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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Bibliographic Details
Published in:PloS one 2017-12, Vol.12 (12), p.e0190319-e0190319
Main Authors: Bittermann, Kai, Goss, Kai-Uwe
Format: Article
Language:English
Subjects:
Acids
Active transport
Biology and Life Sciences
Black lipid membranes
Brain research
Chemical reactions
Chemicals
Chemistry
Datasets
Drug metabolism
Drugs
Experiments
Genetic aspects
Lipid membranes
Lipids
Mathematical models
Membrane permeability
Membranes
Monolayers
Organic chemicals
Penetration
Permeability
pH effects
Physical Sciences
Physiological aspects
Research and Analysis Methods
Solutes
Water resistance
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0190319