Modulation of drug transport by citrus fruit juices

Abstract

Fruit juice-drug interactions involving drug transporters have been variously studied with 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. Grapefruit and pummelo are classified under the neohesperidosyl species based on 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 dominant flavonoid pattern. Fruit juice-mediated solute transport data for the paracellular and transcellular diffusive pathways and on P-gp-mediated efflux activity across the Caco-2 cells supported the hypothesis. Bi-directional digoxin transport data across the MDR1-transfected L-MDR1 cells also produced a similar conclusion. The hypothesis could further be extended to the pOCT2-mediated transport in the LLC-PK1 cells. Data for the orange juice 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 the P-gp and pOCT2 expression in cells or rodent tissues, nor on the CYP3A4-mediated metabolism of midazolam, which appeared to be influenced by the furanocoumarins content of the fruit juices.