PT  - JOURNAL ARTICLE
AU  - Kazuyoshi Michiba
AU  - Kazuya Maeda
AU  - Osamu Shimomura
AU  - Yoshihiro Miyazaki
AU  - Shinji Hashimoto
AU  - Tatsuya Oda
AU  - Hiroyuki Kusuhara
TI  - Usefulness of Human Jejunal Spheroid–Derived Differentiated Intestinal Epithelial Cells for the Prediction of Intestinal Drug Absorption in Humans
AID  - 10.1124/dmd.121.000796
DP  - 2022 Mar 01
TA  - Drug Metabolism and Disposition
PG  - 204--213
VI  - 50
IP  - 3
4099  - http://dmd.aspetjournals.org/content/50/3/204.short
4100  - http://dmd.aspetjournals.org/content/50/3/204.full
SO  - Drug Metab Dispos2022 Mar 01; 50
AB  - This study aimed to demonstrate the usefulness of human jejunal spheroid-derived differentiated intestinal epithelial cells as a novel in vitro model for clarifying the impact of intestinal drug-metabolizing enzymes and transporters on the intestinal absorption of substrate drugs in humans. Three-dimensional human intestinal spheroids were successfully established from surgical human jejunal specimens and expanded for a long period using L-WRN-conditioned medium, which contains Wnt3a, R-spondin 3, and noggin. The mRNA expression levels of intestinal pharmacokinetics-related genes in the human jejunal spheroid-derived differentiated intestinal epithelial cells were drastically increased over a 5-day period after seeding compared with those in human jejunal spheroids and were approximately the same as those in human jejunal tissue over a culture period of at least 13 days. Activities of typical drug-metabolizing enzymes [cytochrome P450 (CYP) 3A, CYP2C9, uridine 5′-diphospho-glucuronosyltransferase 1A, and carboxylesterase 2] and uptake/efflux transporters [peptide transporter 1/solute carrier 15A1], P-glycoprotein, and breast cancer resistance protein) in the differentiated cells were confirmed. Furthermore, intestinal availability (Fg) values estimated from the apical-to-basolateral permeation clearance across cell monolayer showed a good correlation with the in vivo Fg values in humans for five CYP3A substrate drugs (Fg range, 0.35–0.98). In conclusion, the functions of major intestinal drug-metabolizing enzymes and transporters could be maintained in human jejunal spheroid-derived differentiated intestinal epithelial cells. This model would be useful for the quantitative evaluation of the impact of intestinal drug-metabolizing enzymes and transporters on the intestinal absorption of substrate drugs in humans.SIGNIFICANCE STATEMENT Limited information is available regarding the quantitative prediction of the impact of drug-metabolizing enzymes and transporters on the human intestinal absorption of substrates using in vitro assays with differentiated cells derived from human intestinal spheroids/organoids. This study confirmed the functions of typical drug-metabolizing enzymes and transporters in human jejunal spheroid-derived differentiated intestinal epithelial cells and demonstrated that intestinal availability (Fg) estimated from apical-to-basolateral permeation clearance across cell monolayers showed a good correlation with in vivo human Fg for CYP3A substrates.