An On-Chip Small Intestine-Liver Model for Pharmacokinetic Studies
An On-Chip Small Intestine-Liver Model for Pharmacokinetic Studies
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DOI：
10.1177/2211068214557812
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发表时间：
2015-06-01
期刊：
影响因子：
--
通讯作者：
Fujii, Teruo
中科院分区：
文献类型：
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作者：
Kimura, Hiroshi;Ikeda, Takashi;Fujii, Teruo
使用培养细胞测试药物作用和细胞毒性已作为动物测试的替代方法被广泛进行。然而，由于无法评估多器官效应，因此通过传统的基于细胞的测定方法来估计药代动力学是困难的。该领域的一个重要挑战是通过使用基于最近新兴的 MicroTAS（微全分析系统）技术连接小规模组织的微流体网络来模拟人体内的器官到器官网络，以预测药代动力学。在这里，我们描述了用于药代动力学研究的片上小肠-肝脏耦合模型。为了构建适当模拟体内条件的体外药代动力学模型，使用微流体网络模拟了内循环结构、各器官的体积比以及门静脉与肝动脉的血流量比等生理参数。为了在体外药代动力学研究中证明器官之间的相互作用，Caco-2、HepG2和A549细胞培养物分别用作小肠、肝脏和肺的器官模型，并通过微孔膜和微通道相互连接，以制备生理器官到器官网络的简单模型。使用三种类型的底物表阿霉素 (EPI)、伊立替康 (CPT-11) 和环磷酰胺 (CPA) 进行芯片上器官模型测定，以模拟口服或生物活性抗癌药物的效果。结果表明，该装置可以复制生理现象，例如抗癌药物对靶细胞的活性。因此，该微流体装置可以用作体外器官模型来预测药物在人体内的药代动力学，因此不仅可以提供动物测试的替代方案，而且可以提供一种获得基于生理学的药代动力学的计算机模型参数的方法。
Testing of drug effects and cytotoxicity by using cultured cells has been widely performed as an alternative to animal testing. However, the estimation of pharmacokinetics by conventional cell-based assay methods is difficult because of the inability to evaluate multiorgan effects. An important challenge in the field is to mimic the organ-to-organ network in the human body by using a microfluidic network connecting small-scale tissues based on recently emerging MicroTAS (Micro Total Analysis Systems) technology for prediction of pharmacokinetics. Here, we describe an on-chip small intestine-liver coupled model for pharmacokinetic studies. To construct an in vitro pharmacokinetic model that appropriately models in vivo conditions, physiological parameters such as the structure of internal circulation, volume ratios of each organ, and blood flow ratio of the portal vein to the hepatic artery were mimicked using microfluidic networks. To demonstrate interactions between organs in vitro in pharmacokinetic studies, Caco-2, HepG2, and A549 cell cultures were used as organ models of the small intestine, liver, and lung, respectively, and connected to each other through a microporous membrane and microchannels to prepare a simple model of a physiological organ-to-organ network. The on-chip organ model assay using three types of substrateepirubicine (EPI), irinotecan (CPT-11), and cyclophosphamide (CPA)were conducted to model the effects of orally administered or biologically active anticancer drugs. The result suggested that the device can replicate physiological phenomena such as activity of the anticancer drugs on the target cells. This microfluidic device can thus be used as an in vitro organ model to predict the pharmacokinetics of drugs in the human body and may thus provide not only an alternative to animal testing but also a method of obtaining parameters for in silico models of physiologically based pharmacokinetics.