Physicochemical selectivity of the BBB microenvironment governing passive diffusion--matching with a porcine brain...

To mimic the physicochemical selectivity of the blood-brain barrier (BBB) and to predict its passive permeability using a PAMPA model based on porcine brain lipid extract (PBLE 10%w/v in alkane).

Three PAMPA (BD pre-coated and PBLE with 2 different lipid volumes) models were tested with 108 drugs. Abraham solvation descriptors were used to interpret the in vitro-in vivo correlation with 282 in situ brain perfusion measurements, spanning over 5 orders of magnitude. An in combo PAMPA model was developed from combining measured PAMPA permeability with one H-bond descriptor.

The in combo PAMPA predicted 93% of the variance of 197 largely efflux-inhibited in situ permeability training set. The model was cross-validated by the "leave-many-out" procedure, with q(2) = 0.92 ± 0.03. The PAMPA models indicated the presence of paramembrane water channels. Only the PBLE-based PAMPA-BBB model with sufficient lipid to fill all the internal pore space of the filter showed a wide dynamic range window, selectivity coefficient near 1, and was suitable for predicting BBB permeability.

BBB permeability can be predicted by in combo PAMPA. Its speed and substantially lower cost, compared to in vivo measurements, make it an attractive first-pass screening method for BBB passive permeability.