Indexes of polar interactions between ionizable drugs and membrane phospholipids measured by IAM–HPLC: Their relationships with data of Blood–Brain Barrier passage

• Published in: European journal of pharmaceutical sciences Vol. 65; pp. 139 - 146
• Main Authors: Grumetto, Lucia, Russo, Giacomo, Barbato, Francesco
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 18.12.2014
• Subjects: 1-Octanol - metabolism; BBB – Blood–Brain Barrier; Biological Transport - physiology; Blood-Brain Barrier - metabolism; Chromatography, High Pressure Liquid - methods; Hydrophobic and Hydrophilic Interactions; IAM–HPLC; Lipophilicity; Membrane; Membranes, Artificial; Permeability; Pharmaceutical Preparations - metabolism; Phospholipids; Phospholipids - metabolism; Static Electricity; IAM–HPLC; Membrane; Phospholipids; BBB – Blood–Brain Barrier; Lipophilicity
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2014.09.015

[Display omitted] Phospholipid affinity indexes logkwIAM for 21 structurally non-related basic, acidic, ampholytic, and neutral drugs were measured by HPLC on two different phospholipid stationary phases (Immobilized Artificial Membrane – IAM). The differences between the experimental values and those expected for neutral isolipophilic compounds Δ/Δ′logkwIAM were assumed as a measure of polar and electrostatic forces involved in the interactions drug/membrane. Blood Brain Barrier (BBB) permeation data (logBB) weakly related with n-octanol lipophilicity values of the neutral forms (logPN), but only after the exclusion of two analytes. No relationship was observed with the lipophilicity of the mixture of charged and neutral forms (logD7.4) and very poor relationships were also found with logkwIAM values. In contrast, a good linear inverse relationship was found between log BB and Δ/Δ′logkwIAM values. This relationship was also observed on an enlarged set of 42 data points obtained by assembling the drugs considered with 21 drugs examined in our previous works (acids and bases). The results suggest that Δ/Δ′logkwIAM parameter, as a sole descriptor, is effective in evaluating the capability of a compound to cross the BBB, indicating that the polar/electrostatic interactions, which are the additional interactions described by IAM, are of prime importance in predicting BBB passage.