Physiologically Relevant, Humanized Intestinal Systems to Study Metabolism and Transport of Small Molecule Therapeutics.

Intestinal disposition of small molecules involves interplay of drug metabolizing enzymes (DMEs), transporters, and host-microbiome interactions, which has spurred the development of in vitro intestinal models derived from primary tissue sources. Such models have been bioengineered from intestinal crypts, mucosal extracts, induced pluripotent stem cell (iPSC)-derived organoids, and human intestinal tissue. This minireview discusses the utility and limitations of these human-derived models in support of small molecule drug metabolism and disposition. Enteroids from human intestinal crypts, organoids derived from iPSCs using growth factors or small molecule compounds, and enterocytes extracted from mucosal scrapings show key absorptive cell morphology while are limited in quantitative applications due to the lack of accessibility to the apical compartment, the lack of monolayers, or low expression of key DMEs, transporters, and nuclear hormone receptors. Despite morphogenesis to epithelial cells, similar challenges have been reported by more advanced technologies that have explored the impact of flow and mechanical stretch on proliferation and differentiation of Caco-2 cells. Most recently, bioengineered human intestinal epithelial or ileal cells have overcome many of the challenges, as the DME and transporter expression pattern resembles that of native intestinal tissue. Engineering advances may improve such models to support longer-term applications and meet end-user needs. Biochemical characterization and transcriptomic, proteomic, and functional endpoints of emerging novel intestinal models, when referenced to native human tissue, can provide greater confidence and increased utility in drug discovery and development.