title: Ingredients in fruit juices interact with dasatinib through inhibition of BCRP: a new mechanism of beverage-drug interaction.
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.
authors.affiliation: College of Pharmacy, University of Florida, Orlando, Florida.
authors.forename: Brett
authors.initials: B
authors.lastname: Fleisher
authors.forename: Jesse
authors.initials: J
authors.lastname: Unum
authors.forename: Jie
authors.initials: J
authors.lastname: Shao
authors.forename: Guohua
authors.initials: G
authors.lastname: An
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D001628:Beverages / Q000032:analysis; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D003374:Coumarins / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology; D000069439:Dasatinib; D004285:Dogs; D005419:Flavonoids / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology; D018565:Food-Drug Interactions; D005638:Fruit / Q000737:chemistry; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D049990:Membrane Transport Modulators / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D064209:Phytochemicals / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011743:Pyrimidines / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D034421:Sus scrofa; D013844:Thiazoles / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology
chemical_list: C513055:ABCB1 protein, human; C116614:ABCG2 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D003374:Coumarins; D005419:Flavonoids; D049990:Membrane Transport Modulators; D009363:Neoplasm Proteins; D064209:Phytochemicals; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011994:Recombinant Proteins; D013844:Thiazoles; D011505:Protein-Tyrosine Kinases; D000069439:Dasatinib
keywords: ABC transporters; drug interactions; drug transport; food interactions; natural products; tyrosine kinase inhibitor