Received for publication June 28, 2006.
Revised November 1, 2006.
Accepted for publication November 3, 2006.

Effects of the Flavonoid Chrysin on Nitrofurantoin Pharmacokinetics in Rats: Potential Involvement of ABCG2

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 demonstrated in vitro as 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 MDCK 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, oral coadministration of chrysin (200 mg/kg) significantly increased the AUC and C_max 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 intravenously, 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 following 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.

Key words: ABC transporters, bioavailability, cellular transport, drug clearance, drug interactions, hepatobiliary transport, intestinal bioavailability, pharmacokinetics