Choe Aerim, Ha Sang Keun, Choi Inwook, Choi Nakwon, Sung Jong Hwan
Department of Chemical Engineering, Hongik University, Seoul, 121-791, South Korea.
Korea Food Research Institute, Seongnam-si, Gyenggi-do, Republic of Korea.
Biomed Microdevices. 2017 Mar;19(1):4. doi: 10.1007/s10544-016-0143-2.
After oral intake of drugs, drugs go through the first pass metabolism in the gut and the liver, which greatly affects the final outcome of the drugs' efficacy and side effects. The first pass metabolism is a complex process involving the gut and the liver tissue, with transport and reaction occurring simultaneously at various locations, which makes it difficult to be reproduced in vitro with conventional cell culture systems. In an effort to tackle this challenge, here we have developed a microfluidic gut-liver chip that can reproduce the dynamics of the first pass metabolism. The microfluidic chip consists of two separate layers for gut epithelial cells (Caco-2) and the liver cells (HepG2), and is designed so that drugs go through a sequential absorption in the gut chamber and metabolic reaction in the liver chamber. We fabricated the chip and showed that the two different cell lines can be successfully co-cultured on chip. When the two cells are cultured on chip, changes in the physiological function of Caco-2 and HepG2 cells were noted. The cytochrome P450 metabolic activity of both cells were significantly enhanced, and the absorptive property of Caco-2 cells on chip also changed in response to the presence of flow. Finally, first pass metabolism of a flavonoid, apigenin, was evaluated as a model compound, and co-culture of gut and liver cells on chip resulted in a metabolic profile that is closer to the reported profile than a monoculture of gut cells. This microfluidic gut-liver chip can potentially be a useful platform to study the complex first pass metabolism of drugs in vitro.
口服药物后，药物会在肠道和肝脏中经历首过代谢，这会极大地影响药物疗效和副作用的最终结果。首过代谢是一个涉及肠道和肝脏组织的复杂过程，转运和反应在不同位置同时发生，这使得用传统细胞培养系统在体外难以重现。为了应对这一挑战，我们在此开发了一种微流控肠道-肝脏芯片，它能够重现首过代谢的动态过程。该微流控芯片由用于肠道上皮细胞（Caco-2）和肝细胞（HepG2）的两个独立层组成，其设计使得药物在肠道腔室中依次吸收，并在肝脏腔室中发生代谢反应。我们制作了该芯片，并证明两种不同的细胞系能够在芯片上成功共培养。当在芯片上培养这两种细胞时，观察到Caco-2和HepG2细胞的生理功能发生了变化。两种细胞的细胞色素P450代谢活性均显著增强，并且芯片上Caco-2细胞的吸收特性也因流动的存在而发生了变化。最后，以黄酮类化合物芹菜素作为模型化合物评估了首过代谢，与肠道细胞单培养相比，芯片上肠道和肝脏细胞的共培养产生了更接近报道结果的代谢谱。这种微流控肠道-肝脏芯片有可能成为体外研究药物复杂首过代谢的有用平台。
