CIPROFLOXACIN AND SPARFLOXACIN PENETRATION INTO HUMAN BRAIN-TISSUE AND THEIR ACTIVITY AS ANTAGONISTS OF GABA(A) RECEPTOR OF RAT VAGUS NERVE

Patients undergoing elective surgery for removal of brain tumors, aneu rysms, or other vascular malformations were administered a single oral dose of sparfloxacin (400 mg; 16 patients) or ciprofloxacin (750 mg; 5 patients) either 3 to 5 h or 22 to 26 h before surgery. Serum sample s were taken from all patients at 0, 1, 3 to 5, 7 to 9, and 22 to 26 h after dosing; an additional serum sample was obtained at 48 h from pa tients who received sparfloxacin. A single sample of brain tissue was taken from all patients; a sample of cerebrospinal fluid (CSF) unconta minated with blood was obtained from five patients. Serum and brain ti ssue samples were assayed by high-pressure liquid chromatography, Drug concentrations in brain tissue exceeded those in CSF by 1.8- to 19.4- fold. Kinetic modeling suggested that peak sparfloxacin concentrations in brain tissue may have occurred later than 3 to 5 h and that actual peak concentrations mag therefore have been higher (up to 10 mu g/g o f tissue). The activities of ciprofloxacin and sparfloxacin as antagon ists of the gamma-aminobutyric acid antagonist (GABA(A)) receptor were measured with the rat vagus nerve preparation. The 50% inhibitory con centration (IC50) of ciprofloxacin was 250 mu M (95.25 mu g/ml), but i n the presence of biphenyl acetic acid (BPAA), the IC50 of ciprofloxac in was only 0.6 mu M (0.23 mu g/ml). In contrast, the IC50 of sparflox acin alone or in the presence of BPAA was >300 mu M (>100 mu g/ml). We conclude that the concentrations of ciprofloxacin and sparfloxacin in brain tissue may exceed serum drug concentrations and cannot be predi cted from the concentrations in CSF. Sparfloxacin does not have any ac tivity as a GABA antagonist, either alone or in the presence of BPAA, at the concentrations which are likely to be reached in human brain ti ssue.