Pharmacokinetic-pharmacodynamic contributions to the convulsant activity of pefloxacin and norfloxacin in rats.

The purpose of this investigation was to compare the convulsant activity of two quinolones differing, respectively, by the presence (pefloxacin) or absence (norfloxacin) of a methyl group on the piperazine moiety at the position 7 of their parent nuclei and consequently by their lipophilicity. An in vivo model was used, which can distinguish between ease in reaching pharmacological receptors at the central nervous system level, and ability to interact with these receptors. Male Sprague-Dawley rats (approximately 230g-300g) received an i.v. infusion of pefloxacin or norfloxacin at one of four different rates: 480, 960, 1440 and 1920 micromol/hr, until the onset of maximal seizures. This occurred after an average of 12.7 to 69.4 min. We found enough evidence to suggest that in these conditions the contribution of pefloxacin metabolites, including norfloxacin, to its convulsant activity was negligible. Doses of pefloxacin and concentrations in cerebrospinal fluid and plasma (total and unbound) at the pharmacodynamic endpoint were all independent of infusion rate, whereas only cerebrospinal fluid concentrations of norfloxacin were independent of infusion rate. The overall cerebrospinal fluid concentration of norfloxacin (47.3 +/- 9.9 micromol/liter) was about 8-fold lower than that of pefloxacin (380 +/- 27 micromol/liter), indicating that on average the "intrinsic convulsant activity" of norfloxacin is 8-fold greater than that of pefloxacin. However, total doses of pefloxacin and norfloxacin at the onset of maximal seizures were in the same order of magnitude (1500-2000 micromol/kg), suggesting that the higher ability of the more lipophilic pefloxacin to reach central nervous system compensates for its lower intrinsic convulsant activity.