QT-RR relationships and suitable QT correction formulas for halothane-anesthetized dogs.
Several QT correction (QTc) formulas have been used for assessing the QT liability of drugs. However, they are known to under- and over-correct the QT interval and tend to be specific to species and experimental conditions. The purpose of this study was to determine a suitable formula for halothane-anesthetized dogs highly sensitive to drug-induced QT interval prolongation. Twenty dogs were anesthetized with 1.5% halothane and the relationship between the QT and RR intervals were obtained by changing the heart rate under atrial pacing conditions. The QT interval was corrected for the RR interval by applying 4 published formulas (Bazett, Fridericia, Van de Water, and Matsunaga); Fridericia's formula (QTcF = QT/RR(0.33)) showed the least slope and lowest R(2) value for the linear regression of QTc intervals against RR intervals, indicating that it dissociated changes in heart rate most effectively. An optimized formula (QTcX = QT/RR(0.3879)) is defined by analysis of covariance and represents a correction algorithm superior to Fridericia's formula. For both Fridericia's and the optimized formula, QT-prolonging drugs (d,l-sotalol, astemizole) showed QTc interval prolongation. A non-QT-prolonging drug (d,l-propranolol) failed to prolong the QTc interval. In addition, drug-induced changes in QTcF and QTcX intervals were highly correlated with those of the QT interval paced at a cycle length of 500 msec. These findings suggest that Fridericia's and the optimized formula, although the optimized is a little bit better, are suitable for correcting the QT interval in halothane-anesthetized dogs and help to evaluate the potential QT prolongation of drugs with high accuracy.
Tabo
Mitsuyasu
M
Safety Assessment Department, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan. tabomty@chugai-pharm.co.jp
Nakamura
Mikiko
M
Kimura
Kazuya
K
Ito
Shigeo
S
D000704:Analysis of Variance; D000758:Anesthesia; D000818:Animals; D016589:Astemizole / Q000494:pharmacology; D004285:Dogs; D004562:Electrocardiography / Q000187:drug effects*; D006221:Halothane / Q000494:pharmacology*; D008297:Male; D011433:Propranolol / Q000494:pharmacology; D013015:Sotalol / Q000494:pharmacology
D016589:Astemizole; D011433:Propranolol; D013015:Sotalol; D006221:Halothane