Precise prediction of the fraction of compounds reaching the portal vein (FaFg) in humans, which could indicate the rate-limiting step of polyphenol metabolism, is particularly important for accurately evaluating the efficacy and safety of polyphenols. In this study, we aimed to develop a novel in vitro method to predict human FaFg of polyphenols using commercially available human induced pluripotent stem cell-derived small intestinal epithelial cells (hiPSC-SIECs). First, the chemicals were used at fixed test concentrations, considering their physicochemical properties and cytotoxicity. The apparent permeability coefficient (P) values of the six tested polyphenols in hiPSC-SIECs were considerably higher than those of the seven tested pharmaceuticals, resulting in a poor correlation between P in hiPSC-SIECs and human FaFg. A detailed assessment of the relationship between in vitro test concentration and metabolic activity suggested that the higher P value of polyphenols would be due to inadequate reflection of phase II metabolism in the human intestine. By optimizing test concentrations to reflect enzymatic metabolism in the human intestine, a good correlation was observed between the P values in hiPSC-SIECs and human FaFg for tested polyphenols and pharmaceuticals (R = 0.81). The developed method could be useful for precisely predicting human FaFg of polyphenols.
