Microfluidic Gut-liver chip for reproducing the first pass metabolism
- 1.6k Downloads
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.
KeywordsGut-liver-on-a-chip First-pass metabolism Organ-on-a-chip Microfluidic
This work was supported by Ministry of Trade, Industry and Energy (MOTIE), Republic of Korea (10050154, Establishment of Infrastructure for industrialization of Korean Useful Microbes, R0004073), and KFRI (Korea Food Research Institute, grant no: E0121705), and Hongik University Research Fund. This work was also supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (No. NRF-2016R1A2B2008691) and by the KIST Institutional Program (No. 2 V04950).
- S. Choi, M. Nishikawa, A. Sakoda, Y. Sakai, Toxicol. In Vitro 18, 393 (2004)Google Scholar
- S. Ferruzza, C. Rossi, M.L. Scarino, Y. Sambuy, Toxicol. In Vitro 26, 1252 (2012)Google Scholar
- H. Lee, D. S. Kim, S. K. Ha, I. Choi, J. M. Lee, J. H. Sung, Biotechnol. Bioeng. (2016)Google Scholar
- D. Patel, S. Shukla, S. Gupta, Int. J. Oncol. 30, 233 (2007)Google Scholar
- J. Strovel, S. Sittampalam, N.P. Coussens, M. Hughes, J. Inglese, A. Kurtz, A. Andalibi, L. Patton, C. Austin, M. Baltezor, M. Beckloff, M. Weingarten, S. Weir, in Assay Guidance Manual, ed by G. S. Sittampalam, N. P. Coussens, H. Nelson, et al.. Early Drug Discovery and Development Guidelines: For Academic Researchers, Collaborators, and Start-up Companies (Eli Lilly & Company and the National Center for Advancing Translational Sciences, Bethesda, 2004)Google Scholar
- W.M. Westerink, W.G. Schoonen, Toxicol. In Vitro 21, 1581 (2007)Google Scholar