Abstract
Breast cancer resistance protein (BCRP/ABCG2) is an ATP-binding cassette efflux transporter, important in drug disposition and in the development of multidrug resistance in cancer. Flavonoids, a large class of natural compounds widely present in the diet and herbal products, have been shown in vitro to be BCRP inhibitors. The flavonoid chrysin is a potent inhibitor of BCRP, inhibiting the efflux of mitoxantrone with an IC50 of 0.39 μM in BCRP-overexpressing human MCF-7 breast cancer cells. The purpose of this study was to investigate the potential pharmacokinetic interactions between chrysin and nitrofurantoin (a specific BCRP substrate) in rats. In Madin-Darby canine kidney cells expressing human BCRP or murine Bcrp1, the polarized transport of nitrofurantoin was effectively inhibited by chrysin at concentrations of 20 and 100 μM. Compared with the vehicle-treated group, p.o. coadministration of chrysin (200 mg/kg) significantly increased the area under the curve (AUC) and Cmax of nitrofurantoin (10 mg/kg) by 1.76- (p < 0.01) and 1.72-fold (p < 0.05), respectively. When nitrofurantoin (2 mg/kg) was given i.v., administration of chrysin (50 mg/kg i.p.) significantly increased the AUC of nitrofurantoin (123 ± 34.0 versus 91.5 ± 18.0 μg/ml · min in controls, p < 0.05). Moreover, the cumulative hepatobiliary excretion of nitrofurantoin (1.5 mg/kg i.v.) was significantly decreased by approximately 75% at the end of 120 min after the coadministration of chrysin (50 mg/kg i.p.). Taken together, these results indicate that the flavonoid chrysin significantly inhibits nitrofurantoin transport mediated by human BCRP and murine Bcrp1. Bcrp1 inhibition by chrysin is likely one potential mechanism for the observed chrysin-nitrofurantoin pharmacokinetic interactions in rats.
Footnotes
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Financial support for this study was provided by grants from the Susan G. Komen Breast Cancer and Cancer Research and Prevention Foundations.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.106.011684.
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ABBREVIATIONS: BCRP, breast cancer resistance protein; GF120918, N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide; MRP, multidrug resistance-associated protein; SD, Sprague-Dawley; HBSS, Hanks' buffered salt solution; FTC, fumitremorgin C; HPLC, high-performance liquid chromatography; MDCK, Madin-Darby canine kidney; AUC, area under the plasma concentration-time curve.
- Received June 27, 2006.
- Accepted November 3, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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