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Predicting the absorption of orally administered drugs is crucial to drug development. Current in vitro models lack physiological relevance, robustness, and reproducibility, thus hindering reliable predictions. In this study, we developed a reproducible and robust culture method to generate a human intestinal organoid-derived monolayer model that can be applied to study drug absorption through a step-by-step approach. Our model showed similarity to primary enterocytes in terms of the drug absorption-related gene expression profile, tight barrier function, tolerability toward artificial bile juice, drug transporter and metabolizing enzyme function, and nuclear receptor activity. This method can be applied to organoids derived from multiple donors. The permeability of launched 19 drugs in our model demonstrated a correlation with human Fa values, with an R 2 value of 0.88. Additionally, by combining the modeling and simulation approaches, the estimated FaFg values for seven out of nine drugs, including CYP3A substrates, fell within 1.5 times the range of the human FaFg values. Applying this method to the drug discovery process might bridge the gap between preclinical and clinical research and increase the success rates of drug development.
Tanaka et al. (Thu,) studied this question.