Influence of molecular lipophilicity on the diffusion of arylpropionate non-steroidal anti-inflammatory drugs into the cerebrospinal fluid

The diffusion of seven arylpropionic acid non-steroidal anti-inflammatory d rugs (NSAIDs) into the cerebrospinal fluid (CSF) has been investigated in m ale Wistar rats by means of quantitative structure-activity relationship (Q SAR) study. After intraperitoneal administration of each drug (5 mg/kg), bl ood and CSF samples were collected at different times (0.5, 1, 3, and 6 h). The fraction bound to plasma proteins (f(b)) was determined using ultracen trifugation. The total (CT) and free (CF) plasma concentrations and the con centrations in CSF (C-CSF) were measured by a reversed-phase high performan ce liquid chromatographic (RP-HPLC) method. The areas under the curve of th e free plasma (AUC(F)) and CSF (AUC(CSF)) concentrations were calculated ac cording to the trapezoidal rule. The overall drug transit into CSF Was esti mated by the ratio R-AUC (AUC(CSF) : AUCF). The lipophilicity of the compou nds was expressed as their polycratic capacity factors (log k'w) measured i n a RP-HPLC system. The R-AUC ranged from 0.24 to 6.58 and fb from 91.4 to 99.8 %. The compounds with an intermediate lipophilicity value (3 < logk'(w ) < 3.6) easily entered the CSF (R-AUC > 1) A parabolic relationship was fo und between log k'(w) and log R-AUC, emphasizing the role of molecular lipo philicity in the diffusion into CSF Considering the f(b) value of each drug in regard to this non-linear relationship, it can be hypothesized that the diffusion rate of NSAIDs into the CSF depends primarily on the lipophilici ty.