Use of physiologically based kinetic (PBK) modeling to study interindividual human variation and species differences in plasma concentrations of quercetin and its metabolites

Abstract

This version is distributed under a non-commencial no derivatives Creative Commons (CC-BY-NC-ND) user license, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited and not used for commercial purposes. Further, the restriction applies that if you remix, transform, or build upon the material, you may not distribute the modified material.Please cite this publication as follows: Biological activities of flavonoids in vivo ultimately depend on the systemic 3 bioavailability of the aglycones and their metabolites. We aimed to develop physiologically based 4 kinetic (PBK) models to predict plasma concentrations of the flavonoid quercetin and its 5 metabolites in individual human subjects and to define species differences compared with male 6 rat. The human models were developed based on in vitro metabolic parameters derived from 7 incubations with pooled and 20 individual human tissue fractions and by fitting kinetic 8 parameters to available in vivo data. The outcomes obtained were compared to a previously 9 developed model for quercetin and its metabolites formation in male rat. Quercetin-3´-O-10 glucuronide was predicted to be the major circulating metabolite in 19 out of 20 individuals, 11 while in male rat di-and tri-conjugates of quercetin containing a glucuronic acid, sulfate and/or 12 methyl moiety are the major metabolites. Significant species differences occur in major 13 circulating metabolites of quercetin suggesting that rat is not an adequate model to study effects 14 of quercetin in man. The defined PBK models can be used to guide the experimental design of in 15 vitro experiments with flavonoids, especially to better take into account the relevance of 16 metabolism and the contribution of metabolites to the biological activity in humans.

Physiologically based kinetic modeling of hesperidin metabolism and its use to predict in vivo effective doses in humans

“…Mass balance equations for hesperetin and its metabolites were similar to those previously described by Boonpawa et al. for PBK models of quercetin. Model performance was evaluated by comparing the predicted concentrations of urinary profiles to reported data in human urine .…”

“…A PBK model for dietary hesperidin was developed in a similar manner as previously described for the development of a PBK model for quercetin . The PBK model was defined to gain more insight in the ADME characteristics of hesperidin and the various metabolites formed in humans and to provide a method for conversion of in vitro effective concentrations to in vivo dose levels (Section ).…”

Actions of Quercetin, a Polyphenol, on Blood Pressure

“…Then, in the cells the quercetin aglycone is glucuronidated, sulfated, or methylated ( Figure 1 ) and these modified types of quercetin molecules enter circulation [ 33 ]. The major metabolites in rats are di- and tri-conjugates of quercetin, such as glucuronidated, sulfate and/or methylated ones [ 33 , 34 ], while in humans, quercetin-3′- O -glucuronide is the major circulating metabolite [ 34 ]. These observations suggest that significant species differences occur in major circulating metabolites of quercetin.…”

In vitro‐in silico‐based analysis of the dose‐dependent in vivo oestrogenicity of the soy phytoestrogen genistein in humans

“…Mass balance equations were numerically integrated in Berkeley Madonna version 8.3.18 (Macey and Oster, UC Berkeley, CA, USA) using Rosenbrock's algorithm for stiff system. Mass balance equations for genistein and its metabolites were similar to those previously described by Boonpawa et al (2014Boonpawa et al ( , 2015 for quercetin. Model performance was evaluated by comparing the predicted amounts of genistein metabolites excreted in urine to the reported amounts of genistein metabolites in human urine (Hosoda et al, 2011;Yuan et al, 2012b).…”

“…For other reactions including sulfation of genistein, G‐7G and G4′G as well as glucuronidation of G‐7G, G4′G and G‐7S, the kinetic constants were obtained in the present study based on in vitro experiments. The apparent V max values for formation of the different mono‐ and di‐conjugates were scaled to in vivo V max values using an S9 content of 11.4 and 143 mg (g tissue) −1 for small intestine and liver as scaling factors (Boonpawa et al, ). It is of importance to note that the current PBK model does not include the formation of the microflora metabolite equol, a potent oestrogenic metabolite (Morito et al, ; Hwang et al, ), because equol is a major metabolite of daidzein, not of genistein and only approximately one‐third to one‐half of the population are actually equol producers (Yuan et al, ).…”