Effects of the isoflavonoid biochanin A on the transport of mitoxantrone in vitro and in vivo

Abstract

The aim of our study was to investigate the effect of biochanin A on the accumulation and transport of mitoxantrone in breast cancer resistance protein (BCRP)-expressing normal cells and its impact on the pharmacokinetics (PK) and tissue distribution of mitoxantrone. In accumulation studies, the intracellular level of mitoxantrone was significantly increased in the presence of 2.5 or 25 microM of biochanin A in both murine and human BCRP-expressing Madin-Darby canine kidney (MDCK) cells, with no effect in corresponding MDCK/Mock cells. In bi-directional transport studies, the P(app,B-A) value of mitoxantrone with biochanin A co-treatment was much lower (6.66+/-0.84x10(-7) cm/s) than that in the absence of biochanin A (21.4+/-4.14x10(-7) cm/s), indicating inhibition of Bcrp1-mediated efflux. To evaluate whether our in vitro results might translate into an in vivo interaction, mitoxantrone PK and tissue distribution, with and without co-administration of biochanin A, was investigated. In contrast to our in vitro results, biochanin A (10 mg/kg, i.v.) had no impact on the concentration of mitoxantrone in plasma and most tissues collected (brain, heart, liver and lung). Surprisingly, the concentrations of mitoxantrone in spleen and kidney were even decreased when biochanin A was co-administered. Interestingly, it was found that the intracellular fluorescence of mitoxantrone was decreased 31.9% when co-incubated with 10 microM biochanin A in P-glycoprotein (P-gp) expressing MCF-7/ADR cells, indicating potential P-gp stimulation. The species difference of the inhibitory effect of biochanin A on BCRP, the extensive metabolism of biochanin A, as well as the stimulation effect of biochanin A on P-gp, may contribute to this in vitro-in vivo disconnect.

The membrane transport of flavonoids from Crossostephium chinense across the Caco‐2 monolayer

“…Flavonoids, as natural antioxidants, have been shown to enhance a variety of biological effects including the inhibition of tumor development at various stages in animal models [1]. The significance of flavonoids as inhibitors of multidrug resistance proteins (MRP) in cancer chemotherapy has been emerging [2][3][4][5]. Since the extent of flavonoid absorption is important in predicting the health effects of flavonoids, many studies have been conducted on the properties and mechanisms of absorption, metabolism and excretion [6][7][8].…”

ABCG2/BCRP interaction with the sea grass Thalassia testudinum

“…Of these, chrysoeriol, one of the main components of Thalassia t., exhibited IC 50 values of < 0.1 μM and of a similar magnitude to Ko143 (0.026±0.003 μM). Multiple flavonoid combinations act additively and exhibit strong BCRP inhibition for increasing MTX accumulation in breast cancer cells [19]. In the present study, MDCK-II parental cells and cells that overexpress human BCRP (HBCRP) and murine Bcrp1-transduced subclones were used to investigate the interaction of the extract obtained from marine plant T. testudinum with the transporter through the efflux of fluorescent Thalassia t. in direct accumulation assays and in MTT assays.…”

Mutual interactions between flavonoids and enzymatic and transporter elements responsible for flavonoid disposition via phase II metabolic pathways

“…In contrast to in vitro data, biochanin A administrated by i.v. at 10 mg/kg had no impact on the plasma concentration of mitoxantrone and AUC values in most tissues (brain, heart, liver and lung) 142 . Thus, when extrapolating results of in vitro inhibition on BCRP by flavonoids to in vivo , we should pay particular attention to the fact the low bioavailability may severely limit their in vivo levels necessary to achieve observed inhibition effects (in vitro).…”

“…However, conclusion from in vitro study was not always consistent with in vivo study. Discrepancy was observed when biochanin A was used as inhibitor to treat MDCKII-BCRP or MDCKII-Bcrp cells or given to mice 142 . In vitro , accumulation of cellular mitoxantrone was enhanced with biochanin A at concentration of 2.5 or 25 μM in MDCK cells overexpressing human BCRP or murine Bcrp.…”