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Vol. 280, Issue 2, 983-987, 1997
EA 1223, Faculté de Médecine and Pharmacie, Poitiers,
France
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
(~230g-300g) received an i.v. infusion of pefloxacin or norfloxacin
at one of four different rates: 480, 960, 1440 and 1920 µmol/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 µmol/liter) was about 8-fold lower than that of pefloxacin (380 ± 27 µmol/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 µmol/kg), suggesting that the higher ability of the more
lipophilic pefloxacin to reach central nervous system compensates for
its lower intrinsic convulsant activity.
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