Amygdala-kindling as a model for chronic efficacy studies on antiepileptic drugs: experiments with carbamazepine

The anticonvulsant properties of carbamazepine were evaluated after single and multiple doses in the kindled amygdaloid seizure model in rats. Carbamazepine significantly reduced severity and duration of motor seizures and the duration of afterdischarges recorded from the stimulated amygdala after a single dose of 30 mg/kg (i.p.), but tolerance developed during chronic treatment of rats with three times daily intraperitoneal injection of 30 mg/kg of the drug for 2 weeks. Tolerance was also observed with respect to central side-effects (ataxia, muscle relaxation) of the treatment. Determinations of plasma levels confirmed previous studies in rats and other species in that concentrations of carbamazepine declined during chronic treatment, which may be related to autoinduction of the metabolism of the drug. Indeed, carbamazepine-10,11-epoxide, the major active metabolite of carbamazepine, could not be quantified in the plasma after the first dose but accumulated during chronic treatment, indicating an enhanced metabolism of the parent drug. As a consequence of decreasing concentrations of carbamazepine but increasing levels of the epoxide, the sum of concentrations of both compounds after 1 or 2 weeks of treatment did not differ from the concentration of unchanged carbamazepine initially determined. Determinations of the acute anticonvulsant potency in kindled rats indicated that carbamazepine-10,11-epoxide was about half as potent as the parent drug. In view of the anticonvulsant activity of carbamazepine-10,11-epoxide, the loss of anticonvulsant efficacy observed during chronic treatment with carbamazepine cannot be related solely to metabolic tolerance, i.e. due to enhanced metabolism of drug, but should also relate to functional tolerance, i.e. induced by central adaptation to the long-term presence of the drug and its metabolite.