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Lucifer Yellow - A Robust Paracellular Permeability Marker in a Cell Model of the Human Blood-brain Barrier
Published on: August 19, 2019
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Blood-brain barrier permeability revisited: Predicting intrinsic passive BBB permeability using the
1Department of Computational Biology & Chemistry, Helmholtz Centre for Environmental Research (UFZ), Permoserstraße 15, Leipzig, 04318, Germany.
Summary
This study confirms that intrinsic passive blood-brain barrier (BBB) permeability is comparable to Caco-2/MDCK assays. The solubility-diffusion model (SDM) effectively predicts BBB permeability, offering a valuable alternative to in vitro methods.
Area of Science:
- Pharmacokinetics and Drug Delivery
- Computational Chemistry and Molecular Modeling
Background:
- Accurate modeling of drug uptake across the blood-brain barrier (BBB) is crucial for predicting drug efficacy and safety.
- Passive permeability is a key parameter, but its accurate determination and prediction remain challenging.
Purpose of the Study:
- To test if intrinsic passive BBB permeability (P0,BBB) is equivalent to intrinsic membrane permeabilities from Caco-2 or MDCK assays.
- To evaluate the predictive power of the solubility-diffusion model (SDM) for P0,BBB.
- To assess the influence of molecular size on BBB permeability predictions.
Main Methods:
- Re-analysis of literature brain perfusion data, focusing on membrane-limited passive permeation.
- Comparison of intrinsic passive permeability (P0) data with experimental Caco-2/MDCK permeabilities.
- Application of the solubility-diffusion model (SDM) using COSMOtherm and LSER methods for partition coefficient estimation.
Main Results:
- A dataset of 84 membrane-limited P0 values showed good correlation with Caco-2/MDCK permeabilities (RMSE = 0.86).
- SDM predictions demonstrated satisfactory performance (RMSE = 1.73-2.29), with improved accuracy for small molecules (MW < 500 g/mol).
- No molecular size cutoff effect was observed; the model also performed well for zwitterionic compounds.
Conclusions:
- Intrinsic passive BBB permeability (P0,BBB) is directly comparable to permeabilities measured in Caco-2 and MDCK assays.
- The solubility-diffusion model (SDM) is a reliable tool for predicting BBB permeability.
- SDM can potentially reduce the need for resource-intensive in vitro assays for BBB permeability assessment.
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