J. D. Unum,1 B. Fleisher,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: Small molecule tyrosine kinase inhibitors (TKIs) are a group of highly novel and target-specific anticancer drugs. As TKIs are usually taken orally on a daily basis, there is a high risk of the interaction between TKIs and the concomitant intake of beverages/food. Our objective was to assess the effect of the major components of orange juice (OJ) and apple juice (AJ) on P-glycoprotein (P-gp)- and Breast Cancer Resistance Protein (BCRP)-mediated dasatinib transport.
METHODS: The uptake of dasatinib, with and without different ingredients of OJ and AJ, was assessed in both wild type and P-gp-transfected LLC-PK1 cells, and both wild type and BCRP-transfected MDCK-II cells. The intracellular concentration of dasatinib was measured via Liquid Chromatography-Tandem Mass Spectrometry.
RESULTS: Among the OJ and AJ ingredients screened, they either have no or only moderate inhibitory effect on P-gp-mediated dasatinib efflux. In contrast, OJ ingredients tangertein and nobiletin, and AJ ingredient hesperetin, produced dramatic increase in dasatinib uptake in BCRP-expressing cells at the concentration of 50 µM (p <0.001, percentage increase relative to the control group ranges from +548% to +949%). Further concentration-dependent studies showed that Nobiletin and Tangeretin are potent BCRP inhibitors, with IC50 values of 1.05 μM and 1.19 μM, respectively.
CONCLUSION: OJ components have moderate P-gp inhibitory effects, while OJ and AJ components have potent BCRP inhibitory effects. Subsequent in vivo studies are necessary to evaluate the BCRP-mediated OJ/AJ-TKI interaction. As the concentrations of tangeretin and nobiletin in OJ are well above their IC50 values on BCRP inhibition, the BCRP-mediated OJ-drug interaction are expected to be clinically relevant.