LAUSR

Biological membranes define boundaries between and within cells and organelles, which drugs have to cross in order to reach the various compartments where their receptors are located. For years, transport across membranes has been associated with lipophilicity, expressed by octanol-water partition coefficient, logP, or distribution coefficient logD for ionizable drugs [1,2]. Despite its extensive use in prediction models for both ADME properties and receptor affinity, the octanol-water system has received serious criticism as a superficial and oversimplified simulation for membrane partitioning [2,3], although themicroscopic structure of wet octanol differs from the structure of the dry solvent, consisting of cylindrical micelles with water cores [4]. On the other hand, the use of liposomes as direct models for biological membranes is restricted due to difficulties in their preparation, standardization, and stability as well as to the limited reproducibility of partitioning experiments [5]. Cell-culture techniques, like the Caco-2 and MDCK (Madin Darby Canine Kidney) cell lines, offer another option for assessing membrane permeability. They need however long culture periods and extensive cost, while results are influenced by inter-laboratory conditions [6]. Advances in column technology enabled the development of Immobilized Artificial Membrane Chromatography (IAM), which exhibits complexity in-between that of octanol-water partitioning and cell line approaches, combining the advantages and characteristics of chromatographic techniques with simulation of the environment in cell membranes [7]. In Figure 1, a schematic comparison of wet n-octanol, liposomes, IAM stationary phase, and membrane bilayer is presented. During three decades, a large number of publications support the use of IAM chromatography for rapid estimation of membrane permeability as well as for drug–membrane interactions in early drug discovery [2,7,10]. However, its advantages are still not completely realized by the medicinal chemistry community and IAM retention is in fact not yet integrated in candidate optimization protocols. Further information on experimental issues, understanding of the retention mechanism, updating of IAM models in respect to different biological processes, and eventually prediction on IAM retention per se would strengthen its position to this direction. 2. IAM column characteristics and measurements