PBK Model‐Based Prediction of Intestinal Microbial and Host Metabolism of Zearalenone and Consequences for its Estrogenicity

Scope The aim of the present study is to develop physiologically‐based kinetic (PBK) models for rat and human that include intestinal microbial and hepatic metabolism of zearalenone (ZEN) in order to predict systemic concentrations of ZEN and to obtain insight in the contribution of metabolism by the intestinal microbiota to the overall metabolism of ZEN. Methods and Results In vitro derived kinetic parameters, apparent maximum velocities ( V max ) and Michaelis–Menten constants ( K m ) for liver and intestinal microbial metabolism of ZEN are included in the PBK models. The models include a sub‐model for the metabolite, α‐zearalenol (α‐ZEL), a metabolite known to be 60‐times more potent as an estrogen than ZEN. Integrating intestinal microbial ZEN metabolism into the PBK models revealed that hepatic metabolism drives the formation of α‐ZEL. Furthermore, the models predicted that at the tolerable daily intake (TDI) of 0.25 µg kg −1 bw the internal concentration of ZEN and α‐ZEL are three‐orders of magnitude below concentrations reported to induce estrogenicity in vitro. Conclusion It is concluded that combining kinetic data on liver and intestinal microbial metabolism in a PBK model facilitates a holistic view on the role of the intestinal microbiota in the overall metabolism of the foodborne xenobiotic ZEN and its bioactivation to α‐ZEL.