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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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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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