TY - JOUR
T1 - Duodenum intestine-chip for preclinical drug assessment in a human relevant model
AU - Kasendra, Magdalena
AU - Luc, Raymond
AU - Yin, Jianyi
AU - Manatakis, Dimitris V.
AU - Kulkarni, Gauri
AU - Lucchesi, Carolina
AU - Sliz, Josiah
AU - Apostolou, Athanasia
AU - Sunuwar, Laxmi
AU - Obrigewitch, Jenifer
AU - Jang, Kyung Jin
AU - Hamilton, Geraldine A.
AU - Donowitz, Mark
AU - Karalis, Katia
N1 - Publisher Copyright:
© Kasendra et al.
PY - 2020/1/1
Y1 - 2020/1/1
N2 - Induction of intestinal drug metabolizing enzymes can complicate the development of new drugs, owing to the potential to cause drug-drug interactions (DDIs) leading to changes in pharmacokinetics, safety and efficacy. The development of a human-relevant model of the adult intestine that accurately predicts CYP450 induction could help address this challenge as species differences preclude extrapolation from animals. Here, we combined organoids and Organs-on-Chips technology to create a human Duodenum Intestine-Chip that emulates intestinal tissue architecture and functions, that are relevant for the study of drug transport, metabolism, and DDI. Duodenum Intestine-Chip demonstrates the polarized cell architecture, intestinal barrier function, presence of specialized cell subpopulations, and in vivo relevant expression, localization, and function of major intestinal drug transporters. Notably, in comparison to Caco-2, it displays improved CYP3A4 expression and induction capability. This model could enable improved in vitro to in vivo extrapolation for better predictions of human pharmacokinetics and risk of DDIs.
AB - Induction of intestinal drug metabolizing enzymes can complicate the development of new drugs, owing to the potential to cause drug-drug interactions (DDIs) leading to changes in pharmacokinetics, safety and efficacy. The development of a human-relevant model of the adult intestine that accurately predicts CYP450 induction could help address this challenge as species differences preclude extrapolation from animals. Here, we combined organoids and Organs-on-Chips technology to create a human Duodenum Intestine-Chip that emulates intestinal tissue architecture and functions, that are relevant for the study of drug transport, metabolism, and DDI. Duodenum Intestine-Chip demonstrates the polarized cell architecture, intestinal barrier function, presence of specialized cell subpopulations, and in vivo relevant expression, localization, and function of major intestinal drug transporters. Notably, in comparison to Caco-2, it displays improved CYP3A4 expression and induction capability. This model could enable improved in vitro to in vivo extrapolation for better predictions of human pharmacokinetics and risk of DDIs.
UR - http://www.scopus.com/inward/record.url?scp=85077785933&partnerID=8YFLogxK
U2 - 10.7554/eLife.50135
DO - 10.7554/eLife.50135
M3 - Article
C2 - 31933478
AN - SCOPUS:85077785933
SN - 2050-084X
VL - 9
JO - eLife
JF - eLife
M1 - e50135
ER -