Effects of nortriptyline on QT prolongation: A safety pharmacology study

• Published in: Human & experimental toxicology 2011-10, Vol.30 (10), p.1649-1656
• Main Authors: Jeon, Seol-Hee, Jaekal, Jun, Lee, Seung Ho, Choi, Bok-Hee, Kim, Ki-Suk, Jeong, Ho-Sang, Han, Soon Young, Kim, Eun-Jung
• Format: Article
• Language: English
• Subjects: Action Potentials - drug effects; Animals; Antidepressants; Antidepressive Agents, Tricyclic - adverse effects; Antidepressive Agents, Tricyclic - pharmacology; Biological and medical sciences; Blood Pressure - drug effects; Cardiac dysrhythmias; Cardiology; Cardiology. Vascular system; Dogs; Electrocardiography - drug effects; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels - physiology; Heart; Heart Rate - drug effects; HEK293 Cells; Humans; In Vitro Techniques; Long QT Syndrome - chemically induced; Male; Medical sciences; Nortriptyline - adverse effects; Nortriptyline - pharmacology; Patient safety; Pharmacology; Purkinje Fibers - drug effects; Purkinje Fibers - physiology; Rabbits; Side effects; Toxicology
• ISSN: 0960-3271; 1477-0903
• DOI: 10.1177/0960327110396528

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 IC50 value of 2.20 ± 0.09 μM (n = 4). In the APD assay, total amplitude, Vmax, and resting membrane potential were not significantly changed by 1 μM nortriptyline, but nortriptyline at 0.3 and 1 μM shortened APD50 and APD90. 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.