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

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 (V (max)) and Michaelis–Menten constants (K (m)) 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.