Effects of Citrus Fruit Juices on P-glycoprotein-mediated Transport in L-MDR1 Cells and CYP3A4-mediated Metabolism in Human Intestinal Microsomes

Fruit juice-drug interactions involving drug transporters and metabolic enzymes have been studied with various citrus fruit juices. The collective data led us to hypothesize that the modulating activity of citrus fruit juices on cellular transport and metabolic pathways is dependent on the dominant flavonoid pattern and taxonomy of the citrus fruits. This hypothesis has important implications given the difficult task of compiling complete constituent profiles for fruit juice, and the limited success in identifying the active modulating component(s) in the juice. Grapefruit and pummelo are classified under the neohesperidosyl species based on a dominant flavonoid pattern, while lime and lemon belong to the rutinosyl species. Classification of these fruits based on taxonomy yielded parallel groupings. Orange belongs to the same taxonomic family as grapefruit and pummelo, but is classified as a rutinosyl species, with lime and lemon, based on a dominant flavonoid pattern. In the present study, the citrus fruit juices were found to modulate bi-directional digoxin transport across the MDR1-transfected L-MDR1 cells in a manner consistent with the proposed hypothesis. Orange juice, like grapefruit and pummelo juices, inhibited P-gp-mediated transport of digoxin by 60-70% when applied at 50% concentration. Lime and lemon juices, however, did not modulate the digoxin transport profile characteristically of a P-gp inhibitor. Data for orange juice thus suggested that taxonomy, rather than dominant flavonoid pattern, had a greater influence on its capacity to modulate cellular permeation. The hypothesis could not, however, be applied to predict the effects of the citrus fruit juices on P-glycoprotein expression in the L-MDR1 cells. Neither could it be applied to the effects of the fruit juices on cytochrome P450 3A4-mediated metabolism of midazolam, which appeared to be predominantly influenced by the furanocoumarins content of the juices. _____________________________________________________________________________________________________________