Potential of immobilized artificial membranes for predicting drug penetration across the blood-brain barrier

Purpose. The present study evaluates immobilized artificial membrane (IAM) chromatography for predicting drug permeability across the blood-brain barrier (BBB) and outlines the potential and limitations of IAMs as a predictive tool by comparison with conventional methods based on octanol/water partitioning and octadecylsilane (ODS)-HPLC. Methods. IAM- and ODS-HPLC capacity factors were determined in order to derive the hydrophobic indices log k(IAM) and log k(W) for two sets of compounds ranging from very lipid soluble (steroids) to more hydrophilic agents (biogenic amines). The uptake of the compounds across the in vivo BBB expressed as brain uptake index (BUI) has been correlated with these HPLC capacity factors as well as octanol/water partition (ClogP) and distribution coefficients (log D(7.4)). Results. For both test groups log k(IAM) correlates significantly with the respective log BUI of the drug (r(2) = 0.729 and 0.747, p < 0.05), whereas with log k(W) log D(7.4) and ClogP there is only a correlation for the group of steroids (r(2) = 0.789, 0.659 and 0.809, p < 0.05) but not for the group of biogenic amines. There is a good correlation between log k(IAM) and log k(W). ClogP or log D(7.4) for the group of steroids (r(2) = 0.935, 0.867 and 0.974, p < 0.01) but not for the biogenic amines. Conclusions. All physico-chemical descriptors examined in this study equally well describe brain uptake of lipophilic compounds, while log k(IAM) is superior over log D(7.4), ClogP and log k(W) when polar and ionizable compounds are included. The predictive value of IAMs combined with the power of HPLC holds thus great promise for the selection process of drug candidates with high brain penetration.