Inhibitory effects of flavonoids on P-glycoprotein in vitro and in vivo: Food/herb-drug interactions and structure-activity relationships

Flavonoids are a class of polyphenol antioxygen, despite various known biological activities and therapeutic potential, scattered but not much is known about their interactions with drug transporters. P-glycoprotein (P-gp) as a cellular defense mechanism by effluxing its substrates has been widely investigated. The aim of this study was to investigate the inhibitory effects of 75 flavonoids on P-gp in vitro and in vivo and to illuminate the structure-activity relationships of flavonoids with P-gp. Five flavonoids, including tangeretin, sinensetin, isosinensetin, sciadopitysin and oroxylin A exhibited significant inhibition on P-gp in MDR1-MDCKIIcells, which reduced the P-gp-mediated efflux of paraquat and taxol and consequently increased their cell toxicity. In addition, co-administration of digoxin with five flavonoids increased the AUC(0-t), of digoxin in different extents in rats, from 19.84% to 81.51%. Molecular docking assays elucidated the inhibitory effect of flavonoids might be related to Pi interactions, but not hydrogen bonds. The pharmacophore model suggested the hydrophobic groups in B benzene ring may play a vital role in the potency of flavonoids inhibition on P-gp. Taken together, our findings would provide the basis for a reliable assessment of the potential risks of flavonoid-containing food/ herb-drug interactions in humans.