title: Interaction of quercetin and its metabolites with warfarin: Displacement of warfarin from serum albumin and inhibition of CYP2C9 enzyme.
abstract: Flavonoids are ubiquitous molecules in nature with manifold pharmacological effects. Flavonoids interact with several proteins, and thus potentially interfere with the pharmacokinetics of various drugs. Though much is known about the protein binding characteristics of flavonoid aglycones, the behaviour of their metabolites, which are extensively formed in the human body has received little attention. In this study, the interactions of the flavonoid aglycone quercetin and its main metabolites with the albumin binding of the oral anticoagulant warfarin were investigated by fluorescence spectroscopy and ultrafiltration. Furthermore, the inhibitory effects of these flavonoids on CYP2C9 enzyme were tested because the metabolic elimination of warfarin is catalysed principally by this enzyme. Herein, we demonstrate that each tested flavonoid metabolite can bind to human serum albumin (HSA) with high affinity, some with similar or even higher affinity than quercetin itself. Quercetin metabolites are able to strongly displace warfarin from HSA suggesting that high quercetin doses can strongly interfere with warfarin therapy. On the other hand, tested flavonoids showed no or weaker inhibition of CYP2C9 compared to warfarin, making it very unlikely that quercetin or its metabolites can significantly inhibit the CYP2C9-mediated inactivation of warfarin.
authors.affiliation: Department of Pharmacology, University of Pécs, Faculty of Pharmacy, Szigeti út 12, Pécs, H-7624, Hungary. Electronic address: poor.miklos@pte.hu.
authors.forename: Miklós
authors.initials: M
authors.lastname: Poór
authors.affiliation: Department of Pharmacology, University of Pécs, Faculty of Pharmacy, Szigeti út 12, Pécs, H-7624, Hungary.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Boda
authors.affiliation: Institute of Food Research, Norwich Research Park, Norwich, NR4 7UA, UK.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Needs
authors.affiliation: Institute of Food Research, Norwich Research Park, Norwich, NR4 7UA, UK.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Kroon
authors.affiliation: Department of General and Physical Chemistry, University of Pécs, Ifjúság útja 6, Pécs, H-7624, Hungary; János Szentágothai Research Center, Ifjúság útja 20, Pécs, H-7624, Hungary.
authors.forename: Beáta
authors.initials: B
authors.lastname: Lemli
authors.affiliation: Institute of Pharmacognosy, University of Pécs, Faculty of Pharmacy, Rókus utca 2, Pécs, H-7624, Hungary.
authors.forename: Tímea
authors.initials: T
authors.lastname: Bencsik
mesh_terms: D065729:Cytochrome P-450 CYP2C9 / Q000378:metabolism*; D065688:Cytochrome P-450 CYP2C9 Inhibitors / Q000494:pharmacology*; D004008:Diclofenac / Q000031:analogs & derivatives / Q000494:pharmacology; D004347:Drug Interactions; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D055442:Metabolome / Q000187:drug effects; D011794:Quercetin / Q000737:chemistry / Q000378:metabolism*; D012709:Serum Albumin / Q000378:metabolism*; D013050:Spectrometry, Fluorescence; D014462:Ultrafiltration; D014859:Warfarin / Q000378:metabolism*
chemical_list: D065688:Cytochrome P-450 CYP2C9 Inhibitors; D005419:Flavonoids; D012709:Serum Albumin; D004008:Diclofenac; D014859:Warfarin; D011794:Quercetin; D065729:Cytochrome P-450 CYP2C9; C108036:4'-hydroxydiclofenac
keywords: CYP2C9; Food-drug interaction; Human serum albumin; Quercetin metabolites; Warfarin