Received for publication September 27, 2004.
Revised December 7, 2004.
Accepted for publication December 16, 2004.

Flavonoids Chrysin and Benzoflavone, Potent BCRP Inhibitors, Have No Significant Effect on Topotecan Pharmacokinetics in Rats or Mdr1a/1b (-/-) Mice

Abstract

Breast cancer resistance protein (BCRP) is a newly identified ABC transporter, important in drug disposition and in the development of multidrug resistance in cancer. Flavonoids, a major class of natural compounds widely present in foods and herbal products, have been shown to be human BCRP inhibitors. The objective of the present study was to evaluate the potential for in vivo pharmacokinetic interactions by comparing the pharmacokinetics of topotecan (a model BCRP substrate) after oral administration of 2 mg/kg topotecan with and without different doses of the flavonoids chrysin or 7,8-benzoflavone (BF) in rats and mdr1a/1b (-/-) mice. Co-administration of 50 mg/kg GF120918 with 2 mg/kg topotecan significantly increased the AUC and bioavailability of topotecan by more than four-fold in these animals, indicating the importance of BCRP in the bioavailability and disposition of topotecan in rats. Chrysin (50 µM) and BF (5 µM) significantly inhibited the BCRP-mediated transport of topotecan in BCRP-overexpressing MCF-7 MX100 cells to a comparable level as observed with 10 µM fumitremorgin C (FTC, a potent BCRP inhibitor). However, neither chrysin nor BF significantly altered topotecan pharmacokinetics in rats or in mdr1a/1b (-/-) mice after oral co-administration of doses up to 50 mg/kg. The reason(s) for this lack of in vitro-in vivo association may be due to the lack of potent inhibition activity of the flavonoids against mouse or rat BCRP, as evidenced by our observation that these flavonoids have only weak, if any, inhibition activity against mouse Bcrp1 mediated transport of topotecan in MDCK-Bcrp1 cells.

Key words: ABC transporters, cellular transport, drug interactions, drug transport, intestinal bioavailability, oral absorption, pharmacokinetics

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