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.