Effects of nortriptyline on QT prolongation: A safety pharmacology study
Effects of nortriptyline on QT prolongation: A safety pharmacology study
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DOI：
10.1177/0960327110396528
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发表时间：
2011-10-01
影响因子：
2.8
通讯作者：
Kim, Eun-Jung
中科院分区：
文献类型：
--
作者：
Jeon, Seol-Hee;Jaekal, Jun;Kim, Eun-Jung
去甲替林是第二代三环类抗抑郁药，是阿米替林的活性代谢物。阿米替林可引起QT延长和尖端扭转肌(TDP)，导致猝死。我们研究了去甲替林的心血管安全性，包括QT延长的风险。根据ICH-S7B指南，我们检测了去甲替林在体内和体外对心血管系统的影响。我们在清醒的遥测狗身上测试了它对QT间期的影响。我们还利用稳定转染人胚胎肾293(HEK293)细胞进行了HERG尾电流的体外电生理学研究。研究了分离的兔浦肯野纤维的动作电位参数。去甲替林可剂量依赖性地阻断Herg电流，其尾部IC(50)值为2.20+/-0.09µM(n=-4)。在动作电位时程测定中，1mU M去甲替林对总波幅、Vmax和静息膜电位无明显影响，但0.3和1mU M去甲替林使动作电位时程(50)和时程(90)缩短。去甲替林在2 mg/kg和6 mg/kg时对QTcV无影响，但在20 mg/kg时略有增加。综上所述，去甲替林在治疗剂量下不太可能影响心室复极过程。
Nortriptyline, a second-generation tricyclic antidepressant, is an active metabolite of amitriptyline. Amitriptyline induces QT prolongation and torsades de pointes (TdP), which causes sudden death. We studied the cardiovascular safety of nortriptyline, including QT prolongation risk. We examined the effects of nortriptyline on the cardiovascular system in vivo and in vitro in accordance with the ICH-S7B guideline. We tested its effect on QT interval in conscious telemetered dogs. We also performed in vitro electrophysiological studies on hERG tail currents using stably transfected human embryonic kidney 293 (HEK293) cells. Action potential parameters were studied in isolated rabbit purkinje fibers. Nortriptyline dose-dependently blocked hERG current, with a tail IC(50) value of 2.20 +/- 0.09 mu M (n =-4). In the APD assay, total amplitude, Vmax, and resting membrane potential were not significantly changed by 1 mu M nortriptyline, but nortriptyline at 0.3 and 1 mu M shortened APD(50) and APD(90). Nortriptyline did not affect QTcV at 2 or 6 mg/kg, but slightly increased QTcV at 20 mg/kg. In conclusion, it is unlikely that nortriptyline affects the ventricular repolarization process at therapeutic dosages.