Comparison of the anticonvulsant efficacy of primidone and phenobarbital during chronic treatment of amygdala-kindled rats.

In amygdala-kindled rats, single-dose administration of primidone did not reduced seizure activity 2 h after i.p. injection, i.e. when plasma levels of the drug were highest, but significant anticonvulsant effects were found 24 h after administration, when the drug was almost completely eliminated. During chronic treatment with primidone, marked anticonvulsant efficacy was determined after 3-15 days of three times daily treatment with 50 mg/kg i.p., indicating that this effect was due to the accumulation of metabolites, especially phenobarbital. Maximum anticonvulsant activity attained during chronic primidone medication was almost equal to that found during chronic treatment of kindled rats with phenobarbital, 30 mg/kg once daily. However, drug plasma level determinations during both treatments showed that on days when both treatments were about equieffective, levels of metabolically derived phenobarbital in the primidone group were significantly lower than levels in rats treated with phenobarbital alone, thus indicating that primidone potentiated the anticonvulsant effect of metabolically derived phenobarbital. Additional evidence for potentiation of the anticonvulsant effect of phenobarbital by primidone was found in single dose experiments with combined injection of both drugs, whereas side-effects, such as ataxia and muscle relaxation, induced by phenobarbital were not increased by combined treatment with primidone. Accordingly, side-effects occurring during chronic primidone treatment were less pronounced than side-effects found during chronic phenobarbital medication. In both treatment groups, tolerance to the anticonvulsant effect developed during the 2nd week of administration, while attenuation of side-effects took place already in the first week. Following cessation of treatment, signs of physical dependence, such as withdrawal hyperexcitability and weight loss, were observed. The data indicate that, at least in kindled rats, the anticonvulsant activity of primidone during chronic treatment is due to the combined and possibly synergistic actions of primidone and metabolically derived phenobarbital.