Effects of nortriptyline on QT prolongation: A safety pharmacology study

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 th...

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Bibliographic Details
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
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Summary: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.
ISSN:0960-3271
1477-0903
DOI:10.1177/0960327110396528