Meta-analysis of permeability literature data shows possibilities and limitations of popular methods

30 August 2024, Version 2
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

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-micrometer liposomes. Furthermore, many in silico approaches have been developed for permeability prediction. Meta-analysis of publicly available databases for permeability data (MolMeDB and ChEMBL) was performed to establish their usability. 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 often a strong discrepancy between individual 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.

Keywords

membrane
permeability
PAMPA
BLM
liposome
CACO-2
MDCK
PerMM
COSMOperm
MolMeDB

Supplementary materials

Title
Description
Actions
Title
Supporting Information For How Usable Are Published Permeability Data?
Description
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).
Actions

Supplementary weblinks

Comments

Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.