Diffusion of arylpropionate non‐steroidal anti‐inflammatory drugs into the cerebrospinal fluid: a quantitative structure–activity relationship approach

A quantitative structure-activity relationship (QSAR) analysis of a series of arylpropionic acid non-steroidal anti-inflammatory drugs (NSAIDs) has been performed to determine which physicochemical properties of these compounds are involved in their diffusion into the cerebrospinal fluid (CSF). The penetration of eight arylpropionic acid derivatives into CSF was studied in male Wistar rats. After intraperitoneal administration of each compound (5 mg/kg), blood and CSF samples were collected at different times (0.5, 1, 3 and 6 h). The fraction unbound to plasma protein was determined using ultrafiltration. The areas under the curve of the free plasma (AUC F ) and CSF (AUC CSF ) concentrations were calculated according to the trapezoidal rule. The overall drug transit into CSF was estimated by the ratio R AUC (AUC CSF : AUC F ). The lipophilicity was expressed as the chromatographic capacity factor (log k IAM ) determined by high-performance liquid chromatography on an immobilized artificial membrane (IAM) column. A significant parabolic relationship was sought between lipophilicity (log k IAM ) and the capacity of diffusion across the blood-brain barrier (log R AUC ) (r = 0.928; p 1). The molecular weight (MW) was included in this parabolic relationship by means of a multiple regression analysis. This physicochemical parameter improved the correlation (r = 0.976; p < 0.005). Based on our findings, diffusion of arylpropionic acid NSAIDS into CSF appears to depend primarily on their lipophilicity and MW.