Effects of H1 antihistamines on animal models of QTc prolongation.

OBJECTIVE: The clinical use of some nonsedating H1 antihistamines (histamine H1 receptor antagonists) has been associated with a rare but life-threatening type of arrhythmia, torsade de pointes, especially when these drugs are coadministered with cytochrome P450 (CYP) 3A4 enzyme inhibitors. On the basis of the latter observation and the fact that most of these H1 antihistamines undergo extensive first-pass metabolism to active metabolites apparently devoid of cardiovascular adverse effects, this arrhythmogenicity has been attributed to the parent drug. The objective of this study was to find an animal model with the ability to predict the proclivity of drugs to produce torsade de pointes.
DESIGN: Two experimental approaches were used: (i) blockade of CYP3A4 metabolism by coadministration of ketoconazole to increase the plasma concentrations of the parent compound in the conscious guinea-pig, and (ii) administration of the compound directly into the coronary circulation of the anaesthetised dog in order to circumvent first-pass metabolism.
RESULTS: The first approach demonstrated that terfenadine administered in the presence of ketoconazole prolongs the corrected QT (QTc) interval of the electrocardiogram, whereas ebastine does not. Similarly, when terfenadine was administered through the coronary circulation, a statistically significant increase in the QTc interval was also seen, whereas ebastine and carebastine were without effect. Thus, it is clear that ebastine was much better tolerated than terfenadine from a cardiovascular standpoint, since ebastine and its metabolite are devoid of effects on cardiac repolarisation, as measured by the QTc interval in these animal models.