Prediction of Human Drug Absorption Using Liposome Electrokinetic Chromatography

With the tremendously increasing numbers of novel drug candidates, there remains a compelling need for rapid screening methods for drug-like physiochemical and pharmacokinetic properties. Different technologies have emerged that enable rapid screening in vitro for sorting out new chemical entity (NCE) classes. It is invaluable for these technologies being developed early in the drug discovery process to avoid the loss of cost and time in late development due to poor absorption and/or bioavailability. In this study, liposome electrokinetic chromatography (LEKC) serves as a convenient, rapid and cost-effective tool to determine lipophilicity and to predict human oral absorption. Twenty-seven organic neutral molecules were evaluated by octanol/water system (log P _ow) and LEKC (log k), and linear solvation energy relationship (LSER) analysis was conducted to compare the retention mechanism between LEKC and octanol/water system. LEKC can provide a rapid indirect measurement of log P _ow for small organic neutral molecules. A clearly sigmoidal relationship could be seen by correlating log k with the fraction of 25 drugs absorbed in humans (Fa), and the outliers suggested the involvement of non-transcellular passive diffusion, e.g. active transport, paracellular route; on the contrary, it is not the case with the octanol/water system. Therefore, LEKC, in combination with other permeability prediction model, can provide a primary screen for a large number of drug candidates at early stage of the drug discovery process with high-throughput and at low-cost.