The cardiac effects of terfenadine after inhibition of its metabolism by grapefruit juice

Eur J Clin Pharmacol. 1997;52(4):311-5. doi: 10.1007/s002280050296.

Abstract

Objective: To determine whether the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine are affected by the concomitant administration of grapefruit juice.

Methods: Six healthy volunteers were recruited for a balanced cross-over study. Each volunteer received 120 mg terfenadine 30 min after drinking 300 ml of either water or freshly squeezed grapefruit juice. The alternative treatment was administered on the second study day 2 weeks later. Measurements of the area under the terfenadine plasma concentration-time curve (AUC), maximum terfenadine concentration (Cmax) and the time to maximum concentration (tmax) were made, and the corrected QT (QTc) interval was measured from the surface electrocardiogram.

Results: Terfenadine was quantifiable in plasma in all 6 subjects on both study days for up to 24 h post-dosing. The AUC of terfenadine was significantly increased by concomitant grapefruit administration (median values 40.6 vs 16.3 ng.ml-1.h), as was the Cmax (median values 7.2 vs 2.1 ng.ml-1). The tmax 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 interval at Cmax was -13 to +38 ms.

Conclusion: Administration of grapefruit juice concomitantly with terfenadine may lead to an increase in terfenadine bioavailability, but the increase observed in this study did not lead to significant cardiotoxicity in normal subjects. However, this does not exclude the risk of cardiotoxicity in high-risk subjects given greater doses of grapefruit juice over longer periods of time.

MeSH terms

  • Adult
  • Area Under Curve
  • Beverages*
  • Biological Availability
  • Chromatography, High Pressure Liquid
  • Citrus*
  • Electrocardiography / drug effects*
  • Histamine H1 Antagonists / blood
  • Histamine H1 Antagonists / pharmacokinetics
  • Histamine H1 Antagonists / pharmacology*
  • Humans
  • Male
  • Middle Aged
  • Terfenadine / antagonists & inhibitors
  • Terfenadine / blood
  • Terfenadine / pharmacokinetics
  • Terfenadine / pharmacology*

Substances

  • Histamine H1 Antagonists
  • Terfenadine