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.

中文翻译：

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十二指肠肠芯片用于人类相关模型的临床前药物评估

肠道药物代谢酶的诱导，由于可能引起药物相互作用（DDI），从而导致药代动力学，安全性和功效的改变，可能使新药的开发复杂化。可以准确预测CYP450诱导作用的人肠道相关模型的开发可能有助于解决这一挑战，因为物种差异会阻止动物推断。在这里，我们将类器官和芯片上的器官技术相结合，创建了一个模拟肠组织结构和功能的人十二指肠肠芯片，这与药物运输，代谢和DDI的研究有关。十二指肠肠芯片展示了极化的细胞结构，肠屏障功能，特化细胞亚群的存在以及体内主要肠道药物转运蛋白的相关表达，定位和功能。值得注意的是，与Caco-2相比，它显示出改善的CYP3A4表达和诱导能力。该模型可以改善从体外到体内的推断，从而更好地预测人的药代动力学和DDI的风险。