PT  - JOURNAL ARTICLE
AU  - Aarti Sawant-Basak
AU  - A. David Rodrigues
AU  - Matthew Lech
AU  - Regis Doyonnas
AU  - Marion Kasaian
AU  - Bhagwat Prasad
AU  - Nikolaos Tsamandouras
TI  - Physiologically relevant, humanized intestinal systems to study metabolism and transport of small molecule therapeutics: Mini-review
AID  - 10.1124/dmd.118.082784
DP  - 2018 Jan 01
TA  - Drug Metabolism and Disposition
PG  - dmd.118.082784
4099  - http://dmd.aspetjournals.org/content/early/2018/08/20/dmd.118.082784.short
4100  - http://dmd.aspetjournals.org/content/early/2018/08/20/dmd.118.082784.full
AB  - Intestinal disposition of small molecules involves interplay of drug-metabolizing enzymes, transporters, and host-microbiome, which has spurred the development of in vitro intestinal models derived from primary tissue sources. Such models have been bio-engineered from intestinal crypts, mucosal extracts, iPSC-derived organoids, and human intestinal tissue. The present mini-review 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 scrappings show key absorptive cell morphology; but are limited in quantitative applications due to lack of accessibility to apical compartment, 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, bio-engineered 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, transcriptomic, proteomic, and functional end-points of novel intestinal model systems, when referenced to native human tissue, can provide greater confidence and increased utility in drug discovery and development.