Pharmacokinetic-pharmacodynamic contributions to the convulsant activity of fluoroquinolones in rats

The in vivo convulsant activities in rats of five representative fluoroquin olones (FQs), norfloxacin, enoxacin, sparfloxacin, fleroxacin, and pefloxac in, were compared. The experimental approach allowed distinction between th e drugs' ability to reach the pharmacological receptors at the level of the central nervous system (pharmacokinetic contribution) and their ability to interact with these receptors (pharmacodynamic contribution). The presence of a methyl group on the piperazine moiety decreased the pharmacodynamic c ontribution to the convulsant activity by severalfold, and the ratios of co ncentrations of the FQs in cerebrospinal fluid (CSF) to concentrations of u nbound FQs in plasma varied from about 5 to 75% as a function of lipophilic ity. Interestingly, FQs with the highest intrinsic convulsant activities ha d the lowest levels of diffusion in CSF and vice versa. This in vivo approa ch provides information complementary to that of in vibro experiments and s hould be recommended for early preclinical assessment of a new FQ's epilept ogenic risk.