In vitro models replicating the human intestinal epithelium for absorption and metabolism studies: A systematic review

Absorption, distribution, metabolism and excretion (ADME) studies represent a fundamental step in the early stages of drug discovery. In particular, the absorption of orally administered drugs, which occurs at the intestinal level, has gained attention since poor oral bioavailability often led to failures for new drug approval. In this context, several in vitro preclinical models have been recently developed and optimized to better resemble human physiology in the lab and serve as an animal alternative to accomplish the 3Rs principles. However, numerous models are ineffective in recapitulating the key features of the human small intestine epithelium and lack of prediction potential for drug absorption and metabolism during the preclinical stage. In this review, we provide an overview of in vitro models aimed at mimicking the intestinal barrier for pharmaceutical screening. After briefly describing how the human small intestine works, we present i) conventional 2D synthetic and cell-based systems, ii) 3D models replicating the main features of the intestinal architecture, iii) micro-physiological systems (MPSs) reproducing the dynamic stimuli to which cells are exposed in the native microenvironment. In this review, we will highlight the benefits and drawbacks of the leading intestinal models used for drug absorption and metabolism studies.

EpiIntestinal, bidirectional permeation studies, intestinal absorption, Intestinal metabolism, ADME, preclinical drug screening, drug metabolizing enzymes, uptake and efflux transporters, MRP-1, MRP-2, BCRP, CYP3A4, CYP3A5, CYP2B6, CYP2C19, CYP2C9, UDP-glucuronosyltransferases (UGT), high reproducibility, Caco-2, organoids, TC-7, MDCK, HT-29, HIEC, IEC