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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.


Yoko Honda, Fumihiko Ushigome, Noriko Koyabu, Satoshi Morimoto, Yukihiro Shoyama, Takeshi Uchiumi, Michihiko Kuwano, Hisakazu Ohtani, Yasufumi Sawada. Effects of grapefruit juice and orange juice components on P-glycoprotein- and MRP2-mediated drug efflux. British journal of pharmacology. 2004 Dec;143(7):856-64

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PMID: 15504753

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