5,7-Dimethoxyflavone and multiple flavonoids in combination alter the ABCG2-mediated tissue distribution of mitoxantrone in mice

Purpose: The objective of our study was to investigate the effect of 5,7-DMF on the accumulation of mitoxantrone (MX) in BCRP-expressing normal cells and to investigate its impact on the PK and tissue distribution of MX in mice. Methods: The in vitro effect of 5,7-DMF on MX accumulation was examined in MDCK cells transfected with BCRP. The pharmacokinetic and tissue distribution of mitoxantrone, with and without co-administration of 5,7-DMF or multiple flavonoid combinations, were determined in mice. Results: In the presence of 2.5 μM or 25 μM of 5,7-DMF, the intracellular concentration of MX was significantly increased in MDCK/Bcrp1 and MDCK/BCRP cells, but not in MDCK/Mock cells. The AUC values of MX in several tissues were significantly increased when MX was co-administered with 5,7-DMF. The most substantial elevations of MX AUC in the presence of 5,7-DMF occurred in the liver (94.5%) and kidneys (61.9%), which is in apparent agreement with the relatively high levels of mouse Bcrp1 expression in these two tissues. Conclusions: Bcrp1-mediated DMF-MX interactions occur both in vitro and in vivo. 5,7-DMF represents a novel and very promising chemosensitizing agent for the BCRP-mediated MDR due to its low toxicity and potent BCRP inhibition.