GRAPEFRUIT JUICE ALTERS TERFENADINE PHARMACOKINETICS RESULTING IN PROLONGATION OF REPOLARIZATION ON THE ELECTROCARDIOGRAM

Objectives: To establish whether the pharmacokinetics and electrocardi ographic pharmacodynamics of terfenadine are affected by concomitant a dministration of grapefruit juice and to determine whether any effect of grapefruit juice is dependent on the timing of administration in re lation to the dose of terfenadine. Methods: Twelve healthy volunteers were studied in a prospective randomized trial, The primary end points were QT prolongation on the surface electrocardiogram and the pharmac okinetic parameters: area under the concentration-time curve (AUC), ma ximum concentration, and time to maximum concentration of terfenadine and its acid metabolite terfenadine carboxylate. All subjects received 60 mg terfenadine twice a day with 240 ml water for 7 days, They were then randomized to drink 240 ml of double-strength grapefruit juice s imultaneously with terfenadine (simultaneous group) for an additional 7 days or to drink the same dose of grapefruit juice 2 hours after ter fenadine for 7 days (delayed group), Twelve timed electrocardiograms a nd plasma terfenadine and metabolite levels were measured on days 7 an d 14, Results: None of the 12 subjects had quantifiable levels of terf enadine when the drug was administered with water, All six subjects wh o took terfenadine and drank grapefruit juice simultaneously had quant i fiable terfenadine levels, Only two of six who drank grapefruit juic e 2 hours after terfenadine had quantifiable levels, The AUC of the ac id metabolite increased 55% (p < 0.05) in the simultaneous group and 2 2% (p = NS) in the delayed group, The mean QT interval increased from 420 to 434 msec (p < 0.05) in the simultaneous group and decreased fro m 408 to 407 msec (p = NS) in the delayed group. Conclusions: Administ ration of grapefruit juice concomitantly with terfenadine may lead to an increase in systemic terfenadine bioavailability and result in incr eases in QT interval, The clinical significance of an increase in QT i nterval of this magnitude is unclear.