Predicting apparent passive permeability of Caco-2 and MDCK cell-monolayers: A mechanistic model.
Experimentally derived apparent permeabilities, Papp, through cell monolayers such as Caco-2 and MDCK are considered to be an in-vitro gold standard for assessing the uptake efficiency of drugs. Here, we present a mechanistic model that describes 'passive' Papp values (i.e., neglecting act...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2017-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5744993?pdf=render |
| _version_ | 1819102611431751680 |
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| author | Kai Bittermann Kai-Uwe Goss |
| author_facet | Kai Bittermann Kai-Uwe Goss |
| author_sort | Kai Bittermann |
| collection | DOAJ |
| description | Experimentally derived apparent permeabilities, Papp, through cell monolayers such as Caco-2 and MDCK are considered to be an in-vitro gold standard for assessing the uptake efficiency of drugs. Here, we present a mechanistic model that describes 'passive' Papp values (i.e., neglecting active transport) by accounting for the different resistances solutes encounter when permeating a cell monolayer. We described three parallel permeation pathways, namely a cytosolic-, paracellular-, and lateral route, each of which consists of a number of serial resistances. These resistances were accounted for via a mechanistic depiction of the underlying processes that are largely based on literature work. For the present Papp dataset, about as much chemicals are dominated by the cytosolic route as were dominated by the paracellular route, while the lateral route was negligible. For the cytosolic route by far the most chemicals found their main resistance in the various water layers and not in the membrane. Although correlations within the subclasses of chemicals dominated by a specific permeation route were rather poor, we could overall satisfyingly predict Papp for 151 chemicals at a pH of 7.4 (R2 = 0.77, RMSE = 0.48). For a specific evaluation of the intrinsic membrane permeability, Pm, a second experimental dataset based on experiments with black lipid membranes, BLM, was evaluated. Pm could be predicted for 37 chemicals with R2 = 0.91 and RMSE = 0.64 log units. |
| first_indexed | 2024-12-22T01:37:19Z |
| format | Article |
| id | doaj.art-a9d3b0d8afa3477b9538bf2d63e6c45b |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-22T01:37:19Z |
| publishDate | 2017-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-a9d3b0d8afa3477b9538bf2d63e6c45b2022-12-21T18:43:20ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-011212e019031910.1371/journal.pone.0190319Predicting apparent passive permeability of Caco-2 and MDCK cell-monolayers: A mechanistic model.Kai BittermannKai-Uwe GossExperimentally derived apparent permeabilities, Papp, through cell monolayers such as Caco-2 and MDCK are considered to be an in-vitro gold standard for assessing the uptake efficiency of drugs. Here, we present a mechanistic model that describes 'passive' Papp values (i.e., neglecting active transport) by accounting for the different resistances solutes encounter when permeating a cell monolayer. We described three parallel permeation pathways, namely a cytosolic-, paracellular-, and lateral route, each of which consists of a number of serial resistances. These resistances were accounted for via a mechanistic depiction of the underlying processes that are largely based on literature work. For the present Papp dataset, about as much chemicals are dominated by the cytosolic route as were dominated by the paracellular route, while the lateral route was negligible. For the cytosolic route by far the most chemicals found their main resistance in the various water layers and not in the membrane. Although correlations within the subclasses of chemicals dominated by a specific permeation route were rather poor, we could overall satisfyingly predict Papp for 151 chemicals at a pH of 7.4 (R2 = 0.77, RMSE = 0.48). For a specific evaluation of the intrinsic membrane permeability, Pm, a second experimental dataset based on experiments with black lipid membranes, BLM, was evaluated. Pm could be predicted for 37 chemicals with R2 = 0.91 and RMSE = 0.64 log units.http://europepmc.org/articles/PMC5744993?pdf=render |
| spellingShingle | Kai Bittermann Kai-Uwe Goss Predicting apparent passive permeability of Caco-2 and MDCK cell-monolayers: A mechanistic model. PLoS ONE |
| title | Predicting apparent passive permeability of Caco-2 and MDCK cell-monolayers: A mechanistic model. |
| title_full | Predicting apparent passive permeability of Caco-2 and MDCK cell-monolayers: A mechanistic model. |
| title_fullStr | Predicting apparent passive permeability of Caco-2 and MDCK cell-monolayers: A mechanistic model. |
| title_full_unstemmed | Predicting apparent passive permeability of Caco-2 and MDCK cell-monolayers: A mechanistic model. |
| title_short | Predicting apparent passive permeability of Caco-2 and MDCK cell-monolayers: A mechanistic model. |
| title_sort | predicting apparent passive permeability of caco 2 and mdck cell monolayers a mechanistic model |
| url | http://europepmc.org/articles/PMC5744993?pdf=render |
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