Pharmacokinetics, anticonvulsant efficacy, and adverse effects of trans-2-en-valproate after acute and chronic administration in amygdala-kindled rats

Abstract

The trans isomer of 2-en-valproate (trans-2-en-VPA), an unsaturated metabolite of the clinically established antiepileptic valproate (VPA), was examined in the kindling model of epilepsy. As in the case of VPA, trans-2-en-VPA exerted potent anticonvulsant effects against partial seizures and secondarily generalized clonic seizures in amygdala-kindled rats after i.p. administration of acute doses. The anticonvulsant potency of trans-2-en-VPA appeared to be higher than that of VPA, especially in the case of secondarily generalized seizures. However, as previously reported for effects of valproate in the kindling model, trans-2-en-VPA exerted anticonvulsant effects against kindled seizures only at doses which were associated with motor impairment. Pharmacokinetic experiments with trans-2-en-VPA indicated non-linear kinetics with dose-dependent elimination rate and enterohepatic recirculation. According to the initial rapid decline in plasma concentrations of trans-2-en-VPA, the duration of anticonvulsant action in kindled rats was short-lasting so that an experimental protocol with 3 daily administrations was chosen for chronic experiments with this drug. During chronic treatment of kindled rats with 3 times daily injection of 100 mg/kg trans-2-en-VPA for 2 weeks, there was a marked reduction of anticonvulsant activity during the second week of treatment. This loss of anticonvulsant activity was not due to metabolic tolerance, i.e. reduction of drug levels by increased drug metabolism. Furthermore, additional experiments with altered experimental protocol indicated that the loss of anticonvulsant activity was not due to contingent tolerance, i.e. involvement of learning processes due to too frequent drug testing. However, the size of chronic treatment dose was important for the rate and degree of tolerance development, since an increase of dosage to 150 mg/kg 3 times daily resulted in significant anticonvulsant effects throughout the period of treatment with almost no indication of tolerance. The date indicate that trans-2-en-VPA is as effective as valproate in the kindling model. In view of previously reported experimental evidence that trans-2-en-VPA might have a lower hepatotoxic and teratogenic potential as valproate, the present study substantiates that trans-2-en-VPA might be an interesting alternative to valproate in antiepileptic therapy.