THE CARDIAC EFFECTS OF TERFENADINE AFTER INHIBITION OF ITS METABOLISMBY GRAPEFRUIT JUICE

Objective: To determine whether the pharmacokinetics and electrocardio graphic pharmacodynamics of terfenadine are affected by the concomitan t administration of grapefruit juice. Methods: Six healthy volunteers were recruited for a balanced cross-over study. Each volunteer receive d 120 mg terfenadine 30 min after drinking 300 ml of either water or f reshly squeezed grapefruit juice. The alternative treatment was admini stered on the second study day 2 weeks later. Measurements of the area under the terfenadine plasma concentration-time curve (AUG), maximum terfenadine concentration (C-max) and the time to maximum concentratio n (t(max)) were made, and the corrected QT (QTc) interval was measured from the surface electrocardiogram. Results: Terfenadine was quantifi able in plasma in all 6 subjects on both study days for up to 24 h pos t-dosing. The AUC of terfenadine was significantly increased by concom itant grapefruit administration (median values 40.6 vs 16.3 ng.ml(-1). h), as was the C-max (median values 7.2 vs 2.1 ng.ml(-1)). The t(max) was not significantly increased and there was no significant change in the median QTc interval despite the increased terfenadine levels. The 95% confidence interval for the difference in the change in QTc inter val at C-max was -13 to +38 ms. Conclusion: Administration of grapefru it juice concomitantly with terfenadine may lead to an increase in ter fenadine bioavailability, but the increase observed in this study did not lead to significant cardiotoxicity in normal subjects. However, th is does not exclude the risk of cardiotoxicity in high-risk subjects g iven greater doses of grapefruit juice over longer periods of time.