GRAPEFRUIT JUICE TERFENADINE SINGLE-DOSE INTERACTION - MAGNITUDE, MECHANISM, AND RELEVANCE

Objective: To investigate the single dose-response effects of grapefru it juice on terfenadine disposition and electrocardiographic measureme nts. Methods: Twelve healthy males received 250 ml water or regular- o r double strength grapefruit juice with 60 mg terfenadine in a randomi zed crossover trial. Plasma concentrations of the cardiotoxic agent te rfenadine and the active antihistaminic metabolite terfenadine carboxy late were determined over 8 hours. The QT(c) interval was monitored. R esults: Terfenadine concentrations were measurable (>1 ng/ml) in 27 (2 0%; P < 0.001) and 39 (30%; P < 0.001) samples from individuals treate d with regular- and double-strength grapefruit juice, respectively, co mpared to only four (3%) samples with water. Terfenadine plasma peak d rug concentration (C-max) was also higher. Terfenadine carboxylate are a under the plasma drug concentration-time curve (AUC), C-max and time to reach C-max (t(max)) Were increased by both strengths of juice. Ho wever, terfenadine carboxylate apparent elimination half-life (t(1/2)) was not altered. The magnitude of the interaction of terfenadine carb oxylate AUC and C-max ranged severalfold and correlated among individu als for regular-strength (r(2) = 0.87; p < 0.0001) and double-strength (r(2) = 0.78; P < 0.0001) grapefruit juice. No differences in the pha rmacokinetics of terfenadine and terfenadine carboxylate were observed between the two strengths of grapefruit juice. QT(c) interval was not altered. Conclusions: A normal amount of regular-strength grapefruit juice produced maximum single-dose effects on terfenadine and carboxyl ic acid metabolite pharmacokinetics. The mechanism Likely involved red uced presystemic drug elimination by inhibition of more than one metab olic pathway. The extent of the interaction was not sufficient to prod uce electrocardiographic changes. However, the pharmacokinetic effects were highly variable among individuals. This study further enhances t he awareness of the potential for a serious interaction between grapef ruit juice and terfenadine.