EFFECT OF CONCOMITANT ADMINISTRATION OF CIMETIDINE AND RANITIDINE ON THE PHARMACOKINETICS AND ELECTROCARDIOGRAPHIC EFFECTS OF TERFENADINE

Terfenadine is a widely prescribed non-sedating antihistamine which un dergoes rapid and almost complete first pass biotransformation to an a ctive carboxylic acid metabolite. It is unusual to find unmetabolised terfenadine in the plasma of patients taking the drug. Terfenadine in vitro is a potent blocker of the myocardial potassium channel. Overdos e, hepatic compromise and the coadministration of ketoconazole and ery thromycin result in the accumulation of terfenadine, which is thought to be responsible of QT prolongation and Torsades de Pointes ventricul ar arrhythmia in susceptible individuals. Cimetidine and ranitidine ar e two popular H-2 antagonists which are often taken with terfenadine. The effects of cimetidine and ranitidine on terfenadine metabolism wer e studied in two cohorts of 6 normal volunteers given the recommended dose of terfenadine (60 mg every 12 h) for 1 week prior to initiation of cimetidine 600 mg every 12 h or ranitidine 150 mg every 12 h. Pharm acokinetic profiles and morning pre-dose electrocardiograms were obtai ned whilst the patients were on terfenadine alone and after the additi on of cimetidine or rantidine. One of the subjects in each cohort had a detectable plasma level of parent compound after 1 week of terfenadi ne therapy alone; it did not accumulate further after addition of the H-2 antagonist. The pharmacokinetics of the carboxylic acid metabolite of terfenadine (C(max), t(max), AUC) were not significantly changed a fter co-administration of either H-2 antagonist. None of the remaining 5 subjects in either cohort demonstrated accumulation of unmetabolise d terfenadine after addition of the respective H-2 antagonist and elec trocardiographic QT intervals and T-U morphology in them was not chang ed during the course of the study. We conclude that cimetidine and ran itidine in the dosages used in this study did not affect the metabolis m of terfenadine, and that patients exposed to these drug combinations are not at increased risk of altered cardiac repolarisation.