RT Journal Article
SR Electronic
T1 Electrophysiological Safety of Sertindole in Dogs with Normal and Remodeled Hearts
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 776
OP 784
DO 10.1124/jpet.103.052753
VO 307
IS 2
A1 Morten B. Thomsen
A1 Paul G. A. Volders
A1 Milan Stengl
A1 Roel L. H. M. G. Späatjens
A1 Jet D. M. Beekman
A1 Ulrike Bischoff
A1 Morten A. Kall
A1 Kristen Frederiksen
A1 Jørgen Matz
A1 Marc A. Vos
YR 2003
UL http://jpet.aspetjournals.org/content/307/2/776.abstract
AB 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 μM), 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. The American Society for Pharmacology and Experimental Therapeutics