In vitro non-cellular permeability models such as the parallel artificial membrane
permeability assay (PAMPA) are widely applied tools for early-phase drug candidate
screening. In addition to the commonly used porcine brain polar lipid extract for
modeling the blood–brain barrier’s permeability, the total and polar fractions of
bovine heart and liver lipid extracts were investigated in the PAMPA model by measuring
the permeability of 32 diverse drugs. The zeta potential of the lipid extracts and
the net charge of their glycerophospholipid components were also determined. Physicochemical
parameters of the 32 compounds were calculated using three independent forms of software
(Marvin Sketch, RDKit, and ACD/Percepta). The relationship between the lipid-specific
permeabilities and the physicochemical descriptors of the compounds was investigated
using linear correlation, Spearman correlation, and PCA analysis. While the results
showed only subtle differences between total and polar lipids, permeability through
liver lipids highly differed from that of the heart or brain lipid-based models. Correlations
between the in silico descriptors (e.g., number of amide bonds, heteroatoms, and aromatic
heterocycles, accessible surface area, and H-bond acceptor–donor balance) of drug
molecules and permeability values were also found, which provides support for understanding
tissue-specific permeability.