Sensitivity and specificity of isolated perfused guinea pig heart to test for drug-induced lengthening of QTc.
BACKGROUND
The purpose of this study was to determine the sensitivity and specificity for predicting the liability of a compound to lengthen QTc using isolated, perfused guinea pig hearts (Langendorff preparation).


METHODS
QTc (Fridericia correction) was calculated from bipolar transventricular electrograms. Hearts were exposed to escalating concentrations of 26 compounds thought to lengthen, and 13 compounds thought not to lengthen, QTc in humans.


RESULTS
In this preparation, QTc was found to lengthen in 26 of 26 compounds thought to be positive (sensitivity 1.00) and not to lengthen or to lengthen insignificantly in 13 of 13 compounds thought to be negative (specificity 1.0) in man. Probucol and ontazolast could not be studied because of limited solubility. Successful experiments were conducted on over 98% of guinea pigs anesthetized.


CONCLUSIONS
We believe that the isolated perfused guinea pig heart is an in vitro preparation that could be utilized early in preclinical testing for identifying a liability to lengthen QTc in humans, but we do not believe--as is true also for other in vitro methods--that the concentration at which the liability is demonstrated in vitro necessarily predicts the concentration at which a liability exists in man.
Hamlin
R L
RL
QTest Labs, 6456 Fiesta Drive, Columbus, OH 43235, USA. DHamlin@Qtestlabs.com
Cruze
C A
CA
Mittelstadt
S W
SW
Kijtawornrat
A
A
Keene
B W
BW
Roche
B M
BM
Nakayama
T
T
Nakayama
H
H
Hamlin
D M
DM
Arnold
T
T
D000818:Animals; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions; D004562:Electrocardiography / Q000187:drug effects*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006329:Heart Conduction System / Q000187:drug effects / Q000503:physiopathology; D066298:In Vitro Techniques; D008133:Long QT Syndrome / Q000139:chemically induced; D008297:Male; D008954:Models, Biological; D010477:Perfusion; D012680:Sensitivity and Specificity