Luteolin and naringenin are flavonoids found in various foods/beverages and present in certain dietary supplements. After a high intake of these flavonoids, their sulfate and glucuronide conjugates reach micromolar concentrations in the bloodstream. Some pharmacokinetic interactions of luteolin and naringenin have been investigated in previous studies; however, only limited data are available in regard to their metabolites. In this study, we aimed to investigate the interactions of the sulfate and glucuronic acid conjugates of luteolin and naringenin with human serum albumin, cytochrome P450 (CYP2C9, 2C19, and 3A4) enzymes, and organic anion transporting polypeptide (OATP1B1 and OATP2B1) transporters. Our main findings are as follows: (1) Sulfate conjugates formed more stable complexes with albumin than the parent flavonoids. (2) Luteolin and naringenin conjugates showed no or only weak inhibitory action on the CYP enzymes examined. (3) Certain conjugates of luteolin and naringenin are potent inhibitors of OATP1B1 and/or OATP2B1 enzymes. (4) Conjugated metabolites of luteolin and naringenin may play an important role in the pharmacokinetic interactions of these flavonoids.

Department of Pharmacology Faculty of Pharmacy University of Pécs Rókus u 2 H 7624 Pécs Hungary

Department of Pharmacology Faculty of Pharmacy University of Pécs Rókus u 2 H 7624 Pécs Hungary; Food Biotechnology Research Group János Szentágothai Research Centre University of Pécs Ifjúság útja 20 H 7624 Pécs Hungary

Department of Pharmacology Faculty of Pharmacy University of Pécs Rókus u 2 H 7624 Pécs Hungary; Green Chemistry Research Group János Szentágothai Research Center University of Pécs Ifjúság útja 20 H 7624 Pécs Hungary

Drug Resistance Research Group Institute of Enzymology Research Centre for Natural Sciences Eötvös Loránd Research Network Magyar tudósok krt 2 H 1117 Budapest Hungary

Drug Resistance Research Group Institute of Enzymology Research Centre for Natural Sciences Eötvös Loránd Research Network Magyar tudósok krt 2 H 1117 Budapest Hungary; Doctoral School of Biology Institute of Biology Eötvös Loránd University Pázmány P stny 1 C H 1117 Budapest Hungary

Institute of Microbiology of the Czech Academy of Sciences Vídeňská 1083 CZ 142 20 Prague Czech Republic

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Interaction of myricetin, ampelopsin (dihydromyricetin), and their sulfate metabolites with serum albumin, cytochrome P450 (CYP2C9, 2C19, and 3A4) enzymes, and organic anion-transporting polypeptides (OATP1B1 and OATP2B1)