NS) by amiodarone and 27.9% (p < 0.05) after the metabolite. In animals treated for 6 weeks, amiodarone increased the ventricular APD at 90% repolarization by 58.8% (p < 0.01) and desethylamiodarone by 42.0% the corresponding figures for the ERP were 63.4% (p < 0.01 and 47.4% (p < 0.01), respectively. At the stimulation frequency used, neither compound exerted a significant effect on Vmax. Both amiodarone and desethylamiodarone significantly decreased serum triiodothyronine and increased reverse triiodothyronine levels but had no effect on thyroxine. Neither the electrophysiologic effects nor those in thyroid hormone indices could be related systematically to the serum or tissue levels of amiodarone or desethylamiodarone. The data indicate the after chronic drug administration, desethylaminodarone exerts electrophysiologic effects, the magnitude and latency of onset of which were comparable to those of the parent compound. The metabolite has significant electrophysiologic effects that are likely to be additive to those of the parent compound during chronic administration.