Duodenum intestine-chip for preclinical drug assessment in a human relevant model

Magdalena Kasendra, Raymond Luc, Jianyi Yin, Dimitris V. Manatakis, Gauri Kulkarni, Carolina Lucchesi, Josiah Sliz, Athanasia Apostolou, Laxmi Sunuwar, Jenifer Obrigewitch, Kyung Jin Jang, Geraldine A. Hamilton, Mark Donowitz, Katia Karalis

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Article numbere50135
JournaleLife
Volume9
DOIs
StatePublished - Jan 2020

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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