Evidences for pharmacokinetic interaction of riluzole and topiramate with pilocarpine in pilocarpine-induced seizures in rats

In this study we investigated the effectiveness of two antiepileptic drugs: riluzole and topiramate against pilocarpine-induced seizures, which are considered to be a model of intractable epilepsy commonly used to investigate the antiepileptic effect of drugs and mechanisms of epileptogenesis. Seizures and status epilepticus were induced by pilocarpine in adult male Wistar rats. Riluzole (1-4 mg/kg) administered intraperitoneally before pilocarpine dose-dependently protected rats against seizures with the anticonvulsant ED50 value (50% effective anticonvulsant dose) of 1.8 (1.3-2.6) mg/kg. In contrast, riluzole at 8 and 12 mg/kg administered after the onset of pilocarpine-induced seizures affected neither status epilepticus nor mortality of rats. Topiramate significantly enhanced convulsive action of pilocarpine, lowering the convulsant CD50 value (50% effective convulsant dose) of pilocarpine from 350.8 (329.2-373.8) to 246.4 (218.6-278.2) mg/kg. Riluzole (4 mg/kg) lowered plasma and brain concentration of pilocarpine administered at a dose of 400 mg/kg from 168.0 +/- 8.6 to 75.3 +/- 19.9 mu g/mL and from 193.7 +/- 6.6 to 97.0 +/- 26.1 mu g/g, respectively. Topiramate (200 mg/kg) increased plasma and brain concentration of pilocarpine administered at a dose of 300 mg/kg from 78.1 +/- 2.9 to 106.0 +/- 6.8 mu g/ml and from 138.4 +/- 5.0 to 155.2 +/- 5.1 mu g/g, respectively. It seems that both anticonvulsant effect exerted by riluzole and proconvulsant effect exerted by topiramate in pilocarpine model of seizures are due to a pharmacokinetic interaction. Therefore, we postulate that the concentration of pilocarpine should be measured routinely whenever the anticonvulsant effect of drugs is determined in the pilocarpine model of seizures. (C) 2009 Elsevier B.V. All rights reserved.