How Usable Are Published Permeability Data?

25 March 2024, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Permeability is an important molecular property in drug discovery, as it co-determines pharmacokinetics whenever a drug crosses the phospholipid bilayer, e.g., into the cell, in the gastrointestinal tract or across the blood-brain barrier. Many methods for the determination of permeability have been developed, including cell line assays, cell-free model systems like PAMPA mimicking, e.g., gastrointestinal epithelia or the skin, as well as the Black lipid membrane (BLM) and sub-micrometre liposomes. Furthermore, many in silico approaches have been developed for permeability prediction. Analysis of publicly available databases for permeability data (MolMeDB and ChEMBL) was performed, and interesting phenomena were found. Firstly, experimental data can only be measured between thresholds for the lowest and highest permeation rate obtainable within physical boundaries. These thresholds vary strongly between methods. Secondly, computed data do not obey these thresholds but, on the other hand, can produce incorrect results. Thirdly, even for the same method and molecule, there is a strong discrepancy between measured values. These differences are based not only on the statistics but also on the varying approaches and evaluation of the measured data. Thus, when working with in-house measured or published permeability data, we recommend to be cautious with their interpretation.



Supplementary materials

Supporting Information For How Usable Are Published Permeability Data?
Comparison of mean permeation coefficients of individual molecules in overlaps between datasets: A: CACO-2 and COSMOperm, B: PAMPA and COSMOperm, C: PAMPA and CACO-2, D: PAMPA and BLM, E: CACO-2 and BLM, F: COSMOperm and BLM, G: COSMOperm and PerMM, H: CACO-2 and PerMM, I: PAMPA and PerMM, J: BLM and PerMM. Each point represents one molecule with permeation coefficients determined by both respective methods. The solid line represents equal values; dashed lines represent a logPerm difference of ±1 log unit between methods. All data is displayed in log of cm/s, n - number of unique molecules in overlap, R2 - coefficient of determination (in case of the PAMPA method, this value includes intrinsic and apparent permeability).


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