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Oxcarbazepine, not its active metabolite, potentiates GABA A activation and aggravates absence seizures
Author(s) -
Zheng Thomas,
Clarke Alison L.,
Morris Margaret J.,
Reid Christopher A.,
Petrou Steven,
O'Brien Terence J.
Publication year - 2009
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/j.1528-1167.2008.01759.x
Subject(s) - oxcarbazepine , active metabolite , pharmacology , carbamazepine , long term potentiation , anticonvulsant , chemistry , agonist , metabolite , epilepsy , receptor , medicine , endocrinology , pharmacokinetics , psychiatry
Summary Purpose: Studies in genetic absence epileptic rats from Strasbourg (GAERS) indicate that enhancement of γ aminobutyric acid (GABA A ) receptor activity is a critical mechanism in the aggravation of seizures by carbamazepine (CBZ). We examined whether structural analogs of CBZ, oxcarbazepine (OXC), and its active metabolite, monohydroxy derivative (MHD), also potentiate GABA A receptor current and aggravate seizures. Methods: In vitro studies in Xenopus oocytes compared the three drugs' effect on GABA A receptor currents. In vivo studies compared seizure activity in GAERS after intraperitoneal drug administration. Results: OXC potentiated GABA A receptor current and aggravated seizures in GAERS, similarly to the effect of CBZ. Conversely, MHD showed only a minor potentiation of GABA A receptor current and did not aggravate seizures. Discussion: A hydroxyl group at the C‐10 position on the CBZ tricyclic structure in MHD reduces GABA A receptor potentiation and seizure aggravation. Reports of the aggravation of absence seizures in patients taking OXC may result from circulating unmetabolized OXC rather than MHD.