Assessment of drug-induced QT interval prolongation in conscious rabbits.
BACKGROUND
Most preclinical trials are designed to identify potential torsadogenicity test only for surrogates of torsade de pointes, most commonly prolongation of the heart rate corrected QT interval (QTc). This study was conducted to determine which correction method best accounts for the effects of changes in the RR interval on the QT interval of conscious rabbits. This study was also conducted to validate the use of conscious, sling-trained rabbits to assess the QTc interval, and to evaluate the reliability and accuracy of this preparation in predicting drug-induced QTc prolongation in humans.


METHODS
ECGs were recorded via bipolar transthoracic ECG leads in 7 conscious rabbits previously trained to rest quietly in slings. The heart rate was slowed with 2.0 mg/kg zatebradine to assess the effects of heart rate on the QT interval. The same ECG and sling preparation was used to evaluate the effects in of three drugs known to be torsadogenic in humans (cisapride, dofetilide and haloperidol), two drugs known to be non-torsadogenic in humans (propranolol and enalaprilat) and a control article (vehicle). All of the test articles were administered intravenously to 4 rabbits, and both RR and QT intervals were measured and the corrected QT values were calculated by an investigator blinded to the test article, utilizing our own algorithm (QTc=QT/(RR)(0.72)) which permitted the least dependency of QTc on RR interval.


RESULTS
The following regression equations were obtained relating QT to RR: QT=2.4RR(0.72), r(2)=0.79, with RR intervals varying between 210 and 350 ms. QTc lengthened significantly in all conscious rabbits given intravenous cisapride, dofetilide and haloperidol (p<0.05), and QTc did not change with DMSO (vehicle control), propranolol or enalaprilat.


CONCLUSIONS
Results indicate that a bipolar transthoracic ECG recorded in conscious, sling-trained rabbits may provide an easy and economical methodology useful in predicting QTc lengthening of novel pharmacological entities.
Kijtawornrat
A
A
Department of Veterinary Biosciences, The Ohio State University, VMAB 480, 1900 Coffey Road, Columbus, OH 43210-1093, USA.
Ozkanlar
Y
Y
Keene
B W
BW
Roche
B M
BM
Hamlin
D M
DM
Hamlin
R L
RL
D000818:Animals; D020117:Cisapride / Q000009:adverse effects; D003243:Consciousness; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004562:Electrocardiography / Q000295:instrumentation / Q000379:methods*; D015773:Enalaprilat / Q000494:pharmacology; D005260:Female; D006220:Haloperidol / Q000009:adverse effects; D007275:Injections, Intravenous; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D010627:Phenethylamines / Q000009:adverse effects; D011433:Propranolol / Q000494:pharmacology; D011817:Rabbits; D015203:Reproducibility of Results; D013449:Sulfonamides / Q000009:adverse effects; D018675:Toxicity Tests
D010627:Phenethylamines; D013449:Sulfonamides; D011433:Propranolol; D015773:Enalaprilat; D006220:Haloperidol; C063533:dofetilide; D020117:Cisapride