Li Zhongyu, Su Wentao, Zhu Yujuan, Tao Tingting, Li Dong, Peng Xiaojun, Qin Jianhua
Division of Biotechnology, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
Dalian Municipal Women and Children's Medical Center, Dalian 116024, China.
Biomicrofluidics. 2017 Jun 1;11(3):034114. doi: 10.1063/1.4984768. eCollection 2017 May.
Drug absorption in the intestine is tightly related to drug-induced nephrotoxicity, which is a relatively common side effect in clinical practice. It highlights a great need to develop predictive models with high accuracy in the early stage during new drug discovery and development. Herein, we presented a novel intestine-kidney chip, which recapitulated drug absorption in the intestine and its resultant drug toxicity on the kidney. This work aims to provide an integrated tool for accurate assessment of drug absorption-related nephrotoxicity . A microfluidic device with multi-interfaces was designed, which facilitated the co-culture of the intestinal and glomerular endothelial cells in compartmentalized micro-chambers. Thus, drug absorption and following nephrotoxicity could be explored in a single assay based on the formation of the intact intestine function on the chip. Specifically, we adopt digoxin (DIG) as a model drug combined with colestyramine (COL) or Verapamil (VER), which significantly influence DIG absorption in the intestine. Different degrees of nephrotoxicity under drug combinations were further observed on the chip, including cell apoptosis, cell viability, and lactate dehydrogenase leakage. These features were consistent with the variance of DIG absorption by the intestinal cells. In agreement with clinical observations, our data demonstrated that DIG-induced nephrotoxicity was enhanced combined with VER but weakened with COL. All of these findings suggest that the established microdevice might provide a useful and cost-effective platform for testing drug absorption and nephrotoxicity in preclinical trials during new drug development.
药物在肠道中的吸收与药物诱导的肾毒性密切相关，而肾毒性是临床实践中较为常见的副作用。这凸显了在新药研发早期开发高精度预测模型的迫切需求。在此，我们展示了一种新型的肠-肾芯片，该芯片概括了药物在肠道中的吸收及其对肾脏产生的药物毒性。这项工作旨在提供一种综合工具，用于准确评估与药物吸收相关的肾毒性。设计了一种具有多接口的微流控装置，该装置便于在分隔的微腔中对肠道和肾小球内皮细胞进行共培养。因此，基于芯片上完整肠道功能的形成，可以在单一试验中探索药物吸收及随后的肾毒性。具体而言，我们采用地高辛（DIG）作为模型药物，结合考来烯胺（COL）或维拉帕米（VER），它们会显著影响地高辛在肠道中的吸收。在芯片上进一步观察到药物组合下不同程度的肾毒性，包括细胞凋亡、细胞活力和乳酸脱氢酶泄漏。这些特征与肠道细胞对地高辛吸收的变化一致。与临床观察结果一致，我们的数据表明，地高辛诱导的肾毒性在与维拉帕米联合使用时增强，而与考来烯胺联合使用时减弱。所有这些发现表明，所建立的微装置可能为新药研发临床前试验中测试药物吸收和肾毒性提供一个有用且具有成本效益的平台。
