Oxcarbazepine, not its active metabolite, potentiates GABAA activation and aggravates absence seizures.
OBJECTIVE
Studies in genetic absence epileptic rats from Strasbourg (GAERS) indicate that enhancement of gamma 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.


CONCLUSIONS
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.
Zheng
Thomas
T
Department of Medicine The University of Melbourne, The Royal Melbourne Hospital, Victoria, Australia.
Clarke
Alison L
AL
Morris
Margaret J
MJ
Reid
Christopher A
CA
Petrou
Steven
S
O'Brien
Terence J
TJ
D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D002220:Carbamazepine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D004569:Electroencephalography; D004832:Epilepsy, Absence / Q000139:chemically induced* / Q000175:diagnosis / Q000503:physiopathology; D005260:Female; D000078330:Oxcarbazepine; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects*
D000927:Anticonvulsants; D011963:Receptors, GABA-A; D002220:Carbamazepine; D000078330:Oxcarbazepine