title: Use of physiologically based kinetic (PBK) modeling to study interindividual human variation and species differences in plasma concentrations of quercetin and its metabolites.
abstract: Biological activities of flavonoids in vivo ultimately depend on the systemic bioavailability of the aglycones and their metabolites. We aimed to develop physiologically based kinetic (PBK) models to predict plasma concentrations of the flavonoid quercetin and its metabolites in individual human subjects and to define species differences compared with male rat. The human models were developed based on in vitro metabolic parameters derived from incubations with pooled and 20 individual human tissue fractions and by fitting kinetic parameters to available in vivo data. The outcomes obtained were compared to a previously developed model for quercetin and its metabolites formation in male rat. Quercetin-3'-O-glucuronide was predicted to be the major circulating metabolite in 19 out of 20 individuals, while in male rat di- and tri-conjugates of quercetin containing a glucuronic acid, sulfate and/or methyl moieties are the major metabolites. Significant species differences occur in major circulating metabolites of quercetin suggesting that rat is not an adequate model to study effects of quercetin in man. The defined PBK models can be used to guide the experimental design of in vitro experiments with flavonoids, especially to better take into account the relevance of metabolism and the contribution of metabolites to the biological activity in humans.
authors.affiliation: Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE Wageningen, The Netherlands. Electronic address: Rungnapa2.Boonpawa@wur.nl.
authors.forename: Rungnapa
authors.initials: R
authors.lastname: Boonpawa
authors.affiliation: Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE Wageningen, The Netherlands.
authors.forename: Nooshin
authors.initials: N
authors.lastname: Moradi
authors.affiliation: Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE Wageningen, The Netherlands.
authors.forename: Albertus
authors.initials: A
authors.lastname: Spenkelink
authors.affiliation: Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE Wageningen, The Netherlands.
authors.forename: Ivonne M C M
authors.initials: IM
authors.lastname: Rietjens
authors.affiliation: Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE Wageningen, The Netherlands.
authors.forename: Ans
authors.initials: A
authors.lastname: Punt
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D005260:Female; D006801:Humans; D007313:Insecta; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011794:Quercetin / Q000031:analogs & derivatives / Q000097:blood* / Q000378:metabolism / Q000493:pharmacokinetics*; D051381:Rats; D013045:Species Specificity; D055815:Young Adult
chemical_list: C443401:quercetin 3-O-glucuronide; D011794:Quercetin
keywords: Absorption distribution metabolism excretion (ADME); Human variation; Physiologically based kinetic (PBK) modeling; Quercetin; Species differences