Integrated Gut and Liver Microphysiological Systems for Quantitative In Vitro Pharmacokinetic Studies
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...
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| Format: | Article |
| Language: | English |
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American Association of Pharmaceutical Scientists
2017
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| Online Access: | http://hdl.handle.net/1721.1/111057 https://orcid.org/0000-0003-1137-0413 https://orcid.org/0000-0002-5248-871X https://orcid.org/0000-0002-1801-5548 |
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| author | Stokes, Cynthia L Tsamandouras, Nikolaos Chen, Wen Li Edington, Collin D Griffith, Linda G Cirit, Murat |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Stokes, Cynthia L Tsamandouras, Nikolaos Chen, Wen Li Edington, Collin D Griffith, Linda G Cirit, Murat |
| author_sort | Stokes, Cynthia L |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T15:18:05Z |
| format | Article |
| id | mit-1721.1/111057 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T15:18:05Z |
| publishDate | 2017 |
| publisher | American Association of Pharmaceutical Scientists |
| record_format | dspace |
| spelling | mit-1721.1/1110572022-09-29T14:04:30Z Integrated Gut and Liver Microphysiological Systems for Quantitative In Vitro Pharmacokinetic Studies Stokes, Cynthia L Tsamandouras, Nikolaos Chen, Wen Li Edington, Collin D Griffith, Linda G Cirit, Murat Massachusetts Institute of Technology. Department of Biological Engineering Tsamandouras, Nikolaos Chen, Wen Li Edington, Collin D Griffith, Linda G Cirit, Murat 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. United States. Defense Advanced Research Projects Agency (Grant W911NF-12-2-0039) National Institutes of Health (U.S.) (Grant 4-UH3-TR000496-03) 2017-08-29T17:21:43Z 2017-08-29T17:21:43Z 2017-07 2017-05 2017-08-25T07:08:13Z Article http://purl.org/eprint/type/JournalArticle 1550-7416 http://hdl.handle.net/1721.1/111057 Tsamandouras, Nikolaos et al. “Integrated Gut and Liver Microphysiological Systems for Quantitative In Vitro Pharmacokinetic Studies.” The AAPS Journal 19, 5 (July 2017): 1499–1512 © 2017 The Author(s) https://orcid.org/0000-0003-1137-0413 https://orcid.org/0000-0002-5248-871X https://orcid.org/0000-0002-1801-5548 en http://dx.doi.org/10.1208/s12248-017-0122-4 AAPS Journal Creative Commons Attribution http://creativecommons.org/licenses/by/4.0/ The Author(s) application/pdf American Association of Pharmaceutical Scientists Springer US |
| spellingShingle | Stokes, Cynthia L Tsamandouras, Nikolaos Chen, Wen Li Edington, Collin D Griffith, Linda G Cirit, Murat Integrated Gut and Liver Microphysiological Systems for Quantitative In Vitro Pharmacokinetic Studies |
| title | Integrated Gut and Liver Microphysiological Systems for Quantitative In Vitro Pharmacokinetic Studies |
| title_full | Integrated Gut and Liver Microphysiological Systems for Quantitative In Vitro Pharmacokinetic Studies |
| title_fullStr | Integrated Gut and Liver Microphysiological Systems for Quantitative In Vitro Pharmacokinetic Studies |
| title_full_unstemmed | Integrated Gut and Liver Microphysiological Systems for Quantitative In Vitro Pharmacokinetic Studies |
| title_short | Integrated Gut and Liver Microphysiological Systems for Quantitative In Vitro Pharmacokinetic Studies |
| title_sort | integrated gut and liver microphysiological systems for quantitative in vitro pharmacokinetic studies |
| url | http://hdl.handle.net/1721.1/111057 https://orcid.org/0000-0003-1137-0413 https://orcid.org/0000-0002-5248-871X https://orcid.org/0000-0002-1801-5548 |
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