Relationship between immobilised artificial membrane chromatographic retention and the brain penetration of structurally diverse drugs

Retention factors were determined for a set of 26 drugs, for which brain/blood concentration data are available, using immobilised artificial membrane (IAM) chromatography. The compound set represented acidic, basic and neutral drugs from various structural classes. The relationship between IAM retention and lipophilicity (n-octanol-water partition coefficient K-oct), molecular size and acid/base character of the drugs and the relationship between brain distribution and IAM retention and the other parameters were analysed. IAM retention was increased with increases in lipophilicity and solute size, and decreased by the ionisation of acidic groups. Ionisation of basic groups had no significant effect. A three-parameter regression model with log K-oct, molecular weight and an indicator parameter for the presence of carboxyl group explained 93% of the variation in log k(IAM). The concentration ratio between brain and blood (log BB) was only weakly correlated with the IAM chromatographic retention or n-octanol-water partitioning. Three-parameter models taking ionisation and size into account, in addition to either log K-oct or log k(IAM), explained about 85% of the variation of log BE in the test set. Although IAM chromatography offers no advantage in these models, it seems to provide a better model than n-octanol-water partitioning for the membrane distribution of ionised compounds.