Impact of cholesterol and sphingomyelin on intrinsic membrane permeability

Transwell experiments with Caco-2 or MDCK cells are the gold standard for determining the intestinal permeability of chemicals. The intrinsic membrane permeability (P₀), that can be extracted from these experiments, might be comparable to P₀ measured in black lipid membrane (BLM) experiments and P₀ predicted by the solubility-diffusion model. Unfortunately, the overlap between experimental P_{0,Caco-2/MDCK} and P_0,BLM data is very small. So far, differences between both approaches have been attributed to the cholesterol and sphingomyelin content of cell membranes, but the database is too sparse to thoroughly test this theory. To create a diverse dataset, we measured P_0,BLM of ten chemicals in BLM experiments using DPhPC and DPhPC/cholesterol/sphingomyelin membranes. The results were compared to predicted BLM data and experimental Caco-2/MDCK data obtained from literature. While P_0,BLM of all chemicals was well predicted by the solubility-diffusion model, P_{0,Caco-2/MDCK} was only predictable for rather hydrophilic compounds with logarithmic hexadecane/water partition coefficients below -0.5. The effect of cholesterol and sphingomyelin on P_0,BLM was negligibly small.