Article ; Online: Quantitative Prediction of Intestinal Absorption of Drugs from In Vitro Study: Utilization of Differentiated Intestinal Epithelial Cells Derived from Intestinal Stem Cells at Crypts.
Drug metabolism and disposition: the biological fate of chemicals
2023 Volume 51, Issue 9, Page(s) 1136–1144
Abstract: Prediction of intestinal absorption of drugs in humans is one of the critical elements in the development process for oral drugs. However, it remains challenging, because intestinal absorption of drugs is influenced by multiple factors, including the ... ...
| Abstract | Prediction of intestinal absorption of drugs in humans is one of the critical elements in the development process for oral drugs. However, it remains challenging, because intestinal absorption of drugs is influenced by multiple factors, including the function of various metabolic enzymes and transporters, and large species differences in drug bioavailability hinder the prediction of human bioavailability directly from in vivo animal experiments. For the screening of intestinal absorption properties of drugs, a transcellular transport assay with Caco-2 cells is still routinely used by pharmaceutical companies because of its convenience, but the predictability of the fraction of the oral dose that goes to the portal vein of metabolic enzyme/transporter substrate drugs was not always good because the cellular expression of metabolic enzymes and transporters is different from that in the human intestine. Recently, various novel in vitro experimental systems have been proposed such as the use of human-derived intestinal samples, transcellular transport assay with induced pluripotent stem-derived enterocyte-like cells, or differentiated intestinal epithelial cells derived from intestinal stem cells at crypts. Crypt-derived differentiated epithelial cells have an excellent potential to characterize species differences and regional differences in intestinal absorption of drugs because a unified protocol can be used for the proliferation of intestinal stem cells and their differentiation into intestinal absorptive epithelial cells regardless of the animal species and the gene expression pattern of differentiated cells is maintained at the site of original crypts. The advantages and disadvantages of novel in vitro experimental systems for characterizing intestinal absorption of drugs are also discussed. SIGNIFICANCE STATEMENT: Among novel in vitro tools for the prediction of human intestinal absorption of drugs, crypt-derived differentiated epithelial cells have many advantages. Cultured intestinal stem cells are rapidly proliferated and easily differentiated into intestinal absorptive epithelial cells simply by changing the culture media. A unified protocol can be used for the establishment of intestinal stem cell culture from preclinical species and humans. Region-specific gene expression at the collection site of crypts can be reproduced in differentiated cells. |
|---|---|
| MeSH term(s) | Animals ; Humans ; Caco-2 Cells ; Intestines ; Epithelial Cells/metabolism ; Stem Cells ; Membrane Transport Proteins/metabolism ; Cell Differentiation ; Intestinal Absorption ; Intestinal Mucosa/metabolism |
| Chemical Substances | Membrane Transport Proteins |
| Language | English |
| Publishing date | 2023-05-04 |
| Publishing country | United States |
| Document type | Journal Article ; Review ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 186795-7 |
| ISSN | 1521-009X ; 0090-9556 |
| ISSN (online) | 1521-009X |
| ISSN | 0090-9556 |
| DOI | 10.1124/dmd.122.000966 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
More links
Kategorien
In stock of ZB MED Cologne/Königswinter
| Zs.A 1014: Show issues | Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG) |
Order via subito
This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.