Use of Physiologically Based Pharmacokinetic Modeling to Predict Human Gut Microbial Conversion of Daidzein to S‑Equol

A physiologically
based pharmacokinetic (PBPK) model was developed
for daidzein and its metabolite S-equol. Anaerobic in vitro incubations
of pooled fecal samples from S-equol producers and nonproducers allowed
definition of the kinetic constants. PBPK model-based predictions
for the maximum daidzein plasma concentration (Cmax) were comparable to literature data. The predictions also
revealed that the Cmax of S-equol in producers
was only up to 0.22% that of daidzein, indicating that despite its
higher estrogenicity, S-equol is likely to contribute to the overall
estrogenicity upon human daidzein exposure to a only limited extent.
An interspecies comparison between humans and rats revealed that the
catalytic efficiency for S-equol formation in rats was 210-fold higher
than that of human S-equol producers. The described in vitro–in
silico strategy provides a proof-of-principle on how to include microbial
metabolism in humans in PBPK modeling as part of the development of
new approach methodologies (NAMs).