cΔlog kwIAM: can we afford estimation of small molecules’ blood-brain barrier passage based upon in silico phospholipophilicity?

Abstract

56 compounds, whose log BB values were known from the scientific literature, were considered and their phospholipophilicity values were calculated in silico. These values, along with either experimentally determined or calculated lipophilicity values, were used to extract cΔ/Δ’log kwIAM parameters. cΔ/Δ’log kwIAM values were found inversely related to data of blood-brain barrier passage, especially in the < -0.20 log BB range and on the IAM.PC.DD2 phase (r2 = 0.79). In multiple linear regression, satisfactory statistic models (r2 (n-1) = 0.76), based on cD/D’log kwIAM.MG along with other in silico calculated descriptors, were achieved. This method brings the potential to be applied, along with other methodologies, to filter out solutes whose BBB permeation is foreseen to be substandard, thus allowing pharmaceutical companies/research institutes to focus on candidates that are more likely to concentrate in the brain.

Parabens Permeation through Biological Membranes: A Comparative Study Using Franz Cell Diffusion System and Biomimetic Liquid Chromatography

“…For this reason, an increased demand for higher throughput, more inter-lab reproducible methods emerged. Chromatography performed on stationary phases emulating the asset of biological membranes cannot directly describe the permeation of the analytes but can accidentally assist in the pharmacokinetic (PK) profiling of an array of target compounds and potentially offer usefulness in surrogating permeation data [31].…”

“…10 −4 M), and chromatographic analyses were carried out at 22 ± 2 • C. The two different IAM stationary phases differ from each other in the end-capping of residual amino groups of the silica-propylamine core, which support C10 and C3 alkyl chains being end-capped by both decanoic and propionic anhydrides (IAM.PC.DD2), while IAM.PC.MG supports hydroxy groups being end-capped by methyl glycolate. IAM parameters performed on both stationary phases have already been found to be strongly interrelated, as assessed in our previous studies [25][26][27][28]31]. The affinity of the chemicals for both IAM.PC.MG and IAM.PC.DD2 was measured as a retention factor extrapolated at 100% of the aqueous phase (kw IAM) by performing a polycratic extrapolation method [52].…”

A Historical Review of Brain Drug Delivery

“…A linear correlation between log BB and log P, where P = the drug partition coefficient in 1-octanol and water, was observed [1092]. The log BB is still used today [1093], despite the fact that the limitations of this parameter have been known for many years [1094]. The BB parameter, or brain/blood ratio, is a measure of the brain volume of distribution (VD), which is driven largely by brain tissue binding of drug.…”

Advanced Blood-Brain Barrier Drug Delivery

“…A linear correlation between log BB and log P, where P = the drug partition coefficient in 1-octanol and water, was observed [1092]. The log BB is still used today [1093], despite the fact that the limitations of this parameter have been known for many years [1094]. The BB parameter, or brain/blood ratio, is a measure of the brain volume of distribution (VD), which is driven largely by brain tissue binding of drug.…”