Electrophysiological safety of sertindole in dogs with normal and remodeled hearts.
Inhibition of the potassium current IKr and QT prolongation are associated with drug-induced torsades de pointes arrhythmias (TdP) and sudden cardiac death. We investigated the cardiac electrophysiological effects of sertindole, an antipsychotic drug reported to prolong the QT interval in schizophrenic patients. In cell cultures, sertindole seemed to be a selective blocker of IHERG over other ion currents. For IHERG, the IC50 value was 64 +/- 7 nM, whereas ISCN5A, ICa,L, ICa,T, IKCNQ1/KCNE1, and IKv4.3 were blocked in the micromolar range. In canine ventricular myocytes, the IC50 value for IKr inhibition by sertindole was 107 +/- 21 nM. Action potentials in these cells prolonged in a reverse rate- and concentration-dependent manner at 10 to 300 nM sertindole. In vivo, sertindole was administered to anesthetized dogs at clinically relevant (0.05-0.20 mg/kg) and high doses (1.0-2.0 mg/kg) i.v. At 0.05 to 0.20 mg/kg sertindole (plasma concentrations 30-157 nM), QTc was prolonged by 1 to 5% in normal dogs and by 9 to 20% in dogs with remodeled hearts due to chronic atrioventricular block (CAVB). TdP was not induced at these doses in normal dogs or in CAVB dogs with reproducible induction of TdP by dofetilide in previous experiments. At 1.0 to 2.0 mg/kg sertindole (plasma concentrations 0.5-3.1 microM), QTc prolonged by 6 to 11% in normal dogs and by 22% in dofetilide-sensitive CAVB dogs. TdP occurred in three of five animals in the latter group. Thus, at high i.v. doses sertindole can pose a serious proarrhythmic risk when electrical remodeling of the ventricles is present. At clinically relevant doses, however, sertindole does not cause TdP in anesthetized dogs with normal or remodeled hearts.
Thomsen
Morten B
MB
Department of Cardiology, Cardiovascular Research Institute Maastricht, Academic Hospital Maastricht, P.O. Box 5800, NL 6202 AZ, Maastricht, The Netherlands.
Volders
Paul G A
PG
Stengl
Milan
M
Spätjens
Roel L H M G
RL
Beekman
Jet D M
JD
Bischoff
Ulrike
U
Kall
Morten A
MA
Frederiksen
Kristen
K
Matz
Jørgen
J
Vos
Marc A
MA
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D004285:Dogs; D004594:Electrophysiology; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D007093:Imidazoles / Q000009:adverse effects / Q000494:pharmacology*; D007211:Indoles / Q000009:adverse effects / Q000494:pharmacology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D010627:Phenethylamines / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology
D014150:Antipsychotic Agents; D007093:Imidazoles; D007211:Indoles; D010627:Phenethylamines; D013449:Sulfonamides; C066304:sertindole; C063533:dofetilide