Relationships between Drug Passage across BBB and Partition Data in Phospholipids measured by IAM-HPLC.

The exact mechanism governing drug permeation through blood-brain barrier (BBB) is not fully understood, although it is generally thought that it mainly depends on both lipophilicity and capacity to form H-bonds. We measured the phospholipid affinity of 34 CNS active drugs, expressed as log k , i.e. the logarithm of chromatographic retention factor measured by HPLC on the so-called Immobilized Artificial Membrane (IAM) stationary phases (IAM.PC.MG and IAM.PC.DD2). The drug capacity to pass across BBB was estimated by the log BB value, i.e. the logarithm of the ratio Brain/Blood concentrations, reported in the literature. Besides the intermolecular recognition forces encoded in the n-octanol/aqueous phase log P values, IAM data also encode intermolecular electrostatic forces, such as ionic bonds. We estimated this component by the Δlog k parameter, i.e. the difference between the value of log k observed for each analyte and that calculated for a neutral isolipophilic molecule. Indeed, we had previously found that a single equation relates log k and log P values of neutral compounds, even if structurally unrelated. In the present study we found that log BB values were directly proportional to log k values (as well as to log P values) for only neutral compounds, but not for basic and acidic compounds. We did not identify any physico-chemical property acting as a driving force for ionized compounds, but only observed that their BBB passage was inversely related to Δlog k values. This supports the hypothesis that ionic bonds between drugs and phospholipids, despite promoting drug partition in a membrane, can hinder the passage through it.