B. Fleisher,1 J. Unum,1 J. Shao,2 G. An2; 1College of Pharmacy, University of Florida, Orlando, FL, 2Center for Pharmacometrics & Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Florida, Orlando, FL

BACKGROUND: Recently, most of the approved tyrosine kinase inhibitors (TKIs) were found to be substrates of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). However, there is little information available regarding the interaction of TKIs with co-administered drugs/food/beverage mediated by these two transporters. Our objective was to evaluate the effect of the major ingredients of grapefruit juice (GFJ) and green tea on P-gp- and BCRP-mediated dasatinib transport.
METHODS: The uptake of dasatinib, with or without various ingredients of GFJ and green tea, was evaluated in both P-gp-transfected and wild type LLC-PK1 cells and in both BCRP-transfected and wild type MDCK-II cells. The intracellular concentration of dasatinib was measured by Liquid Chromatography-Tandem Mass Spectrometry.
RESULTS: Among the 9 ingredients screened (5 from GFJ and 4 from green tea), none of them has significant inhibitory effect on P-gp-mediated dasatinib efflux. In contrast, four ingredients in GFJ, namely bergamottin, 6’,7’-dihydroxybergamottin (DHB), quercetin, and kaempferol, greatly inhibited BCRP-mediated dasatinib efflux at the concentration of 50 µM (p<0.001). Further concentration-dependent studies revealed that bergamottin and DHB are potent BCRP inhibitors with IC50 values 3.19 µM and 5.2 µM, respectively. Green tea components have no significant inhibitory effect on P-gp or BCRP.
CONCLUSION: GFJ ingredients are potent BCRP inhibitors. Further in vivo investigations are warranted to evaluate the BCRP-mediated GFJ-TKI interaction. Literature reports only documented the modulatory effect of GFJ and green tea on CYP3A, P-gp and OATP; our novel finding that GFJ ingredients strongly inhibit BCRP may represent a new type of beverage-drug interaction.