Premium
Grapefruit juice—terfenadine single‐dose interaction: Magnitude, mechanism, and relevance
Author(s) -
Rau Susan E.,
Bend John R.,
Arnold J. Malcolm O.,
Tran Lan T.,
Spence J. David,
Bailey David G.
Publication year - 1997
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/s0009-9236(97)90190-9
Subject(s) - terfenadine , grapefruit juice , cmax , chemistry , metabolite , pharmacology , pharmacokinetics , crossover study , active metabolite , drug interaction , biochemistry , medicine , placebo , alternative medicine , pathology
Objective To investigate the single dose‐response effects of grapefruit juice on terfenadine disposition and electrocardiographic measurements. Methods Twelve healthy males received 250 ml water or regular‐ or double‐strength grapefruit juice with 60 mg terfenadine in a randomized crossover trial. Plasma concentrations of the cardiotoxic agent terfenadine and the active antihistaminic metabolite terfenadine carboxylate were determined over 8 hours. The QT c interval was monitored. Results Terfenadine concentrations were measurable (> 1 ng/ml) in 27 (20%; p < 0.001) and 39 (30%; p < 0.001) samples from individuals treated with regular‐ and double‐strength grapefruit juice, respectively, compared to only four (3%) samples with water. Terfenadine plasma peak drug concentration (C max ) was also higher. Terfenadine carboxylate area 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. However, terfenadine carboxylate apparent elimination half‐life (t ½ ) was not altered. The magnitude of the interaction of terfenadine carboxylate AUC and C max ranged severalfold and correlated among individuals 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 pharmacokinetics 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 carboxylic acid metabolite pharmacokinetics. The mechanism likely involved reduced presystemic drug elimination by inhibition of more than one metabolic pathway. The extent of the interaction was not sufficient to produce electrocardiographic changes. However, the pharmacokinetic effects were highly variable among individuals. This study further enhances the awareness of the potential for a serious interaction between grapefruit juice and terfenadine. Clinical Pharmacology & Therapeutics (1997) 61 , 401–409; doi: