Carbamazepine pharmacokinetics-pharmacodynamics in genetically epilepsy-prone rats

Carbamazepine produces dose-related anticonvulsant effects in epilepsy mode ls including the genetically epilepsy-prone rat (GEPR) model and the rat ma ximal electroshock model. Dose-response relationships are quantitatively di fferent among the models. Against electroshock seizures in Sprague-Dawley r ats the ED,(50)dose is 7.5 mg/kg whereas the ED50 against audiogenic seizur es in severe seizure GEPRs (GEPR-9s) is 3 mg/kg. In contrast, the ED50 in m oderate seizure GEPRs (GEPR-3s) is 25 mg/kg. The present study was designed to ascribe dose-response differences among the three rat strains to pharma cokinetic or pharmacodynamic factors. After systemic carbamazepine, pharmac okinetic studies revealed differences in area under the concentration-vs.-t ime curve. In other experiments, carbamazepine-induced serotonin release fr om hippocampus was used as a pharmacodynamic marker. In a concentration-con troIled design using intracerebral microdialysis, hippocampal carbamazepine infusions produced similar concentration-response relations for the three rat strains. These data support the hypothesis that close-response differen ces among the three rat strains are primarily pharmacokinetic in nature. (C ) 1999 Elsevier Science B.V. All rights reserved.