Duodenum Intestine-Chip for preclinical drug assessment in a human relevant model
| Autor: | Athanasia Apostolou, Geraldine A. Hamilton, Laxmi Sunuwar, Carolina Lucchesi, Katia Karalis, Josiah Sliz, Dimitris V. Manatakis, Mark Donowitz, Jenifer Obrigewitch, Gauri Kulkarni, Raymond Luc, Kyung-Jin Jang, Jianyi Yin, Magdalena Kasendra |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
CYP3A4 Drug Evaluation Preclinical duodenum 02 engineering and technology Pharmacology Organs-on-Chips Cytochrome P-450 CYP3A Drug Interactions Biology (General) organoids Barrier function media_common Microvilli General Neuroscience General Medicine 021001 nanoscience & nanotechnology medicine.anatomical_structure Medicine 0210 nano-technology Research Article Human Drug drug transport ATP Binding Cassette Transporter Subfamily B QH301-705.5 Science media_common.quotation_subject Biology Permeability General Biochemistry Genetics and Molecular Biology 03 medical and health sciences Organ Culture Techniques Pharmacokinetics In vivo medicine Animals Humans General Immunology and Microbiology Gene Expression Profiling Computational Biology Transporter Cell Biology drug metabolism 030104 developmental biology Gene Expression Regulation Duodenum Caco-2 Cells Transcriptome Drug metabolism |
| Zdroj: | eLife, Vol 9 (2020) eLife |
| ISSN: | 2050-084X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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