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 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 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 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.
National Institute of Food and Drug Safety Evaluation, Cheongwon-gun, Chungbuk, Korea.
Seol-Hee
SH
Jeon
Jun
J
Jaekal
Seung Ho
SH
Lee
Bok-Hee
BH
Choi
Ki-Suk
KS
Kim
Ho-Sang
HS
Jeong
Soon Young
SY
Han
Eun-Jung
EJ
Kim
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000009:adverse effects / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D004285:Dogs; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography / Q000187:drug effects; D051638:Ether-A-Go-Go Potassium Channels / Q000502:physiology; D057809:HEK293 Cells; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D009661:Nortriptyline / Q000009:adverse effects / Q000494:pharmacology*; D011690:Purkinje Fibers / Q000187:drug effects / Q000502:physiology; D011817:Rabbits
D000929:Antidepressive Agents, Tricyclic; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D009661:Nortriptyline