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 (??/??'logkwIAM) were assumed as a measure of polar and electrostatic forces involved in the interactions drug/membrane. Blood Brain Barrier (BBB) permeation data (log BB) weakly related with n-octanol lipophilicity values of the neutral forms (log PN), but only after the exclusion of two analytes. No relationship was observed with the lipophilicity of the mixture of charged and neutral forms (log D7.4) and very poor relationships were also found with values. In contrast, a good linear inverse relationship was found between log BB and ??/??'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 ??/??' 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.

Indexes of polar interactions between ionizable drugs and membrane phospholipids measured by IAM-HPLC: their relationships with data of blood-brain barrier passage.

GRUMETTO, LUCIA;RUSSO, GIACOMO;BARBATO, FRANCESCO
2014

Abstract

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 (??/??'logkwIAM) were assumed as a measure of polar and electrostatic forces involved in the interactions drug/membrane. Blood Brain Barrier (BBB) permeation data (log BB) weakly related with n-octanol lipophilicity values of the neutral forms (log PN), but only after the exclusion of two analytes. No relationship was observed with the lipophilicity of the mixture of charged and neutral forms (log D7.4) and very poor relationships were also found with values. In contrast, a good linear inverse relationship was found between log BB and ??/??'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 ??/??' 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.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/586749
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