Interactions of nonsteroidal antiinflammatory drugs with phospholipids: Comparison between octanol/buffer partition coefficients and chromatographic indexes on immobilized artificial membranes

A set of seventeen nonsteroidal antiinflammatory drugs (NSAIDs), consisting of structurally unrelated carboxylic acids and piroxicam, was examined by high-performance liquid chromatography (HPLC) on an immobilized artificial membrane (IAM) column that is a solid-phase model of fluid membranes. The chromatographic capacity factors extrapolated to 100% aqueous phase (log k(w)(IAM)) were compared with n-octanol/buffer lipophilicity parameters. The interactions with phospholipids were much better predicted from the intrinsic partition coefficient, log P, than from the apparent partition value, log D-7.4, indicating that phospholipids can counteract the influence of electrically charged functions of analytes on lipophilic interactions. The log k(w)(IAM) and log P values for both NSAIDs and structurally unrelated neutral compounds result in unique scale if uniquely partition-based mechanisms take place. However, an electrostatic repulsion component was observed for the NSAIDs bearing the carboxylic function directly linked to the aromatic ring, and for ibuprofen. Hence, the IAM-derived scale is distinctive from the one obtained by lipophilic parameters. The IC50 values on cyclooxygenase 2 (COX-2) in intact cells determined by different authors have been successfully correlated with respective IAM parameters, whereas no correlation was found with COX-1 activity data. These results suggest that membrane affinity may represent an important prerequisite for the specific binding NSAIDs/COX-2.