Bergamottin contribution to the grapefruit juice-felodipine interaction and disposition in humans

Clin Pharmacol Ther. 2004 Dec;76(6):607-17. doi: 10.1016/j.clpt.2004.08.019.


Objectives: Our objectives were to evaluate the contribution of bergamottin to the grapefruit juice-felodipine interaction and to characterize bergamottin disposition.

Methods: In this study 250 mL grapefruit juice; 2-, 6-, or 12-mg capsules of bergamottin plus water; or water was administered with 5 mg extended-release felodipine to 11 volunteers in a partially randomized, 5-way crossover study. Plasma concentrations of felodipine, its primary metabolite (dehydrofelodipine), bergamottin, and 6',7'-dihydroxybergamottin were determined.

Results: Grapefruit juice (containing 1.7 mg bergamottin) increased peak plasma concentration (C max ) and area under the plasma concentration-time curve (AUC) of felodipine by 89% (P < .025) and 54% (P < .025), respectively, compared with water. With 2 mg bergamottin, felodipine C max increased by 33% (P < .05). The increase by bergamottin was markedly variable among individuals (range, -33% to 125%). With 6 mg bergamottin, felodipine C max was enhanced by 35% (P < .025), and with 12 mg bergamottin, felodipine C max increased by 40% (P < .05) and AUC increased by 37% (P < .05) compared with water. Bergamottin measured in plasma after administration of 6 and 12 mg produced C max values of 2.1 and 5.9 ng/mL, respectively, and times to reach C max of 0.8 and 1.1 hours, respectively. The bergamottin metabolite 6',7'-dihydroxybergamottin was detected in plasma of some subjects after bergamottin administration.

Conclusions: Bergamottin enhanced the oral bioavailability of felodipine and may cause a clinically relevant drug interaction in susceptible individuals. Grapefruit juice-drug interactions likely also involve other furanocoumarins, possibly acting in combination by additive or synergistic mechanisms. Bergamottin has systemic availability and is metabolized in vivo to 6',7'-dihydroxybergamottin.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Area Under Curve
  • Biological Availability
  • Biotransformation
  • Calcium Channel Blockers / pharmacokinetics
  • Calcium Channel Blockers / pharmacology*
  • Capsules
  • Chromatography, High Pressure Liquid
  • Citrus / chemistry*
  • Cross-Over Studies
  • Delayed-Action Preparations
  • Felodipine / pharmacokinetics
  • Felodipine / pharmacology*
  • Female
  • Food-Drug Interactions*
  • Furocoumarins / administration & dosage
  • Furocoumarins / pharmacology*
  • Humans
  • Male
  • Spectrophotometry, Ultraviolet


  • Calcium Channel Blockers
  • Capsules
  • Delayed-Action Preparations
  • Furocoumarins
  • bergamottin
  • Felodipine