Grapefruit-felodipine interaction: effect of unprocessed fruit and probable active ingredients

Clin Pharmacol Ther. 2000 Nov;68(5):468-77. doi: 10.1067/mcp.2000.110774.


Objectives: To determine whether unprocessed grapefruit can cause a drug interaction, whether the active ingredients are naturally occurring, and whether specific furanocoumarins or flavonoids are involved.

Methods: The oral pharmacokinetics of felodipine and its dehydrofelodipine metabolite were determined after administration of felodipine 10 mg extended-release tablet with 250 mL commercial grapefruit juice, homogenized grapefruit segments, or extract of segment-free parts equivalent to one unprocessed fruit or water in a randomized four-way crossover study. Inhibition of recombinant CYP3A4 by furanocoumarins (bergamottin, 6',7'-epoxybergamottin, 6',7'-dihydroxybergamottin) and flavonoids (naringenin optical isomers) was determined. Furanocoumarin and naringenin precursor (naringin) concentrations were measured in each grapefruit treatment.

Results: Felodipine AUC with commercial grapefruit juice, grapefruit segments, or grapefruit extract was on average 3-fold higher than that with water. Felodipine peak concentration was higher, but the half-life was unchanged. The dehydrofelodipine/felodipine AUC ratio was reduced. The furanocoumarins produced mechanism-based and competitive inhibition of CYP3A4. Bergamottin was the most potent mechanism-based inhibitor. Naringenin isomers produced only competitive inhibition. Bergamottin, 6',7'-dihydroxybergamottin, and naringin concentrations varied among grapefruit treatments but were sufficient to inhibit markedly in vitro CYP3A4 activity.

Conclusions: Unprocessed grapefruit can cause a drug interaction with felodipine. The active ingredients are naturally occurring in the grapefruit. Bergamottin is likely important in drug interactions with commercial grapefruit juice. 6',7'-Dihydroxybergamottin and naringin may be more important in grapefruit segments because they are present in higher concentrations. Any therapeutic concern for a drug interaction with commercial grapefruit juice should now be extended to include whole fruit and possibly confectioneries made from grapefruit peel.

Publication types

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

MeSH terms

  • Administration, Oral
  • Adult
  • Antioxidants / pharmacology
  • Area Under Curve
  • Beverages
  • Citrus*
  • Cross-Over Studies
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors
  • Delayed-Action Preparations
  • Drug Interactions
  • Felodipine / analogs & derivatives
  • Felodipine / pharmacokinetics*
  • Female
  • Flavanones*
  • Flavonoids / pharmacology
  • Furocoumarins / pharmacology
  • Half-Life
  • Humans
  • Male
  • Mixed Function Oxygenases / antagonists & inhibitors
  • Radiation-Sensitizing Agents / pharmacology


  • Antioxidants
  • Cytochrome P-450 Enzyme Inhibitors
  • Delayed-Action Preparations
  • Flavanones
  • Flavonoids
  • Furocoumarins
  • Radiation-Sensitizing Agents
  • dehydrofelodipine
  • Mixed Function Oxygenases
  • CYP3A protein, human
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • bergamottin
  • naringin
  • Felodipine