Oxcarbazepine, not its active metabolite, potentiates GABAA activation and aggravates absence seizures

Epilepsia
Thomas ZhengTerence J O'Brien

Abstract

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. 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. 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. 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.

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Citations

Feb 22, 2012·Science Translational Medicine·Elizabeth TringhamTerrance P Snutch
May 29, 2010·Pharmacological Reports : PR·Bogusława Pietrzak, Elzbieta Czarnecka
Aug 17, 2010·Epilepsy & Behavior : E&B·Denise MilovanPatrício Soares-da-Silva
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Oct 16, 2018·Frontiers in Pharmacology·Jaya KumarSrijit Das
Jun 27, 2019·Pharmaceuticals·Daria A BelinskaiaNatalia N Shestakova

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