Abstract
Small molecule tyrosine kinase inhibitors (TKIs) are a group of highly novel and target-specific anticancer drugs. Recently, most TKIs are found to be substrates of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). However, little information is available regarding the Pgp- or BCRP-mediated interaction of TKIs with coadministered drugs/food/beverage. Our objective was to evaluate the effect of the major ingredients of grapefruit juice (GFJ), orange juice (OJ), apple juice (AJ), and green tea on P-gp and BCRP-mediated dasatinib efflux. Among the 14 ingredients screened, only tangeretin and nobiletin moderately inhibited P-gp-mediated dasatinib efflux. In contrast, four ingredients in GFJ [i.e., bergamottin, 6',7'-dihydroxybergamottin (DHB), quercetin, and kaempferol], two ingredients in OJ (tangeretin and nobiletin), and one ingredient in AJ (i.e., hesperetin) greatly inhibited BCRP-mediated dasatinib efflux at the concentration of 50 μM (p < 0.001). Further concentration-dependent studies revealed that bergamottin, DHB, tangeretin, and nobiletin are potent BCRP inhibitors, with IC₅₀ values 3.19, 5.2, 1.19, and 1.04 μM, respectively. Further in vivo investigations are warranted to evaluate the BCRP-mediated FJ-TKI interaction. Literature reports only documented the modulatory effect of FJ and green tea on CYP3A, P-gp, and OATP. Our novel finding that FJ ingredients strongly inhibit BCRP may represent a new mechanism of beverage-drug interaction.
Keywords:
ABC transporters; drug interactions; drug transport; food interactions; natural products; tyrosine kinase inhibitor.
© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter, Subfamily B / antagonists & inhibitors
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ATP Binding Cassette Transporter, Subfamily B / genetics
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ATP Binding Cassette Transporter, Subfamily B / metabolism
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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ATP-Binding Cassette Transporters / antagonists & inhibitors*
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ATP-Binding Cassette Transporters / genetics
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ATP-Binding Cassette Transporters / metabolism
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Animals
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / metabolism*
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Antineoplastic Agents / pharmacology
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Beverages / analysis
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Biological Transport / drug effects
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Cell Line
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Coumarins / analysis
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Coumarins / chemistry
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Coumarins / pharmacology
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Dasatinib
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Dogs
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Flavonoids / analysis
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Flavonoids / chemistry
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Flavonoids / pharmacology
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Food-Drug Interactions
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Fruit / chemistry
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Humans
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Madin Darby Canine Kidney Cells
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Membrane Transport Modulators / analysis
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Membrane Transport Modulators / chemistry
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Membrane Transport Modulators / pharmacology*
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Neoplasm Proteins / antagonists & inhibitors*
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Phytochemicals / analysis
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Phytochemicals / chemistry
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Phytochemicals / pharmacology*
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / metabolism*
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Protein Kinase Inhibitors / pharmacology
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Protein-Tyrosine Kinases / antagonists & inhibitors
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Protein-Tyrosine Kinases / metabolism
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Pyrimidines / antagonists & inhibitors
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Pyrimidines / metabolism*
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Pyrimidines / pharmacology
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Recombinant Proteins / chemistry
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Recombinant Proteins / metabolism
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Sus scrofa
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Thiazoles / antagonists & inhibitors
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Thiazoles / metabolism*
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Thiazoles / pharmacology
Substances
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ABCB1 protein, human
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ABCG2 protein, human
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ATP Binding Cassette Transporter, Subfamily B
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ATP Binding Cassette Transporter, Subfamily G, Member 2
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ATP-Binding Cassette Transporters
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Antineoplastic Agents
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Coumarins
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Flavonoids
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Membrane Transport Modulators
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Neoplasm Proteins
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Phytochemicals
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Protein Kinase Inhibitors
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Pyrimidines
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Recombinant Proteins
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Thiazoles
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Protein-Tyrosine Kinases
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Dasatinib