Predicting the intrinsic membrane permeability of Caco-2/MDCK cells by the solubility-diffusion model.

Membrane permeability is one of the main determinants for the absorption, distribution, metabolism and excretion of compounds and is therefore of crucial importance for successful drug development. Experiments with artificial phospholipid membranes have shown that the intrinsic membrane permeability (P) of compounds is well-predicted by the solubility-diffusion model (SDM). However, using the solubility-diffusion model to predict the P of biological Caco-2 and MDCK cell membranes has proven unreliable so far. Recent publications revealed that many published P extracted from Caco-2 and MDCK experiments are incorrect. In this work, we therefore used a small self-generated set as well as a large revised set of experimental Caco-2 and MDCK data from literature to compare experimental and predicted P. The P extracted from Caco-2 and MDCK experiments were systematically lower than the P predicted by the solubility-diffusion model. However, using the following correlation: log P = 0.84 log P - 1.85, P of biological Caco-2 and MDCK cell membranes was well-predicted by the solubility-diffusion model.