A new approach for early assessment of the epileptogenic potential of quinolones.

The epileptogenic potential of pefloxacin and norfloxacin, two quinolone antibiotics, was investigated in vivo in three different animal species by measuring drug concentrations in cerebrospinal fluid (CSF), which is part of the biophase, at the onset of convulsions. Interestingly, the pefloxacin-to-norfloxacin concentration ratios in CSF were virtually constant across the species (7.0, 6.6, and 6.0 in mice, rats, and rabbits, respectively), suggesting that this approach could be used to predict the relative epileptogenic potential of quinolones in humans.

Cerebrospinal fluid transport and disposition of the quinolones ciprofloxacin and pefloxacin in rats.

The disposition of ciprofloxacin and pefloxacin in the rat cerebrospinal fluid (CSF) was investigated after i.v. and i.c.v. administration. After injection into the lateral ventricle, the terminal half-life of pefloxacin was shorter than that of ciprofloxacin. After i.v. infusions, the relative CSF exposure, expressed as CSF: area under the plasma concentration time curve ratio, were found to be 10.4 +/- 2.8% for ciprofloxacin and 42.4 +/- 3.0% for pefloxacin. The unit impulse response methodology was applied in order to assess the CSF transport profile. The plasma-CSF transport clearance of pefloxacin and the total amount of drug transported into the CSF were significantly higher compared with ciprofloxacin. Although pefloxacin exhibited a linear CSF transport profile, the plasma-CSF transport clearance of ciprofloxacin was found to be nonlinear at the dose level studied. Pefloxacin was converted in the brain to the active metabolite norfloxacin (N-desmethyl pefloxacin). The difference in CSF exposure of both quinolones and the presence of active metabolites of N-methylated quinolones in the CSF may be of clinical relevance in the treatment of CNS infections, but differences in antimicrobial activity have to be taken into account as well.