5,7-Dimethoxyflavone and multiple flavonoids in combination alter the ABCG2-mediated tissue distribution of
Guohua An1, Fang Wu, Marilyn E Morris
1Department of Pharmaceutical Sciences School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, 517 Hochstetter Hall, Amherst, New York 14260-1200, USA.
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.
Insights
5,7-DMF enhances mitoxantrone (MX) accumulation in BCRP-expressing cells and increases MX tissue distribution in mice. This suggests 5,7-DMF is a promising chemosensitizer for BCRP-mediated multidrug resistance (MDR).
Area of Science:
- Pharmacology
- Biochemistry
- Drug Discovery
Background:
- Multidrug resistance (MDR) mediated by Breast Cancer Resistance Protein (BCRP) limits chemotherapy efficacy.
- Mitoxantrone (MX) is an anticancer drug whose efficacy can be compromised by BCRP efflux.
- 5,7-Dimethylflavone (5,7-DMF) is investigated as a potential modulator of BCRP activity.
Purpose of the Study:
- To evaluate the effect of 5,7-DMF on mitoxantrone accumulation in BCRP-expressing cells.
- To determine the impact of 5,7-DMF on the pharmacokinetics and tissue distribution of mitoxantrone in a mouse model.
Main Methods:
- In vitro studies using MDCK cells transfected with BCRP to assess MX accumulation with 5,7-DMF.
- In vivo pharmacokinetic and tissue distribution studies in mice, co-administering MX with 5,7-DMF or flavonoid combinations.
Main Results:
- 5,7-DMF significantly increased intracellular MX concentrations in BCRP-expressing cells (MDCK/Bcrp1, MDCK/BCRP) but not in control cells (MDCK/Mock).
- Co-administration of 5,7-DMF with MX significantly elevated MX AUC values in various tissues, notably the liver and kidneys.
- Elevated MX AUC in liver and kidneys correlated with high mouse Bcrp1 expression in these tissues.
Conclusions:
- 5,7-DMF interacts with BCRP in vitro and in vivo, inhibiting its efflux function.
- 5,7-DMF demonstrates potent BCRP inhibition with low toxicity, positioning it as a promising chemosensitizing agent for BCRP-mediated MDR.
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