INFLUENCE OF LIPOPHILICITY ON THE DIFFUSION OF CEPHALOSPORINS INTO THE CEREBROSPINAL-FLUID

The aim of this quantitative structure-activity relationship (QSAR) st udy was to investigate the influence of lipophilicity on the diffusion of cephalosporins into the cerebrospinal fluid (CSF). The lipophilici ty was expressed as the chromatographic capacity factor (log k'(w)) de termined by high-performance liquid chromatography in a reversed-phase system. The penetration of eight cephalosporins into CSF was studied in male Wistar rats receiving the drugs intramuscularly (1.5 mg/kg). O ne hour after administration, CSF and blood samples were collected, an d concentrations of free drug were measured in CSF (C-CSF) and in plas ma (C-p). A significant parabolic relationship was sought between lipo philicity (log k'w) and the capacity of diffusion across the blood-bra in barrier expressed as log (C-CSF/C-p). The cephalosporins exhibiting a moderate lipophilicity diffused well into CSF. A pharmacokinetic st udy was performed at 1, 2 and 4 h after administration of three cephal osporins: cefazolin, ceftriaxone and cefsulodin. These compounds were choosen according to their lipophilicities (low, moderate and high val ues, respectively). The AUC(0-4h) for both free plasma (AUC(p)) and ce rebrospinal fluid (AUC(CSF)) concentrations were determined. The AU(CS F)/AUC(p) ratio presented a maximum value for a strongly albumin bound cephalosporin, ceftriaxone. In our experimental conditions, the ideal lipophilicity (log k'(w)) range for diffusion of cephalosporins from plasma into CSF was between 1.6 and 1.8.