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.