Duodenum Intestine-Chip for preclinical drug assessment in a human relevant model
Duodenum Intestine-Chip for preclinical drug assessment in a human relevant model
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DOI：
10.7554/elife.50135
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发表时间：
2020-01-14
期刊：
影响因子：
7.7
通讯作者：
Karalis, Katia
中科院分区：
文献类型：
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作者：
Kasendra, Magdalena;Luc, Raymond;Karalis, Katia
肠道药物代谢酶的诱导可能导致药物相互作用（ddi），从而导致药代动力学、安全性和有效性的变化，从而使新药的开发复杂化。开发一种与人类相关的成人肠道模型，准确预测CYP450的诱导，可以帮助解决这一挑战，因为物种差异阻碍了从动物中推断。在这里，我们将类器官和器官芯片技术结合起来，创造了一个模拟肠道组织结构和功能的人体十二指肠-肠道芯片，这与药物运输、代谢和DDI的研究有关。十二指肠- Intestine-Chip显示了极化细胞结构、肠屏障功能、特化细胞亚群的存在以及主要肠道药物转运体在体内的相关表达、定位和功能。值得注意的是，与Caco-2相比，它表现出更高的CYP3A4表达和诱导能力。该模型可以改进体外到体内的外推，从而更好地预测人药代动力学和ddi的风险。
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.