Influence of lipophilicity on the diffusion of cephalosporins into the cerebrospinal fluid

Summary— The aim of this quantitative structure-activity relationship (QSAR) study was to investigate the influence of lipophilicity on the diffusion of cephalosporins into the cerebrospinal fluid (CSF). The lipophilicity was expressed as the chromatographic capacity factor (log k'_w) determined 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). One hour after administration, CSF and blood samples were collected, and concentrations of free drug were measured in CSF (C_CSF) and in plasma (C_P). A significant parabolic relationship was sought between lipophilicity (log k'_w) and the capacity of diffusion across the blood-brain barrier expressed as log (C_CSF/C_P). The cephalosporins exhibiting a moderate lipophilicity diffused well into CSF. A pharmacokinetic study was performed at 1, 2 and 4 h after administration of three cephalosporins: cefazolin, ceftriaxone and cefsulodin. These compounds were choosen according to their lipophilicities (low, moderate and high values, respectively). The AUC_0–4h for both free plasma (AUC_P) and cerebrospinal fluid (AUC_CSF) concentrations were determined. The AUC_CSF/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.