Evaluation of terfenadine and ketoconazole-induced QT prolongation in conscious telemetered guinea pigs

Abstract

Abstract:Terfenadine and ketoconazole are the most widely used positive reference agents in non-clinical cardiac repolarization safety studies. The aim of the present study was to evaluate the effects of terfenadine, ketoconazole and their combination on QT prolongation using conscious guinea pigs. Conscious telemetered guinea pigs were orally administered terfenadine (50 mg/kg), ketoconazole (200 mg/kg) or a combination of the two, and effects on QT were recorded using a telemetry system. The QT correction was carried out with Bazett's formula to eliminate confounding effect of HR. Neither terfenadine nor ketoconazole produced any effect on the RR and QT intervals, QRS complex or heart rate (HR). However, a combination of terfenadine and ketoconazole significantly prolonged the RR and QT intervals and decreased HR in a time-dependent manner. This study demonstrated that the combination of terfenadine and ketoconazole produces QT prolongation in conscious telemetered guinea pigs.

Comparative study of the protective effects of terfenadine and amiodarone on barium chloride/aconitine-induced ventricular arrhythmias in rats: A potential role of terfenadine

“…Measurement of ECG parameters following administration of terfenadine at different concentrations. Previous studies have reported that terfenadine prolonged the QT interval in a dose-dependent manner (10,14,15). In the present study, the impact of terfenadine on the QT interval was also examined.…”

“…A recent study also reported that the use of terfenadine alone did not produce an effect on the RR and QT intervals, QRS complex or heart rate in guinea pigs. However, a combined oral dose of terfenadine and ketoconazole significantly prolonged the RR and QT intervals and decreased the heart rate in a time-dependent manner (10). In another recent study, to detect whether the effect of terfenadine on K + channels was separated from the antihistaminic activity, a series of analogs of terfenadine were prepared with structural variations, and the results demonstrated that the ability to inhibit K + channels was generally in parallel with the antihistaminic activity (11).…”

Metabolic and electrolyte abnormalities as risk factors in drug-induced long QT syndrome

“…Since this enzyme is a major metaboliser of many QT prolonging drugs, this reduction in CYP3A activity can lead to altered pharmacokinetics and hence a greater plasma concentration of either drug (Zhi et al 2015 ). This link between inhibition of drug metabolism and proarrhythmia has been observed across multiple studies including reports that ketoconazole, erythromycin, diltiazem, itraconazole and grapefruit juice — all inhibitors of cytochrome P450 enzymes — have resulted in increased serum concentration of terfenadine, halofantrine and cisapride, leading to QT prolongation and TdP (Charbit et al 2002 ; Paris et al 1994 ; Pohjola-Sintonen et al 1993 ; Rajput et al 2010 ; Thomas et al 1998 ). This phenomenon has also been detected in larger cohorts where coadministration of ketoconazole with domperidone was found to triple the plasma concentration of domperidone, exacerbating QTc prolongation to clinically significant levels, over and above that observed for either agent alone (Boyce et al 2012 ).…”

Safety Pharmacological studies of Kalyanaka ghrita

“…Several drugs have minor or major unwanted side effects. Early detection of these drawbacks was performed by safety pharmacology studies which majorly impact cardiovascular system (Rajput et al, 2010). The cardiovascular system is examined for alterations in ventricular depolarization and repolarization, as well as the QT interval, which is de ined as the time between the commencement of the QRS complex and the end of the electrocardiogram's T wave (ECG) (Redfern et al, 2003) and (Malik and Camm, 2001).…”