title: Flavonoids chrysin and benzoflavone, potent breast cancer resistance protein inhibitors, have no significant effect on topotecan pharmacokinetics in rats or mdr1a/1b (-/-) mice.
abstract: Breast cancer resistance protein (BCRP) is a recently identified ATP-binding cassette 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. Coadministration of 50 mg/kg 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] with 2 mg/kg topotecan significantly increased the area under the plasma concentration-time curve and bioavailability of topotecan by more than 4-fold in these animals, indicating the importance of BCRP in the bioavailability and disposition of topotecan in rats. Chrysin (50 microM) and BF (5 microM) significantly inhibited the BCRP-mediated transport of topotecan in BCRP-overexpressing MCF-7 MX100 cells (MCF-7 cells selected with mitoxantrone) to a level comparable to that observed with 10 microM fumitremorgin C (a potent BCRP inhibitor). However, neither chrysin nor BF significantly altered topotecan pharmacokinetics in rats or in mdr1a/1b (-/-) mice after oral coadministration of doses up to 50 mg/kg. The reason(s) for this lack of in vitro-in vivo association may be 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.
authors.affiliation: Department of Pharmaceutical Sciences, 517 Hochstetter Hall, University at Buffalo, State University of New York, Amherst NY 14260-1200, USA.
authors.forename: Shuzhong
authors.initials: S
authors.lastname: Zhang
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wang
authors.forename: Kazuko
authors.initials: K
authors.lastname: Sagawa
authors.forename: Marilyn E
authors.initials: ME
authors.lastname: Morris
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency / Q000235:genetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics; D000166:Acridines / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001571:Benzoflavones / Q000494:pharmacology*; D001682:Biological Availability; D045744:Cell Line, Tumor; D004347:Drug Interactions; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044005:Tetrahydroisoquinolines / Q000494:pharmacology; D019772:Topotecan / Q000037:antagonists & inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000166:Acridines; D000970:Antineoplastic Agents; D001571:Benzoflavones; D005419:Flavonoids; D009363:Neoplasm Proteins; D044005:Tetrahydroisoquinolines; D019772:Topotecan; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C116614:ABCG2 protein, human; C043561:chrysin; C095122:multidrug resistance protein 3; C083501:Elacridar