Effects of grapefruit juice and orange juice components on P‐glycoprotein‐ and MRP2‐mediated drug efflux

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Abstract
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 [3H]vinblastine (VBL) and [14C]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 [3H]VBL and [14C]saquinavir were greater than those in the opposite direction. The ratio of basal‐to‐apical transport to apical‐to‐basal transport of [3H]VBL and [14C]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 [3H]VBL and [14C]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. British Journal of Pharmacology (2004) 143, 856–864. doi:10.1038/sj.bjp.0706008

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