Effects of nortriptyline on QT prolongation: A safety pharmacology study
| Autor: | Jun Jaekal, Bok-Hee Choi, Ki-Suk Kim, Ho-Sang Jeong, Eunjung Kim, Seol-Hee Jeon, Seungho Lee, Soon Young Han |
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| Rok vydání: | 2011 |
| Předmět: |
Male
ERG1 Potassium Channel medicine.medical_specialty Purkinje fibers Health Toxicology and Mutagenesis hERG Action Potentials Blood Pressure Torsades de pointes Nortriptyline Antidepressive Agents Tricyclic In Vitro Techniques Pharmacology Toxicology QT interval Sudden death Purkinje Fibers Electrocardiography Dogs Heart Rate Internal medicine medicine Animals Humans Amitriptyline biology business.industry Safety pharmacology General Medicine medicine.disease Ether-A-Go-Go Potassium Channels Long QT Syndrome HEK293 Cells medicine.anatomical_structure Endocrinology biology.protein Rabbits business medicine.drug |
| Zdroj: | Human & Experimental Toxicology. 30:1649-1656 |
| ISSN: | 1477-0903 0960-3271 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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