title: Effects of grapefruit juice and orange juice components on P-glycoprotein- and MRP2-mediated drug efflux.
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 [(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.
authors.affiliation: Department of Medico-Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Honda
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Ushigome
authors.forename: Noriko
authors.initials: N
authors.lastname: Koyabu
authors.forename: Satoshi
authors.initials: S
authors.lastname: Morimoto
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Shoyama
authors.forename: Takeshi
authors.initials: T
authors.lastname: Uchiumi
authors.forename: Michihiko
authors.initials: M
authors.lastname: Kuwano
authors.forename: Hisakazu
authors.initials: H
authors.lastname: Ohtani
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Sawada
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000465:Algorithms; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics; D001628:Beverages; D001693:Biological Transport, Active / Q000187:drug effects; D018938:Caco-2 Cells; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002957:Citrus / Q000737:chemistry*; D016572:Cyclosporine / Q000494:pharmacology; D018565:Food-Drug Interactions; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D010936:Plant Extracts / Q000737:chemistry; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D019258:Saquinavir / Q000493:pharmacokinetics; D014162:Transfection; D014700:Verapamil / Q000494:pharmacology; D014747:Vinblastine / Q000493:pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D002121:Calcium Channel Blockers; D016572:Cyclosporine; D017320:HIV Protease Inhibitors; D007166:Immunosuppressive Agents; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010936:Plant Extracts; D011422:Propionates; D011804:Quinolines; D019258:Saquinavir; D014700:Verapamil; D014747:Vinblastine; C000715087:ABCC2 protein, human; C059141:verlukast