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Transwell experiments with Caco-2 or MDCK cells are the gold standard for determining the intestinal permeability of chemicals. The intrinsic membrane permeability (P 0), that can be extracted from these experiments, might be comparable to P 0 measured in black lipid membrane (BLM) experiments and P 0 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. [Display omitted] • Cholesterol and sphingomyelin have no impact on the permeability of DPhPC membranes. • DPhPC membrane permeability is well predicted by the solubility-diffusion model. • Caco-2 permeability of lipophilic compounds differs from solubility-diffusion model. • DPhPC membranes can be used to predict Caco-2 permeability of hydrophilic compounds. [ABSTRACT FROM AUTHOR]

Bipolar cancellation is the phenomenon in which the permeability of cell membranes subjected to high intensity short pulsed electric field (ns-μs range) is reduced or eliminated when the system is subjected to bipolar instead of monopolar pulses. Although several studies have tried to explain bipolar cancellation, the underlying mechanisms remain unclear. Very few articles study bipolar cancellation by means of molecular dynamics (MD) simulation. In this paper, we investigated the molecular mechanisms underlying the difference in electroporation induced by bipolar and monopolar picosecond electric pulses (EPs) using MD simulation. The electric field gradients and electric forces on water molecules of the two pulses were analyzed in detail for the first time. For a certain pulse width, when the field intensity is relatively small, the direction of bipolar electric force on the interfacial water molecule reverses as the bipolar EPs reverse, while the electric force on interfacial water molecules of the cathode side remains in the same direction as that of applied monopolar EPs. The bipolar electric force reversal delays the water protrusion and increases the pore formation time. Therefore, this phenomenon could correspond to bipolar cancellation. When the field intensity is relatively large, although the bipolar electric force direction still reverses, half of the total time of the monopolar EPs has no electric fields. The electric forces of monopolar no-field half-cycles are much smaller than those of the bipolar EPs. Therefore, the pore formation time of bipolar EPs reduces, and this phenomenon is called bipolar enhancement. The occurrence of bipolar cancellation or bipolar enhancement depends on conditions such as the width and intensity of the pulse. [Display omitted] • Hypotheses about the molecular mechanism involved in bipolar cancellation • Hypotheses about the molecular mechanism involved in bipolar enhancement • Molecular mechanisms of electroporation induced by bipolar and monopolar pulse trains [ABSTRACT FROM AUTHOR]