Assessment of drug permeability using a small airway microphysiological system
BackgroundThere is a need to reliably predict the permeability of inhaled compounds during the development of new and generic drugs. A small airway microphysiological system (MPS) that can recapitulate the pulmonary air-liquid interface (ALI) with primary epithelial and vascular endothelial cell lay...
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Frontiers Media S.A.
2025-07-01
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| Series: | Frontiers in Pharmacology |
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| author | Robert M. Geiger Shekh M. Rahman Md Shadiqur Rashid Roni Catherine Sullenberger Sabyasachy Mistry Katherine Shea Isra Tariq Omnia A. Ismaiel Murali K. Matta Paula L. Hyland Sasha Berdichevski Sasha Berdichevski Alexandre J. S. Ribeiro Ksenia Blinova Wenlei Jiang Ross L. Walenga Bryan Newman Donna A. Volpe Kevin A. Ford |
| author_facet | Robert M. Geiger Shekh M. Rahman Md Shadiqur Rashid Roni Catherine Sullenberger Sabyasachy Mistry Katherine Shea Isra Tariq Omnia A. Ismaiel Murali K. Matta Paula L. Hyland Sasha Berdichevski Sasha Berdichevski Alexandre J. S. Ribeiro Ksenia Blinova Wenlei Jiang Ross L. Walenga Bryan Newman Donna A. Volpe Kevin A. Ford |
| author_sort | Robert M. Geiger |
| collection | DOAJ |
| description | BackgroundThere is a need to reliably predict the permeability of inhaled compounds during the development of new and generic drugs. A small airway microphysiological system (MPS) that can recapitulate the pulmonary air-liquid interface (ALI) with primary epithelial and vascular endothelial cell layers may provide a more physiologically relevant environment for measuring drug permeability than simpler two-dimensional in vitro cell culture platforms. Therefore, we evaluated the use of a small airway MPS to measure the permeability of inhaled drugs.MethodologyPrimary human lung epithelial cells were seeded onto the top channel of the chip and cultured for 14 days at ALI to promote monolayer differentiation, followed by addition of endothelial cells into the bottom channel. Due to the non-specific binding properties of polydimethylsiloxane (PDMS), a drug absorption study was conducted to quantify non-specific binding to the material. Drug permeability was evaluated by passing each compound (10 µM) through the top channel and measuring the amount of drug that permeated into the bottom channel over the time course of 30, 60, 120, and 180 min.ResultsConfocal micrographs demonstrated the presence of tight junctions along with basal, goblet, and ciliated cells in the top channel and attachment of endothelial cells in the bottom channel. Insignificant nonspecific binding to the MPS was observed with albuterol sulfate, formoterol fumarate, and olodaterol hydrochloride (HCl), while fluticasone furoate showed significant nonspecific binding as only 6%–44% of the drug was recovered at 30 and 120 min, respectively. As a result, fluticasone furoate was excluded from further analysis. Permeability studies estimated an apparent permeability (Papp) of 1.02 × 10−6 cm/s for albuterol sulfate, 0.0813 × 10−6 cm/s for olodaterol HCl, and 2.44 × 10−6 cm/s for formoterol fumarate.DiscussionTaken together, the small airway MPS recapitulated relevant cell types and many morphological features in the lung. The apparent permeabilities measured indicated that albuterol sulfate and formoterol fumarate would be categorized as highly permeable, while olodaterol HCl would be categorized as a low permeable drug. |
| format | Article |
| id | doaj-art-9241242d1f81465fa26eded833c02a89 |
| institution | DOAJ |
| issn | 1663-9812 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj-art-9241242d1f81465fa26eded833c02a892025-08-20T02:39:58ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122025-07-011610.3389/fphar.2025.16217751621775Assessment of drug permeability using a small airway microphysiological systemRobert M. Geiger0Shekh M. Rahman1Md Shadiqur Rashid Roni2Catherine Sullenberger3Sabyasachy Mistry4Katherine Shea5Isra Tariq6Omnia A. Ismaiel7Murali K. Matta8Paula L. Hyland9Sasha Berdichevski10Sasha Berdichevski11Alexandre J. S. Ribeiro12Ksenia Blinova13Wenlei Jiang14Ross L. Walenga15Bryan Newman16Donna A. Volpe17Kevin A. Ford18Division of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, United StatesDivision of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, United StatesDivision of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, United StatesDivision of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, United StatesDivision of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, United StatesDivision of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, United StatesDivision of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, United StatesDivision of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, United StatesDivision of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, United StatesDivision of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, United StatesEmulate, Inc., Boston, MA, United StatesSciBer Ltd., Cambridge, United KingdomDivision of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, United StatesDivision of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, United StatesOffice of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, United StatesOffice of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, United StatesOffice of Research and Standards, Office of Generic Drugs, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, United StatesDivision of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, United StatesDivision of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, United States Food and Drug Administration, Silver Spring, MD, United StatesBackgroundThere is a need to reliably predict the permeability of inhaled compounds during the development of new and generic drugs. A small airway microphysiological system (MPS) that can recapitulate the pulmonary air-liquid interface (ALI) with primary epithelial and vascular endothelial cell layers may provide a more physiologically relevant environment for measuring drug permeability than simpler two-dimensional in vitro cell culture platforms. Therefore, we evaluated the use of a small airway MPS to measure the permeability of inhaled drugs.MethodologyPrimary human lung epithelial cells were seeded onto the top channel of the chip and cultured for 14 days at ALI to promote monolayer differentiation, followed by addition of endothelial cells into the bottom channel. Due to the non-specific binding properties of polydimethylsiloxane (PDMS), a drug absorption study was conducted to quantify non-specific binding to the material. Drug permeability was evaluated by passing each compound (10 µM) through the top channel and measuring the amount of drug that permeated into the bottom channel over the time course of 30, 60, 120, and 180 min.ResultsConfocal micrographs demonstrated the presence of tight junctions along with basal, goblet, and ciliated cells in the top channel and attachment of endothelial cells in the bottom channel. Insignificant nonspecific binding to the MPS was observed with albuterol sulfate, formoterol fumarate, and olodaterol hydrochloride (HCl), while fluticasone furoate showed significant nonspecific binding as only 6%–44% of the drug was recovered at 30 and 120 min, respectively. As a result, fluticasone furoate was excluded from further analysis. Permeability studies estimated an apparent permeability (Papp) of 1.02 × 10−6 cm/s for albuterol sulfate, 0.0813 × 10−6 cm/s for olodaterol HCl, and 2.44 × 10−6 cm/s for formoterol fumarate.DiscussionTaken together, the small airway MPS recapitulated relevant cell types and many morphological features in the lung. The apparent permeabilities measured indicated that albuterol sulfate and formoterol fumarate would be categorized as highly permeable, while olodaterol HCl would be categorized as a low permeable drug.https://www.frontiersin.org/articles/10.3389/fphar.2025.1621775/fullmicrophysiological systempermeabilityregulatory sciencesmall airwayinhaled drugs |
| spellingShingle | Robert M. Geiger Shekh M. Rahman Md Shadiqur Rashid Roni Catherine Sullenberger Sabyasachy Mistry Katherine Shea Isra Tariq Omnia A. Ismaiel Murali K. Matta Paula L. Hyland Sasha Berdichevski Sasha Berdichevski Alexandre J. S. Ribeiro Ksenia Blinova Wenlei Jiang Ross L. Walenga Bryan Newman Donna A. Volpe Kevin A. Ford Assessment of drug permeability using a small airway microphysiological system Frontiers in Pharmacology microphysiological system permeability regulatory science small airway inhaled drugs |
| title | Assessment of drug permeability using a small airway microphysiological system |
| title_full | Assessment of drug permeability using a small airway microphysiological system |
| title_fullStr | Assessment of drug permeability using a small airway microphysiological system |
| title_full_unstemmed | Assessment of drug permeability using a small airway microphysiological system |
| title_short | Assessment of drug permeability using a small airway microphysiological system |
| title_sort | assessment of drug permeability using a small airway microphysiological system |
| topic | microphysiological system permeability regulatory science small airway inhaled drugs |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2025.1621775/full |
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