Effects of grapefruit juice and orange juice components on P-glycoprotein- and MRP2-mediated drug efflux

Br J Pharmacol. 2004 Dec;143(7):856-64. doi: 10.1038/sj.bjp.0706008. Epub 2004 Oct 25.


We investigated the effects of grapefruit juice (GFJ) and orange juice (OJ) on drug transport by MDR1 P-glycoprotein (P-gp) and multidrug resistance protein 2 (MRP2), which are efflux transporters expressed in human small intestine. We examined the transcellular transport and uptake of [(3)H]vinblastine (VBL) and [(14)C]saquinavir in a human colon carcinoma cell line (Caco-2) and in porcine kidney epithelial cell lines transfected with human MDR1 cDNA and human MRP2 cDNA, LLC-GA5-COL150, and LLC-MRP2, respectively. In Caco-2 cells, the basal-to-apical transports of [(3)H]VBL and [(14)C]saquinavir were greater than those in the opposite direction. The ratio of basal-to-apical transport to apical-to-basal transport of [(3)H]VBL and [(14)C]saquinavir by Caco-2 cells was reduced in the presence of MK571 (MRPs inhibitor), verapamil (P-gp inhibitor), cyclosporin A (inhibitor of both), 50% ethyl acetate extracts of GFJ and OJ, or their components (6',7'-dihydroxybergamottin, bergamottin, tangeretin, hepatomethoxyflavone, and nobiletin). Studies of transport and uptake of [(3)H]VBL and [(14)C]saquinavir with MDR1 and MRP2 transfectants showed that VBL and saquinavir are transported by both P-gp and MRP2. GFJ and OJ components inhibited the transport by MRP2 as well as P-gp. However, their inhibitory potencies for P-gp or MRP2 were substrate-dependent. The present study has revealed that GFJ and OJ interact with not only P-gp but also MRP2, both of which are expressed at apical membranes and limit the apical-to-basal transport of VBL and saquinavir in Caco-2 cells.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Algorithms
  • Antineoplastic Agents, Phytogenic / pharmacokinetics
  • Beverages*
  • Biological Transport, Active / drug effects
  • Caco-2 Cells
  • Calcium Channel Blockers / pharmacology
  • Citrus / chemistry*
  • Cyclosporine / pharmacology
  • Food-Drug Interactions
  • HIV Protease Inhibitors / pharmacokinetics
  • Humans
  • Immunosuppressive Agents / pharmacology
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism*
  • Multidrug Resistance-Associated Proteins / genetics
  • Multidrug Resistance-Associated Proteins / metabolism*
  • Plant Extracts / chemistry
  • Propionates / pharmacology
  • Quinolines / pharmacology
  • Saquinavir / pharmacokinetics
  • Transfection
  • Verapamil / pharmacology
  • Vinblastine / pharmacokinetics


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents, Phytogenic
  • Calcium Channel Blockers
  • HIV Protease Inhibitors
  • Immunosuppressive Agents
  • Membrane Transport Proteins
  • Multidrug Resistance-Associated Proteins
  • Plant Extracts
  • Propionates
  • Quinolines
  • multidrug resistance-associated protein 2
  • verlukast
  • Vinblastine
  • Cyclosporine
  • Verapamil
  • Saquinavir