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Integrated Gut and Liver Microphysiological Systems for Quantitative In Vitro Pharmacokinetic Studies
Open accessAbstract
Investigation of the pharmacokinetics (PK) of a compound is of significant importance during the early stages of drug development, and therefore several in vitro systems are routinely employed for this purpose. However, the need for more physiologically realistic in vitro models has recently fueled the emerging field of tissue-engineered 3D cultures, also referred to as organs-on-chips, or microphysiological systems (MPSs). We have developed a novel fluidic platform that interconnects multiple MPSs, allowing PK studies in multi-organ in vitro systems along with the collection of high-content quantitative data. This platform was employed here to integrate a gut and a liver MPS together in continuous communication, and investigate simultaneously different PK processes taking place after oral drug administration in humans (e.g., intestinal permeability, hepatic metabolism). Measurement of tissue-specific phenotypic metrics indicated that gut and liver MPSs can be fluidically coupled with circulating common medium without compromising their functionality. The PK of diclofenac and hydrocortisone was investigated under different experimental perturbations, and results illustrate the robustness of this integrated system for quantitative PK studies. Mechanistic model-based analysis of the obtained data allowed the derivation of the intrinsic parameters (e.g., permeability, metabolic clearance) associated with the PK processes taking place in each MPS. Although these processes were not substantially affected by the gut-liver interaction, our results indicate that inter-MPS communication can have a modulating effect (hepatic metabolism upregulation). We envision that our integrative approach, which combines multi-cellular tissue models, multi-MPS platforms, and quantitative mechanistic modeling, will have broad applicability in pre-clinical drug development.
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“Furthermore, microfluidic systems can link different organs-on-a-chip to potentially simulate the complexity of multiorgan drug metabolism and pharmacokinetics9,47,50,68–71.”
From Tumor-on-a-chip: from bioinspired design to biomedical application (2021) · cites this paper as [69]
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Recent Advances in Gut‐ and Gut–Organ‐Axis‐on‐a‐Chip Models
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Li, B., Tang, Y., Huang, Z., Ma, L., Song, J., & Xue, L. (2025) · Protein & Cell · doi:10.1093/procel/pwaf058 · Cited by 44
“By simulating the flow of drugs from the intestine to the liver, researchers quantified metabolic rates and clearance, providing critical data for early-stage drug development (Tsamandouras et al., 2017).”
van der Made, T. K., Fedecostante, M., Scotcher, D., Rostami‐Hodjegan, A., Toraño, J. S., Middel, I. R., Koster, A. S., Gerritsen, K. G. F., Jankowski, V., Jankowski, J., et al. (2019) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.9b00681 · Cited by 37
Fraser, K., Bruckner, D. M., & Dordick, J. S. (2018) · Chemical Research in Toxicology · doi:10.1021/acs.chemrestox.8b00054 · Cited by 38
Recent advances in an organ-on-a-chip: biomarker analysis and applications
Li, X., & Tian, T. (2018) · Analytical Methods · doi:10.1039/c8ay00970h · Cited by 37
Imaoka, T., Huang, W., Shum, S., Hailey, D. W., Chang, S., Chapron, A., Yeung, C. K., Himmelfarb, J., Isoherranen, N., & Kelly, E. J. (2021) · Scientific Reports · doi:10.1038/s41598-021-00338-y · Cited by 36
Rajan, S. A. P., Sherfey, J. S., Ohri, S., Nichols, L., Smith, J. T., Parekh, P., Kadar, E. P., Clark, F., George, B. T., Gregory, L., et al. (2023) · The AAPS Journal · doi:10.1208/s12248-023-00870-x · Cited by 35
“…system offers an important advancement to improve drug research while simultaneously reducing the need for experiments in laboratory animals and will serve as a springboard to the construction of integrated multi-organ systems that will recapitulate the overall disposition of drugs in humans (25).”
BackgroundSelf-citationGraf, K., Murrieta-Coxca, J. M., Vogt, T., Besser, S., Geilen, D., Kaden, T., Bothe, A.-K., Prieto, D. M. M., Amiri, B., Schaller, S., et al. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1528748 · Cited by 37
An on-chip intestine-liver model for multiple drugs absorption and metabolism behavior simulation
Jie, M., Lin, H., He, Z., Liu, H., Li, H., & Lin, J. (2017) · Science China Chemistry · doi:10.1007/s11426-017-9167-0 · Cited by 34
Pharmacokinetics‐On‐a‐Chip: In Vitro Microphysiological Models for Emulating of Drugs ADME
Ramadan, Q., Fardous, R. S., Hazaymeh, R., Alshmmari, S. K., & Zourob, M. M. (2021) · Advanced Biology · doi:10.1002/adbi.202100775 · Cited by 37
Shinha, K., Nihei, W., Nakamura, H., Goto, T., Kawanishi, T., Ishida, N., Yamazaki, N., Imakura, Y., Mima, S., Inamura, K., et al. (2021) · Micromachines · doi:10.3390/mi12091007 · Cited by 36
“An MPS integrated with a perfusion system mimicking a peristaltic pump has been developed as an alternative to external pumps [25,26].”
MethodBaker, T. K., Vleet, T. R. V., Mahalingaiah, P. K. S., Grandhi, T. S. P., Evers, R., Ekert, J. E., Gosset, J. R., Chacko, S. A., & Kopec, A. K. (2023) · Drug Metabolism and Disposition · doi:10.1124/dmd.123.001510 · Cited by 41
Organoid-on-a-chip: Current challenges, trends, and future scope toward medicine
Li, Z., Li, Q., Zhou, C., Lu, K., Liu, Y., Xuan, L., & Wang, X. (2023) · Biomicrofluidics · doi:10.1063/5.0171350 · Cited by 33
Dynamic Physiological Culture of Ex Vivo Human Tissue: A Systematic Review
Hughes, D. L., Hughes, A., Soonawalla, Z. F., Mukherjee, S., & O’Neill, E. (2021) · Cancers · doi:10.3390/cancers13122870 · Cited by 39
“As illustrated in the review of Wu et al., OOC systems may vary between manufacturers and models; however, they all possess the same fundamental design concepts [47].”
BackgroundInfluentialAnimal Models in Diabetic Research—History, Presence, and Future Perspectives
Pandey, S., Chmelir, T., & Dvorakova, M. C. (2023) · Biomedicines · doi:10.3390/biomedicines11102852 · Cited by 34
“Moreover, the multi-organ cross-talks can also be facilitated in multi-OoCs to create similar physiological conditions and organ functions, as in humans [182,183].”
BackgroundMicrophysiological systems in absorption, distribution, metabolism, and elimination sciences
Ness, K. P. V., Cesar, F., Yeung, C. K., Himmelfarb, J., & Kelly, E. J. (2021) · Clinical and Translational Science · doi:10.1111/cts.13132 · Cited by 31
Mimicking the Human Physiology with Microphysiological Systems (MPS)
Sung, J. H., Koo, J., & Shuler, M. L. (2019) · BioChip Journal · doi:10.1007/s13206-019-3201-z · Cited by 32
Tissue Chips and Microphysiological Systems for Disease Modeling and Drug Testing
Donoghue, L., Nguyen, K. T. V., Graham, C., & Sethu, P. (2021) · Micromachines · doi:10.3390/mi12020139 · Cited by 31
“[162] Gut–Liver Drug Pharmacokinetics 2018 Oleaga et al.”
BackgroundChallenges in Permeability Assessment for Oral Drug Product Development
Koziolek, M., Augustijns, P., Berger, C., Cristofoletti, R., Dahlgren, D., Keemink, J., Matsson, P., McCartney, F., Metzger, M., Mezler, M., et al. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15102397 · Cited by 31
“GoC have generally been designed based on (i) the traditional transwell system [50–52], using a circular porous membrane, or (ii) a semi-permeable porous membrane separating two sides of a linear channel or tube [53,54].”
BackgroundMethodLab-on-chip technologies for exploring the gut–immune axis in metabolic disease
Wheeler, A., Stoeger, V., & Owens, R. M. (2024) · Lab on a Chip · doi:10.1039/d3lc00877k · Cited by 30
Multi-organ on a chip for personalized precision medicine
Palaninathan, V., Kumar, V., Maekawa, T., Liepmann, D., Paulmurugan, R., Eswara, J. R., Ajayan, P. M., Augustine, S., Malhotra, B. D., Viswanathan, S., et al. (2018) · MRS Communications · doi:10.1557/mrc.2018.148 · Cited by 29
Maaß, C., Dallas, M. R., LaBarge, M. E., Shockley, M., Valdez, J., Geishecker, E., Stokes, C. L., Griffith, L. G., & Cirit, M. (2018) · Scientific Reports · doi:10.1038/s41598-018-25971-y · Cited by 26
Self-citationGo with the flow: modeling unique biological flows in engineered in vitro platforms
Wasson, E. M., Dubbin, K., & Moya, M. L. (2021) · Lab on a Chip · doi:10.1039/d1lc00014d · Cited by 27
Singh, D., Deosarkar, S. P., Cadogan, E. B., Flemington, V., Bray, A., Zhang, J., Reiserer, R. S., Schaffer, D. K., Gerken, G. B., Britt, C. M., et al. (2022) · PLoS Biology · doi:10.1371/journal.pbio.3001624 · Cited by 27
“has been the development of organ-on-chip multi-organ systems, which utilise the metabolic capability of cells often hepatocytes, to clear the compound from a system, creating concentration changes with time [29,30].”
Background
Metadata
- Authors
- Tsamandouras, N., Chen, W. L. K., Edington, C. D., Stokes, C. L., Griffith, L. G., & Cirit, M.
- Affiliations
- Massachusetts Institute of Technology (US)
- Corresponding author
- Cirit, Murat
- Venue
- The AAPS Journal
- Published
- 2017-07-27
- Volume
- 19
- Issue
- 5
- Pages
- 1499-1512
- ISSN
- 1550-7416 (ISSN-L)
- PMC
- PMC6540747
- OpenAlex
- W2741120316
- Cited by
- 222
- References
- 56
- Citations by year
- 2026: 18 · 2025: 21 · 2024: 24 · 2023: 18 · 2022: 21 · 2021: 40 · 2020: 33 · 2019: 20 · 2018: 23 · 2017: 3
- FWCI
- 9.73
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- The AAPS Journal (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- National Institutes of Health (UH3TR000496)
- National Center for Advancing Translational Sciences
- Topics
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Physical Sciences › Engineering › Biomedical Engineering › Microfluidic and Capillary Electrophoresis Applications
- Keywords
- microphysiological systems, organ-on-a-chip, in vitro pharmacokinetics, intestinal permeability, hepatic metabolism, diclofenac, cortisol, mechanistic modeling, oral administration
- MeSH terms
- Diclofenac, Humans, Hydrocortisone, Intestinal Mucosa, Liver, In Vitro Techniques
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