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3D gut-liver chip with a PK model for prediction of first-pass metabolism

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Abstract

Accurate prediction of first-pass metabolism is essential for improving the time and cost efficiency of drug development process. Here, we have developed a microfluidic gut-liver co-culture chip that aims to reproduce the first-pass metabolism of oral drugs. This chip consists of two separate layers for gut (Caco-2) and liver (HepG2) cell lines, where cells can be co-cultured in both 2D and 3D forms. Both cell lines were maintained well in the chip, verified by confocal microscopy and measurement of hepatic enzyme activity. We investigated the PK profile of paracetamol in the chip, and corresponding PK model was constructed, which was used to predict PK profiles for different chip design parameters. Simulation results implied that a larger absorption surface area and a higher metabolic capacity are required to reproduce the in vivo PK profile of paracetamol more accurately. Our study suggests the possibility of reproducing the human PK profile on a chip, contributing to accurate prediction of pharmacological effect of drugs.

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References

  • H.E. Abaci, M.L. Shuler, Integr. Biol. (Camb). 7, 383–391 (2015)

  • S. Alqahtani, L.A. Mohamed, A. Kaddoumi, Expert Opin. Drug Metab. Toxicol. 9, 1241–1254 (2013)

  • P. Artursson, K. Palm, K. Luthman, Adv. Drug Deliv. Rev. 46, 27–43 (2001)

  • B. Atac, I. Wagner, R. Horland, R. Lauster, U. Marx, A.G. Tonevitsky, R.P. Azar, G. Lindner, Lab. Chip 13, 3555–3561 (2013)

  • R. Baudoin, L. Griscom, J.M. Prot, C. Legallais, E. Leclerc, Biochem. Eng. J. 53, 172–181 (2011)

  • R.N. Bergman, Journ. Annu. Diabetol. Hotel Dieu, 127–138 (2007)

  • Z. Brahmi, T. Katho, R. Hatsumata, A. Hiroi, N. Miyakawa, E. Yakou, K. Sugaya, J. Onose, N. Abe, Biosci. Biotechnol. Biochem. 76, 1028–1031 (2012)

  • T. Bricks, J. Hamon, M.J. Fleury, R. Jellali, F. Merlier, Y.E. Herpe, A. Seyer, J.M. Regimbeau, F. Bois, E. Leclerc, Biopharm. Drug Dispos. 36, 275–293 (2015)

  • V. Carriere, J. Chambaz, M. Rousset, Toxicol. in Vitro 15, 373–378 (2001)

  • M. Chi, B. Yi, S. Oh, D.J. Park, J.H. Sung, S. Park, Biomed. Microdevices 17, 9966 (2015)

  • A. Choe, S.K. Ha, I. Choi, N. Choi, J.H. Sung, Biomed. Microdevices 19, 4 (2017)

  • S. Choi, M. Nishikawa, A. Sakoda, Y. Sakai, Toxicol. in Vitro 18, 393–402 (2004)

  • C.M. Costello, R.M. Sorna, Y.L. Goh, I. Cengic, N.K. Jain, J.C. March, Mol. Pharm. 11, 2030–2039 (2014)

  • B. Davies, T. Morris, Pharm. Res. 10, 1093–1095 (1993)

  • M.T. Donato, A. Lahoz, J.V. Castell, M.J. Gomez-Lechon, Curr. Drug Metab. 9, 1–11 (2008)

  • M.B. Esch, G.J. Mahler, T. Stokol, M.L. Shuler, Lab. Chip 14, 3081–3092 (2014)

  • M.B. Esch, J.M. Prot, Y.I. Wang, P. Miller, J.R. Llamas-Vidales, B.A. Naughton, D.R. Applegate, M.L. Shuler, Lab. Chip 15, 2269–2277 (2015)

  • M. Gertz, A. Harrison, J.B. Houston, A. Galetin, Drug Metab. Dispos. 38, 1147–1158 (2010)

  • C.A. Gonzalez-Arias, A. Crespo-Sempere, S. Marin, V. Sanchis, A.J. Ramos, Food Chem. Toxicol. 86, 245–252 (2015)

  • R. Greek, A. Menache, Int. J. Med. Sci. 10, 206–221 (2013)

  • H.F. Helander, L. Fandriks, Scand. J. Gastroenterol. 49, 681–689 (2014)

  • D.D. Huh, Ann. Am. Thorac Soc. 12(Suppl 1), S42–S44 (2015)

  • K.I. Kaitin, Clin. Pharmacol. Ther. 87, 356–361 (2010)

  • H.J. Kim, D.E. Ingber, Integr. Biol. (Camb). 5, 1130–1140 (2013)

  • H.J. Kim, D. Huh, G. Hamilton, D.E. Ingber, Lab. Chip 12, 2165–2174 (2012)

  • S.H. Kim, J.W. Lee, I. Choi, Y.C. Kim, J.B. Lee, J.H. Sung, J. Nanosci. Nanotechnol. 13, 7220–7228 (2013)

  • T. Kniazeva, A.A. Epshteyn, J.C. Hsiao, E.S. Kim, V.B. Kolachalama, J.L. Charest, J.T. Borenstein, Lab. Chip 12, 1686–1695 (2012)

  • Y.Y. Lau, Y.H. Chen, T.T. Liu, C. Li, X. Cui, R.E. White, K.C. Cheng, Drug Metab. Dispos. 32, 937–942 (2004)

  • S.A. Lee, Y. No da, E. Kang, J. Ju, D.S. Kim, S.H. Lee, Lab. Chip 13, 3529–3537 (2013)

  • J. Lee, B. Choi, Y. No da, G. Lee, S.R. Lee, H. Oh, S.H. Lee, Integr. Biol. (Camb). 8, 302–308 (2016)

  • H. Lee, D.S. Kim, S.K. Ha, I. Choi, J.M. Lee, J.H. Sung, Biotechnol. Bioeng. 114, 432–443 (2017)

  • G.J. Mahler, M.B. Esch, R.P. Glahn, M.L. Shuler, Biotechnol. Bioeng. 104, 193–205 (2009)

  • I. Maschmeyer, A.K. Lorenz, K. Schimek, T. Hasenberg, A.P. Ramme, J. Hubner, M. Lindner, C. Drewell, S. Bauer, A. Thomas, N.S. Sambo, F. Sonntag, R. Lauster, U. Marx, Lab Chip 15, 2688–2699 (2015)

  • M.R. McGill, H. Jaeschke, Pharm. Res. 30, 2174–2187 (2013)

  • P.G. Miller, M.L. Shuler, Biotechnol. Bioeng. 113, 2213–2227 (2016)

  • C. Moraes, J.M. Labuz, B.M. Leung, M. Inoue, T.H. Chun, S. Takayama, Integr. Biol. (Camb). 5, 1149–1161 (2013)

  • C. Oleaga, C. Bernabini, A.S. Smith, B. Srinivasan, M. Jackson, W. McLamb, V. Platt, R. Bridges, Y. Cai, N. Santhanam, B. Berry, S. Najjar, N. Akanda, X. Guo, C. Martin, G. Ekman, M.B. Esch, J. Langer, G. Ouedraogo, J. Cotovio, L. Breton, M.L. Shuler, J.J. Hickman, Sci. Rep. 6, 20030 (2016)

  • C.A. O'Neill, G. Monteleone, J.T. McLaughlin, R. Paus, Bioessays 38, 1167–1176 (2016)

  • D.A. Ouattara, S.H. Choi, Y. Sakai, A.R. Pery, C. Brochot, Toxicol. Lett. 205, 310–319 (2011)

  • J.M. Prot, L. Maciel, T. Bricks, F. Merlier, J. Cotton, P. Paullier, F.Y. Bois, E. Leclerc, Biotechnol. Bioeng. 111, 2027–2040 (2014)

  • R.B. Raffa, J.V. Pergolizzi Jr., R. Taylor Jr., J.F. Decker, J.T. Patrick, Pain Pract. 14, 668–677 (2014)

  • S.C. Ramaiahgari, M.W. den Braver, B. Herpers, V. Terpstra, J.N. Commandeur, B. van de Water, L.S. Price, Arch. Toxicol. 88, 1083–1095 (2014)

  • U. Sankar, Scientist 19, 32–34 (2005)

  • K. A. Scott, M. Ida, V. L. Peterson, J. A. Prenderville, G. M. Moloney, T. Izumo, K. Murphy, A. Murphy, R. P. Ross, C. Stanton, T. G. Dinan, J. F. Cryan, Brain Behav Immun. (2017)

  • J. Shemesh, I. Jalilian, A. Shi, G. Heng Yeoh, M.L. Knothe Tate, M. Ebrahimi Warkiani, Lab Chip 15, 4114–4127 (2015)

  • K.Y. Shim, D. Lee, J. Han, N.T. Nguyen, S. Park, J.H. Sung, Biomed. Microdevices 19, 37 (2017)

  • A. Sin, K.C. Chin, M.F. Jamil, Y. Kostov, G. Rao, M.L. Shuler, Biotechnol. Prog. 20, 338–345 (2004)

  • W.R. Stahl, Science 150, 1039–1042 (1965)

  • 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, Early Drug Discovery and Development Guidelines: For Academic Researchers, Collaborators, and Start-up Companies (Assay Guidance Manual, G. S., 2004)

  • J.H. Sung, M.L. Shuler, Ann. Biomed. Eng. 40, 1289–1300 (2012)

  • J.H. Sung, C. Kam, M.L. Shuler, Lab. Chip 10, 446–455 (2010)

  • J.H. Sung, J. Yu, D. Luo, M.L. Shuler, J.C. March, Lab. Chip 11, 389–392 (2011)

  • J.H. Sung, M.B. Esch, J.M. Prot, C.J. Long, A. Smith, J.J. Hickman, M.L. Shuler, Lab Chip 13, 1201–1212 (2013)

  • J.H. Sung, B. Srinivasan, M.B. Esch, W.T. McLamb, C. Bernabini, M.L. Shuler, J.J. Hickman, Exp. Biol. Med. (Maywood). 239, 1225–1239 (2014)

  • L.M. Sweeney, M.L. Shuler, J.G. Babish, A. Ghanem, Toxicol. in Vitro 9, 307–316 (1995)

  • M. Takahashi, T. Washio, N. Suzuki, K. Igeta, S. Yamashita, J. Pharm. Sci. 98, 4343–4353 (2009)

  • N. Ucciferri, T. Sbrana, A. Ahluwalia, Front Bioeng. Biotechnol. 2, 74 (2014)

  • K. Viravaidya, A. Sin, M.L. Shuler, Biotechnol. Prog. 20, 316–323 (2004)

  • F. Vozzi, D. Mazzei, B. Vinci, G. Vozzi, T. Sbrana, L. Ricotti, N. Forgione, A. Ahluwalia, Biotechnol. Bioeng. 108, 2129–2140 (2011)

  • W.M. Westerink, W.G. Schoonen, Toxicol. in Vitro 21, 1581–1591 (2007)

  • J.P. Wikswo, E.L. Curtis, Z.E. Eagleton, B.C. Evans, A. Kole, L.H. Hofmeister, W.J. Matloff, Lab. Chip 13, 3496–3511 (2013)

  • S. Wilkening, F. Stahl, A. Bader, Drug Metab. Dispos. 31, 1035–1042 (2003)

  • J. Yu, S. Peng, D. Luo, J.C. March, Biotechnol. Bioeng. 109, 2173–2178 (2012)

  • T.J. Zurlinden, B. Reisfeld, Eur. J. Drug Metab. Pharmacokinet. 41, 267–280 (2016). https://doi.org/10.1007/s10544-017-0242-8

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Acknowledgments

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: E0124200), and Hongik University Research Fund.

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Authors and Affiliations

  1. Department of Chemical Engineering, Hongik University, Seoul, 121-791, Korea

    Dong Wook Lee & Jong Hwan Sung

  2. Korea Food Research Institute, Seongnam-si, Gyenggi-do, Republic of Korea

    Sang Keun Ha & Inwook Choi

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  1. Dong Wook Lee
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Correspondence to Jong Hwan Sung.

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Lee, D.W., Ha, S.K., Choi, I. et al. 3D gut-liver chip with a PK model for prediction of first-pass metabolism. Biomed Microdevices 19, 100 (2017). https://doi.org/10.1007/s10544-017-0242-8

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