Use of Physiologically Based Kinetic Modeling to Predict Rat Gut Microbial Metabolism of the Isoflavone Daidzein to S‐Equol and Its Consequences for ERα Activation

Abstract

Scope To predict gut microbial metabolism of xenobiotics and the resulting plasma concentrations of metabolites formed, an in vitro–in silico‐based testing strategy is developed using the isoflavone daidzein and its gut microbial metabolite S‐equol as model compounds. Methods and results Anaerobic rat fecal incubations are optimized and performed to derive the apparent maximum velocities (Vmax) and Michaelis–Menten constants (Km) for gut microbial conversion of daidzein to dihydrodaidzein, S‐equol, and O‐desmethylangolensin, which are input as parameters for a physiologically based kinetic (PBK) model. The inclusion of gut microbiota in the PBK model allows prediction of S‐equol concentrations and slightly reduced predicted maximal daidzein concentrations from 2.19 to 2.16 µm. The resulting predicted concentrations of daidzein and S‐equol are comparable to in vivo concentrations reported. Conclusion The optimized in vitro approach to quantify kinetics for gut microbial conversions, and the newly developed PBK model for rats that includes gut microbial metabolism, provide a unique tool to predict the in vivo consequences of daidzein microbial metabolism for systemic exposure of the host to daidzein and its metabolite S‐equol. The predictions reveal a dominant role for daidzein in ERα‐mediated estrogenicity despite the higher estrogenic potency of its microbial metabolite S‐equol.

Physiologically based kinetic modelling predicts the in vivo relative potency of riddelliine N-oxide compared to riddelliine in rat to be dose dependent

“…The importance of taking differences kinetics into account when defining relative potencies of PAs was previously shown to also hold for the PAs themselves for which substantial differences in clearance may exist (Lester et al 2019). Successful incorporation of intestinal microbiota in PBK models has been demonstrated so far in only a few other studies (Mendez-Catala et al 2020;Wang et al 2020) and the current study provides another proof-of-principle for this approach.…”

“…The conditions for anaerobic rat fecal incubations with riddelliine N-oxide were optimized with respect to linearity in time and with respect to the amount of fecal sample as previously described (Wang et al 2020;Yang et al 2019). Using the optimized linear conditions, the riddelliine N-oxide 1 REP values for riddelliine N-oxide relative to riddelliine as derived based on literature data a A dose correction was performed for the data reported by Wang et al (2005) and Chou et al (2003), since these studies did not apply equimolar dose levels.…”

An in vitromodel to quantify interspecies differences in kinetics for intestinal microbial bioactivation and detoxification of zearalenone

“…The bacterial communities in colon and feces have been reported to be highly comparable [ [38] , [39] , [40] ]. Furthermore, proofs of principle that show that anaerobic in vitro incubations using fecal communities can be used to predict intestinal microbial metabolic activities have been reported [ 41 ], supporting the use of anaerobic fecal samples as a representative population of intestinal microbes. Therefore, the use of anaerobic fecal samples for the study of intestinal microbial metabolism represents a first tier approach to estimate its contribution to the total metabolism in the host.…”

Species Differences in in vitro and Estimated in vivo Kinetics for Intestinal Microbiota Mediated Metabolism of Acetyl‐deoxynivalenols

“…However, the colon, harboring 70% of the total bacteria present in the gut, is the main site for bacterial fermentation. [24] Furthermore, it has been shown that the bacterial communities in colon and feces are highly comparable. [25][26][27] In addition, proofs of principle have shown that anaerobic in vitro incubations using fecal communities can be used to predict intestinal microbial metabolic activities, [24] supporting the use of anaerobic fecal samples as a representative population of intestinal microbes.…”