Skip to main content
SpringerLink
Log in

An on-chip intestine-liver model for multiple drugs absorption and metabolism behavior simulation

  • Articles
  • Published:
Science China Chemistry Aims and scope Submit manuscript

Abstract

A double-layer microfluidic chip integrated with a hollow fiber (HF) was developed to reconstitute the intestine-liver functionality for studying the absorption and metabolism of combination drugs. Caco-2 cells were inoculated in the HF cavity at the top of the serpentine channel to simulate the intestinal tissue for drug absorption and transport studied, and HepG2 cells, seeded in the bottom chamber, were used to mimic the liver for metabolism-related studies. Genistein and dacarbazine were selected for combination drug therapy and its effects on cell viability, hepatotoxicity, and cell cycle arrest under drug-conditioned culture were investigated. The results suggested that the combined concentration below −100 μg/mL had no significant inhibitory effect on HepG2 cell viability, and therefore HepG2 cells maintained their drug metabolism ability. When the drug concentration was increased above 250 μg/mL, HepG2 cells underwent apoptosis. Detection of metabolites by mass spectrometry proved the effective metabolism in the microchip model. This dynamic, co-culture microchip successfully provided a podium for long-term observation of absorption, transport, and metabolism of combination drugs, and could be an effective in vitro simulation model for further clinical research.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Esch EW, Bahinski A, Huh D. Nat Rev Drug Discov, 2015, 14: 248–260

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Kaitin KI. Clin Pharmacol Ther, 2010, 87: 356–361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Scannell JW, Blanckley A, Boldon H, Warrington B. Nat Rev Drug Discov, 2012, 11: 191–200

    Article  CAS  PubMed  Google Scholar 

  4. Hughes B. Nat Rev Drug Discov, 2009, 8: 93–96

    Article  CAS  PubMed  Google Scholar 

  5. Gao Q, Zhang Y, Wo S, Zuo Z. J Pharm Biomed Anal, 2014, 91: 60–67

    Article  CAS  PubMed  Google Scholar 

  6. Shin BS, Yoo SD, Kim TH, Bulitta JB, Landersdorfer CB, Shin JC, Choi JH, Weon KY, Joo SH, Shin S. Drug Metab Dispos, 2014, 42: 974–982

    Article  CAS  PubMed  Google Scholar 

  7. Henderson CJ, McLaughlin LA, Osuna-Cabello M, Taylor M, Gilbert I, McLaren AW, Wolf CR. Biochem J, 2015, 465: 478–488

    Article  CAS  Google Scholar 

  8. Caplin JD, Granados NG, James MR, Montazami R, Hashemi N. Adv Healthc Mater, 2015, 4: 1426–1450

    Article  CAS  PubMed  Google Scholar 

  9. Lee JB, Sung JH. Biotech J, 2013, 8: 1258–1266

    Article  CAS  Google Scholar 

  10. Bhatia SN, Ingber DE. Nat Biotechnol, 2014, 32: 760–772

    Article  CAS  PubMed  Google Scholar 

  11. Ghaemmaghami AM, Hancock MJ, Harrington H, Kaji H, Khademhosseini A. Drug Discov Today, 2011, 17: 173–181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Neuži P, Giselbrecht S, Länge K, Huang TJ, Manz A. Nat Rev Drug Discov, 2012, 11: 620–632

    Article  CAS  PubMed  Google Scholar 

  13. Huh D, Matthews BD, Mammoto A, Montoya-Zavala M, Hsin HY, Ingber DE. Science, 2010, 328: 1662–1668

    Article  CAS  PubMed  Google Scholar 

  14. Mu X, Zheng W, Xiao L, Zhang W, Jiang X. Lab Chip, 2013, 13: 1612–1618

    Article  CAS  PubMed  Google Scholar 

  15. Kim HJ, Huh D, Hamilton G, Ingber DE. Lab Chip, 2012, 12: 2165–2174

    Article  CAS  PubMed  Google Scholar 

  16. Choe A, Ha SK, Choi I, Choi N, Sung JH. Biomed Microdevices, 2017, 19: 4

    Article  CAS  PubMed  Google Scholar 

  17. Wagner I, Materne EM, Brincker S, Sü ssbier U, Frädrich C, Busek M, Sonntag F, Sakharov DA, Trushkin EV, Tonevitsky AG, Lauster R, Marx U. Lab Chip, 2013, 13: 3538–3547

    Article  CAS  PubMed  Google Scholar 

  18. Jie M, Li HF, Lin L, Zhang J, Lin JM. RSC Adv, 2016, 6: 54564–54572

    Article  CAS  Google Scholar 

  19. Imura Y, Yoshimura E, Sato K. Anal Chem, 2013, 85: 1683–1688

    Article  CAS  PubMed  Google Scholar 

  20. Imura Y, Sato K, Yoshimura E. Anal Chem, 2010, 82: 9983–9988

    Article  CAS  PubMed  Google Scholar 

  21. Maschmeyer I, Lorenz AK, Schimek K, Hasenberg T, Ramme AP, Hü bner J, Lindner M, Drewell C, Bauer S, Thomas A, Sambo NS, Sonntag F, Lauster R, Marx U. Lab Chip, 2015, 15: 2688–2699

    Article  CAS  PubMed  Google Scholar 

  22. Markowitz M, Evering TH, Garmon D, Caskey M, La Mar M, Rodriguez K, Sahi V, Palmer S, Prada N, Mohri H. J Acquir Immune Defic Syndr, 2014, 66: 140–147

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Liu Y, Fei T, Zheng X, Brown M, Zhang P, Liu XS, Wang H. Sci Rep, 2016, 6: 22120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chou TC. Cancer Res, 2010, 70: 440–446

    Article  CAS  PubMed  Google Scholar 

  25. Kim J, Taylor D, Agrawal N, Wang H, Kim H, Han A, Rege K, Jayaraman A. Lab Chip, 2012, 12: 1813–1822

    Article  CAS  PubMed  Google Scholar 

  26. Du GS, Pan JZ, Zhao SP, Zhu Y, den Toonder JMJ, Fang Q. Anal Chem, 2013, 85: 6740–6747

    Article  CAS  PubMed  Google Scholar 

  27. Chen Q, Wu J, Zhang Y, Lin JM. Anal Chem, 2012, 84: 1695–1701

    Article  CAS  PubMed  Google Scholar 

  28. Mao S, Zhang J, Li H, Lin JM. Anal Chem, 2013, 85: 868–876

    Article  CAS  PubMed  Google Scholar 

  29. Zhang J, Wu J, Li H, Chen Q, Lin JM. Biosens Bioelectron, 2015, 68: 322–328

    Article  CAS  PubMed  Google Scholar 

  30. Prot JM, Maciel L, Bricks T, Merlier F, Cotton J, Paullier P, Bois FY, Leclerc E. Biotechnol Bioeng, 2014, 111: 2027–2040

    Article  CAS  PubMed  Google Scholar 

  31. Maschmeyer I, Hasenberg T, Jaenicke A, Lindner M, Lorenz AK, Zech J, Garbe LA, Sonntag F, Hayden P, Ayehunie S, Lauster R, Marx U, Materne EM. Eur J Pharm Biopharm, 2015, 95: 77–87

    Article  CAS  PubMed  Google Scholar 

  32. van Midwoud PM, Merema MT, Verpoorte E, Groothuis GMM. Lab Chip, 2010, 10: 2778–2786

    Article  CAS  PubMed  Google Scholar 

  33. Tsamandouras N, Chen WLK, Edington CD, Stokes CL, Griffith LG, Cirit M. AAPS J, 2017, 19: 1499–1512

    Article  CAS  PubMed  Google Scholar 

  34. Pavese JM, Krishna SN, Bergan RC. Am J Clin Nutr, 2014, 100: 431S–436S

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Yang Z, Zhu W, Gao S, Xu H, Wu B, Kulkarni K, Singh R, Tang L, Hu M. J Pharm Biomed Anal, 2011, 53: 81–89

    Article  CAS  Google Scholar 

  36. Hosoda K, Furuta T, Yokokawa A, Ogura K, Hiratsuka A, Ishii K. Drug Metab Dispos, 2008, 36: 1485–1495

    Article  CAS  PubMed  Google Scholar 

  37. Hosoda K, Furuta T, Yokokawa A, Ishii K. Anal Bioanal Chem, 2010, 397: 1563–1572

    Article  CAS  PubMed  Google Scholar 

  38. Kgomotso T, Chiu F, Ng K. Mol Nutr Food Res, 2008, 52: 1457–1466

    Article  CAS  PubMed  Google Scholar 

  39. Robert C, Thomas L, Bondarenko I, O’Day S, Weber J, Garbe C, Lebbe C, Baurain JF, Testori A, Grob JJ, Davidson N, Richards J, Maio M, Hauschild A, Miller Jr WH, Gascon P, Lotem M, Harmankaya K, Ibrahim R, Francis S, Chen TT, Humphrey R, Hoos A, Wolchok JD. N Engl J Med, 2011, 364: 2517–2526

    Article  CAS  PubMed  Google Scholar 

  40. Antman K, Crowley J, Balcerzak SP, Rivkin SE, Weiss GR, Elias A, Natale RB, Cooper RM, Barlogie B, Trump DL. J Clin Oncol, 1993, 11: 1276–1285

    Article  CAS  PubMed  Google Scholar 

  41. Larsimont V, Meins J, Fieger-Bü schges H, Henning Blume H. J Chromatogr B-Biomed Sci Appl, 1998, 719: 222–226

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Natural Science Foundation of China (81373373, 21435002, 21621003).

Author information

Authors and Affiliations

  1. State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, 100029, China

    Mingsha Jie

  2. Department of Chemistry, Beijing Key Laboratory of Microanalytical Methods and Instrumentation, Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Ministry of Education, Tsinghua University, Beijing, 100084, China

    Mingsha Jie, Haifeng Lin, Ziyi He, Hanyang Liu, Haifang Li & Jin-Ming Lin

Authors
  1. Mingsha Jie
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Haifeng Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ziyi He
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hanyang Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Haifang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jin-Ming Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jin-Ming Lin.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Jie, M., Lin, H., He, Z. et al. An on-chip intestine-liver model for multiple drugs absorption and metabolism behavior simulation. Sci. China Chem. 61, 236–242 (2018). https://doi.org/10.1007/s11426-017-9167-0

Download citation

  • Received:

  • Revised:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11426-017-9167-0

Keywords

Search

Navigation