Τίτλος:
Duodenum intestine-chip for preclinical drug assessment in a human relevant model
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. © Kasendra et al.
Συγγραφείς:
Kasendra, M.
Luc, R.
Yin, J.
Manatakis, D.V.
Kulkarni, G.
Lucchesi, C.
Sliz, J.
Apostolou, A.
Sunuwar, L.
Obrigewitch, J.
Jang, K.-J.
Hamilton, G.A.
Donowitz, M.
Karalis, K.
Εκδότης:
eLife Sciences Publications Ltd
Λέξεις-κλειδιά:
cytochrome P450 3A4; ABCB1 protein, human; CYP3A4 protein, human; cytochrome P450 3A; transcriptome, Article; Caco-2 cell line; cell subpopulation; controlled study; cytoarchitecture; duodenum; human; human cell; human tissue; in vivo study; intestine mucosa permeability; organoid; polarization; protein expression; protein function; protein induction; protein localization; animal; biology; devices; drug interaction; duodenum; gene expression profiling; gene expression regulation; metabolism; microvillus; organ culture technique; permeability; preclinical study, Animals; ATP Binding Cassette Transporter, Subfamily B; Caco-2 Cells; Computational Biology; Cytochrome P-450 CYP3A; Drug Evaluation, Preclinical; Drug Interactions; Duodenum; Gene Expression Profiling; Gene Expression Regulation; Humans; Microvilli; Organ Culture Techniques; Organoids; Permeability; Transcriptome
