ReviewFoundationModels for drug absorption from the small intestine: where are we and where are we going?

•It is of primary importance to obtain relevant models in drug discovery.•Physiology and biology of the oral route is complex to model.•In silico models allow high-throughput screening but can be less relevant.•In vivo models raise ethical issues.•In vitro complex models are a good compromise between relevancy and throughput.

The small intestine is a complex organ with movements, flora, mucus and flows. Despite this, the most widely used absorption models consider the organ a cylindrical monoepithelial tube. This review presents the recent evolution of models to take into consideration the complex nature of gut physiology. The most commonly encountered issues are ethical (in vivo models) and differences in drug transport as a result of a modified expression of drug transporters or metabolic enzymes compared with human (in vitro and in vivo models). Finally, this review discusses the way forward to reach an ideal equilibrium between reproducibility, predictability and efficiency for predicting permeability. The features of an ideal model are listed as a guideline for future development.

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