Modulation of digoxin transport across Caco-2 cell monolayers by citrus fruit juices: lime, lemon, grapefruit, and pummelo

Pharm Res. 2003 Feb;20(2):169-76. doi: 10.1023/a:1022254617664.


Purpose: To evaluate the effects of fresh lime, lemon, grapefruit, and pummelo juices on the transport of digoxin, a P-glycoprotein (P-gp) substrate, in Caco-2 cell monolayers.

Methods: Bidirectional [3H]-digoxin fluxes across confluent Caco-2 cell monolayers were determined in 0-50% fruit juices at pH 7.4. Verapamil HCl (100 microM) served as positive control. Juice toxicity was evaluated by the 3-(4,5 dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide assay.

Results: Apical-to-basal (A-to-B) digoxin flux was enhanced by 50% fruit juice in the order of lemon > lime > pummelo > grapefruit. The four fruit juices could be divided into two groups based on their effects on transepithelial electrical resistance (TEER), viability, and digoxin transport activity of the Caco-2 cells. Grapefruit and pummelo juices produced similar digoxin transport profiles that were characteristic of those observed with P-gp inhibitors. Both juices decreased net digoxin efflux by 1.2 U per 10% increase in juice concentration and had a propensity to increase cellular TEER at high concentrations (>30%). However, cellular TEER and viability decreased with increasing concentration of lime and lemon juices. Both juices also produced similar digoxin transport profiles, the A-to-B and B-to-A digoxin Papp increasing with increasing juice concentration above 5%. Net digoxin efflux was 30% of control value and relatively independent of juice concentration. These results paralleled the groupings of the four fruits according to their prominent flavonoid pattern and taxonomy.

Conclusion: The effects of lime, lemon, grapefruit, and pummelo juices on the TEER, viability, and digoxin transport activity of the Caco-2 cells appeared to be dependent on the dominant flavonoid pattern and taxonomy of the citrus fruits.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Beverages*
  • Biological Transport / physiology
  • Caco-2 Cells / metabolism*
  • Citrus / metabolism*
  • Citrus aurantiifolia / metabolism
  • Citrus paradisi / metabolism
  • Digoxin / pharmacokinetics*
  • Humans


  • Digoxin