Chromatographic indexes on immobilized artificial membranes for local anesthetics: relationships with activity data on closed sodium channels.

PURPOSE: To elucidate the effectiveness of the different parameters for the prediction of biological activity, the n-octanol/buffer partition coefficients and theoretical calculated lipophilicity parameters of thirteen local anesthetic drugs (LAs), including two beta-blockers, were compared to the affinity values for phospholipids, calculated by a recent technique.
METHODS: Interactions with phospholipids were measured by high performance liquid chromatography on a stationary phase made up of phospholipids, the so-called "Immobilized Artificial Membrane" (IAM). Reference lipophilicity parameters were measured by shake-flask method between n-octanol and buffer phases.
RESULTS: Interactions with phospholipids were predicted from log P for all compounds except tocainide, which also showed additive polar extra-interactions. Moreover, when the retention on Immobilized Artificial Membrane (IAM) phase was mainly lipophilicity-based, a unique scale included the correlation between log kwIAM and log P values, for both LAs (bases) and the structurally unrelated (nonionizable and acidic) compounds previously studied. IAM interaction values for LAs were predictive of the partition measures on liposome membranes already reported in literature. The half-blocking doses for closed sodium channel, corrected for ionization at pH 7.4, were successfully correlated with the respective IAM values for eleven compounds while procaine and tetracaine, which are ester-linked compounds and have a p-amino group as well, gave more potent results than predicted by phospholipid interactions.
CONCLUSIONS: The IAM chromatographic parameters were much more effective than reference lipophilicity values in describing partition on model membranes and in predicting pharmacological potency on closed sodium channels.