Anticonvulsant action of clobazam and desmethylclobazam in reflex epilepsy in rodents and baboons

The anticonvulsant action of N-desmethylclobazam, the metabolite of clobazam, has been evaluated acutely in DBA/2 mice with audiogenic seizures and in baboons (Papio papio) with photosensitive epilepsy, and compared with the effect of clobazam. In mice, desmethylclobazam appears less potent than clobazam, in terms of the ED50 for abolition of the tonic or clonic phase of the seizure response, but it has a longer time course of action. In baboons, desmethylclobazam, 1 to 4 mg/kg i.v., has a protective action against photically-induced myoclonus comparable to that seen after similar doses of clobazam. After clobazam, 4 mg/kg, plasma clobazam concentration shows a rapid, approximately exponential, clearance (t1/2 = 2.0 to 2.5 hr), and plasma desmethylclobazam content increases progressively to a peak at 6 hr or later. Plasma concentrations of desmethylclobazam after clobazam injection rapidly exceed those associated with potent anticonvulsant action when desmethylclobazam itself is administered. It is concluded that in the baboon and probably also in man the metabolite desmethylclobazam is responsible for a substantial part of the antiepileptic effect of clobazam.