Interaction of tiagabine with valproate in the mouse pentylenetetrazole-induced seizure model: an isobolographic analysis for non-parallel dose-response relationship curves.

PURPOSE: To characterize the interaction between tiagabine (TGB) and valproate (VPA)--two antiepileptic drugs in the mouse pentylenetetrazole (PTZ)-induced clonic seizure model, type I isobolographic analysis for non-parallel dose-response relationship curves (DRRCs) was used.

MATERIAL AND METHODS: Clonic seizures were evoked in albino Swiss mice by subcutaneous injection of PTZ at its CD97 (100 mg/ kg). To ascertain the nature of interaction between TGB and VPA administered in combination, total brain concentrations of TGB and VPA were estimated by using high-performance liquid chromatography (HPLC) and fluorescence polarization immunoassay (FPIA).

RESULTS: TGB and VPA produced clear-cut anticonvulsant effects against PTZ-induced clonic seizures in mice and their DRRCs were not parallel to one another. The type I isobolographic analysis for non-parallel DRRCs revealed that the combination of TGB with VPA at the fixed-ratio of 1:1 exerted additive interaction against PTZ-induced clonic seizures in mice. With FPIA, it was found that TGB did not affect total brain VPA concentrations in experimental animals. Moreover, VPA had no significant impact on total brain concentrations of TGB in mice, as measured with HPLC.

CONCLUSION: The additive interaction between TGB and VPA at the fixed-ratio of 1:1 in the mouse PTZ model was pharmacodynamic in nature.