Monolayer platform using human biopsy-derived duodenal organoids for pharmaceutical research
Tomoki Yamashita, Tatsuya Inui, Jumpei Yokota, Kentaro Kawakami, Gaku Morinaga, Masahito Takatani, Daisuke Hirayama, Ryuga Nomoto, Kohei Ito, Yunhai Cui, Stephanie Ruez, Kazuo Harada, Wataru Kishimoto, Hiroshi Nakase, Hiroyuki Mizuguchi
Abstract
The human small intestine is the key organ for absorption, metabolism, and excretion of orally administered drugs. To preclinically predict these reactions in drug discovery research, a cell model that can precisely recapitulate the in vivo human intestinal monolayer is desired. In this study, we developed a monolayer platform using human biopsy-derived duodenal organoids for application to pharmacokinetic studies. The human duodenal organoid-derived monolayer was prepared by a simple method in 3–8 days. It consisted of polarized absorptive cells and had tight junctions. It showed much higher cytochrome P450 (CYP)3A4 and carboxylesterase (CES)2 activities than did the existing models (Caco-2 cells). It also showed efflux activity of P-glycoprotein (P-gp) and inducibility of CYP3A4. Finally, its gene expression profile was closer to the adult human duodenum, compared to the profile of Caco-2 cells. Based on these findings, this monolayer assay system using biopsy-derived human intestinal organoids is likely to be widely adopted.