EFFECTS OF OXCARBAZEPINE AND 10-HYDROXYCARBAMAZEPINE ON ACTION-POTENTIAL FIRING AND GENERALIZED SEIZURES

The anticonvulsant compound oxcarbazepine and its principal 10-monohyd roxy metabolite protected potently against electroshock-induced tonic hindlimb extension. Maximal plasma concentrations depended on dose and were reached less than or equal to 1 h after an oral dose of oxcarbaz epine and < 2 h after monohydroxy derivative. In mice, the ED(50) was 14 mg/kg for oxcarbazepine and 20.5 mg/kg for the monohydroxy derivati ve, p.o. In rats, the ED(50) was 13.5 mg/kg for oxcarbazepine and 17.0 mg/kg for monohydroxy derivative, p.o. This protective effect compare d favorably with the efficacy of carbamazepine, phenytoin, phenobarbit al and diazepam in the same test. As observed previously, valproate an d ethosuximide were markedly less potent. The effect of oxcarbazepine and its monohydroxy derivative on sustained high frequency repetitive firing of sodium-dependent action potentials of mouse spinal cord neur ons in cell culture was also examined using intracellular recording te chniques. Both compounds reduced the percentage of neurons capable of sustained action potential firing in concentration-dependent manner. T he EC(50) for oxcarbazepine was 5 x 10(-8) M and that for monohydroxy derivative was 2 x 10(-8) M (P > 0.05 vs. oxcarbazepine). For comparis on, the EC(50) for carbamazepine was significantly higher (6 x 10(-7) M, P < 0.001 vs. oxcarbazepine and monohydroxy derivative). Limitation of firing by oxcarbazepine and the monohydroxy derivative depended on firing frequency and membrane potential and was enhanced by depolariz ation. Input resistance and resting membrane potential were not altere d by either drug. The in vitro effect on action potential firing frequ ency occurred at concentrations below plasma levels of oxcarbazepine a nd monohydroxy derivative which protected animals against electroshock and were therapeutically effective in patients. This suggests that li mitation of sodium-dependent action potential firing frequency could c ontribute to the anticonvulsant efficacy of both oxcarbazepine and its metabolite.