The role of ketoconazole in the QTc interval prolonging effects of H₁‐antihistamines in a guinea‐pig model of arrhythmogenicity

Abstract

We have carried out experiments to re-evaluate the influence of ketoconazole (400 mg kg-1,p.o.) on the effects of ebastine, terfenadine and loratadine on the QTc interval in conscious guinea-pigs. Following a previously described protocol of oral drug administration, but using telemetric recording of the ECG, we have found that the prolongation of the QTc interval attributed to ebastine and terfenadine is in fact entirely due to ketoconazole, and that neither terfenadine, ebastine nor loratadine produce any additional effects on subsequent administration.

Supplemental Studies for Cardiovascular Risk Assessment in Safety Pharmacology: A Critical Overview

“…However, as compared to the anesthetized guinea-pig model, there are relatively few reports on cardiovascular effects of drugs obtained from conscious guinea-pigs, particularly from studies using telemetry. This lack of in vivo data can be explained at least partly by the difficulties to achieve proper anesthesia/surgery and appropriate placement of ABP catheters in guinea-pigs as compared to other species [98][99][100][101]. Some teams use restrained conscious guinea-pigs, maintained quiet in slings, to assess the proarrhythmic liabilities of drugs.…”

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

“…Although QT prolongation and/or torsades de pointes caused by coadministration of terfenadine and ketoconazole has been studied in animals and humans [16,17], most of the studies were done in anesthetized animals [1,4,5]. With the use of a telemetry system, experimentation can be performed on conscious unstressed animals [7,13,[19][20][21]. Few studies have reported the ef-fects of drug-induced QT interval prolongation in conscious guinea pigs using a telemetry system [7,21].…”

“…With the use of a telemetry system, experimentation can be performed on conscious unstressed animals [7,13,[19][20][21]. Few studies have reported the ef-fects of drug-induced QT interval prolongation in conscious guinea pigs using a telemetry system [7,21]. Among them, a high dose of ketoconazole (400 mg/kg, po) administered to guinea pigs induced a significant prolongation of the QTc interval [7].…”

“…Few studies have reported the ef-fects of drug-induced QT interval prolongation in conscious guinea pigs using a telemetry system [7,21]. Among them, a high dose of ketoconazole (400 mg/kg, po) administered to guinea pigs induced a significant prolongation of the QTc interval [7]. The subsequent administration of terfenadine (120 mg/kg, po) 120 min after ketoconazole administration did not show any further increase in QTc interval.…”

Effects of 5-HT₄ Receptor Agonist Prokinetic Agents on the Action Potential Parameters of Isolated Rabbit Myocardium

“…In fact, these drugs administered orally at an overdose or concomitantly with ketoconazole, erythromycin or itraconazole, which inhibit hepatic cytochrome P450, lead to QT interval prolongation. Some possibilities have been proposed as a common mechanism for these noncardiovascular drugs to produce QT prolongation [13,14].…”