Oxcarbazepine and its active metabolite, (S)-licarbazepine, exacerbate seizures in a mouse model of genetic generalized epilepsy.

Abstract

Oxcarbazepine (OXC), widely used to treat focal epilepsy, is reported to exacerbate seizures in patients with generalized epilepsy. OXC is metabolized to monohydroxy derivatives in two enantiomeric forms: (R)-licarbazepine and (S)-licarbazepine. Eslicarbazepine acetate is a recently approved antiepileptic drug that is rapidly metabolized to (S)-licarbazepine. It is not known whether (S)-licarbazepine exacerbates seizures. Here, we test whether OXC or either of its enantiomers exacerbates the number of spike-and-wave discharges (SWDs) in mice harboring the human γ-aminobutyric acid A receptor (GABAA)γ2(R43Q) mutation. OXC (20 mg/kg), (S)-licarbazepine (20 mg/kg), and (R)-licarbazepine (20 mg/kg) all significantly increased the number of SWDs, while their duration was unaffected. The potential for (S)-licarbazepine to exacerbate SWDs suggests that eslicarbazepine acetate should be used with caution in generalized epilepsy. Furthermore, generalized seizure exacerbation for first-, second-, and third-generation carbamazepine-based compounds is likely to occur through a common mechanism.