PHARMACOKINETIC-PHARMACODYNAMIC CONTRIBUTIONS TO THE CONVULSANT ACTIVITY OF PEFLOXACIN AND NORFLOXACIN IN RATS

The purpose of this investigation was to compare the convulsant activi ty of two quinolones differing, respectively, by the presence (pefloxa cin) or absence (norfloxacin) of a methyl group on the piperazine moie ty at the position 7 of their parent nuclei and consequently by their lipophilicity. An in vivo model was used, which can distinguish betwee n ease in reaching pharmacological receptors at the central nervous sy stem level, and ability to interact with these receptors. Male Sprague -Dawley rats (similar to 230g-300g) received an i.v. infusion of peflo xacin or norfloxacin at one of four different rates: 480, 960, 1440 an d 1920 mu mol/hr, until the onset of maximal seizures. This occurred a fter an average of 12.7 to 69.4 min. We found enough evidence to sugge st that in these conditions the contribution of pefloxacin metabolites , including norfloxacin, to its convulsant activity was negligible. Do ses of pefloxacin and concentrations in cerebrospinal fluid and plasma (total and unbound) at the pharmacodynamic endpoint were all independ ent of infusion rate, whereas only cerebrospinal fluid concentrations of norfloxacin were independent of infusion rate. The overall cerebros pinal fluid concentration of norfloxacin (47.3 +/- 9.9 mu mol/liter) w as about 8-fold lower than that of pefloxacin (380 +/- 27 mu mol/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 mu mol/kg), suggesting that the higher ability of the more lipophilic pefloxacin to reach cen tral nervous system compensates for its lower intrinsic convulsant act ivity.