Grapefruit juice and its constituents augment colchicine intestinal absorption: potential hazardous interaction and the role of p-glycoprotein

Pharm Res. 2009 Apr;26(4):883-92. doi: 10.1007/s11095-008-9789-7. Epub 2008 Dec 2.


Purpose: To investigate the potential interaction between grapefruit juice (GFJ) and the oral microtubule polymerization inhibitor colchicine, a P-gp and CYP3A4 substrate.

Methods: Colchicine intestinal epithelial transport was investigated across Caco-2 cell monolayers in both AP-BL and BL-AP directions, in the absence/presence of known P-gp inhibitors (verapamil and quinidine). The concentration-dependent effects of GFJ and its major constituents (6'-7'-dihydroxybergamottin, naringin and naringenin) on colchicine Caco-2 mucosal secretion were examined. The effect of GFJ on colchicine intestinal-permeability was then investigated in-situ in the rat perfusion model, in both jejunum and ileum.

Results: Colchicine exhibited 20-fold higher BL-AP than AP-BL Caco-2 permeability, indicative of net mucosal secretion, which was reduced by verapamil/quinidine. Colchicine AP-BL permeability was increased and BL-AP was decreased by GFJ in a concentration-dependent manner (IC(50) values of 0.75% and 0.46% respectively), suggesting inhibition of efflux transport, rather than metabolizing enzyme. Similar effects obtained following pre-experiment incubation with GFJ, even though the juice was not present throughout the transepithelial study. 6'-7'-Dihydroxybergamottin, naringin and naringenin displayed concentration-dependent inhibition on colchicine BL-AP secretion (IC(50) values of 90, 592 and 11.6 microM respectively). Ten percent GFJ doubled colchicine rat in-situ ileal permeability, and increased 1.5-fold jejunal permeability.

Conclusion: The data suggest that GFJ may augment colchicine oral bioavailability. Due to colchicine narrow therapeutic-index and severely toxic side-effects, awareness of this interaction is prudent.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Administration, Oral
  • Animals
  • Beverages / adverse effects*
  • Caco-2 Cells
  • Cell Polarity
  • Citrus paradisi* / chemistry
  • Colchicine / administration & dosage
  • Colchicine / metabolism*
  • Dose-Response Relationship, Drug
  • Flavanones / isolation & purification
  • Flavanones / pharmacology
  • Food-Drug Interactions*
  • Fruit
  • Furocoumarins / isolation & purification
  • Furocoumarins / pharmacology
  • Humans
  • Ileum / drug effects
  • Ileum / metabolism*
  • Intestinal Absorption* / drug effects
  • Jejunum / drug effects
  • Jejunum / metabolism*
  • Male
  • Permeability
  • Quinidine / pharmacology
  • Rats
  • Rats, Wistar
  • Risk Assessment
  • Time Factors
  • Tubulin Modulators / administration & dosage
  • Tubulin Modulators / metabolism*
  • Verapamil / pharmacology


  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Flavanones
  • Furocoumarins
  • Tubulin Modulators
  • Verapamil
  • naringenin
  • Quinidine
  • naringin
  • 6',7'-dihydroxybergamottin
  • Colchicine