Pharmacokinetic and pharmacodynamic interactions of aminophylline and topiramate in the mouse maximal electroshock-induced seizure model.

ABSTRACT

The aim of this study was to determine the influence of acute (single) and chronic (twice daily for 14 consecutive days) treatments with aminophylline (theophylline(2).ethylenediamine) on the anticonvulsant potential of topiramate (a broad-spectrum antiepileptic drug) in the mouse maximal electroshock-induced seizure model. Additionally, the effects of acute and chronic administration of aminophylline on the adverse effect potential of topiramate were assessed in the chimney test (motor performance). To evaluate pharmacokinetic characteristics of interaction between topiramate and aminophylline, total brain concentrations of topiramate and theophylline were estimated with fluorescence polarization immunoassay technique. Results indicate that aminophylline in non-convulsive doses of 50 and 100 mg/kg (i.p.), both in acute and chronic experiments, markedly attenuated the anticonvulsant potential of topiramate by raising its ED(50) value against maximal electroconvulsions. Aminophylline at a lower dose of 25 mg/kg did not affect significantly the ED(50) value of topiramate in the acute experiment, but the drug markedly increased the ED(50) value of topiramate during the chronic treatment in mice. Only, aminophylline at 12.5 mg/kg, in both acute and chronic experiments, did not affect the antielectroshock action of topiramate in mice. Moreover, aminophylline at a dose of 100 mg/kg had no impact on the adverse effect potential of topiramate in the chimney test. Pharmacokinetic evaluation of total brain concentrations of topiramate and theophylline revealed that topiramate significantly increased total brain theophylline concentrations following both acute and chronic applications of aminophylline. Conversely, aminophylline did not alter total brain concentrations of topiramate in mice. Based on this preclinical study, one can conclude that aminophylline attenuated the antiseizure action of topiramate in the mouse maximal electroshock-induced seizure model and the observed interaction between drugs was both pharmacokinetic and pharmacodynamic in nature.