Comparative study of permeability into rat cerebrospinal fluid of the quinolones: dependency on their lipophilicities

Pharmacokinetic behavior involved in the entry of four quinolone antibacterial agents, norfloxacin (NFLX), ciprofloxacin (CPFX), ofloxacin (OFLX) and nalidixic acid (NA), into cerebrospinal fluid (CSF) was comparatively investigated in rats. Periodically, after the bolus i.v. dose of each quinolone (10 mg/kg), aliquots of CSF were collected by cisternal puncture and blood samples were then withdrawn from the jugular vein. CSF and serum (total and unbound) levels of the drugs were determined by HPLC method. Transport parameters for three new quinolones (NFLX, CPFX, OFLX) into CSF were obtained by physiological model analysis. Serum levels of OFLX and NFLX declined bi-exponentially with time, whereas the serum levels of NA and CPFX declined in mono-exponential and tri-exponential fashion, respectively. Fractions of each quinolone unbound to serum protein (approximately 0.7 for NFLX, CPFX, and OFLX, 0.12 for NA) were almost the same at any point in time. The CSF levels of these quinolones rose quite rapidly after drug administration, and then declined, along with their serum levels. Both the CSF level and the ratio of CSF concentration to serum unbound concentration were the highest for NA, followed by OFLX, CPFX and NFLX. These values of the four quinolones were almost proportional to the apparent partition coefficient (Papp) between n-octanol and phosphate buffer (pH 7.0) values of each reported in a previous paper [Tsuji et al., Antimicrob. Agents Chemother., 32, 190 (1988)]. In the three new quinolones, OFLX had a larger value of apparent diffusional clearance between blood and CSF (PAc) than CPFX and NFLX.(ABSTRACT TRUNCATED AT 250 WORDS)