Oxcarbazepine: Preclinical Anticonvulsant Profile and Putative Mechanisms of Action

Abstract

Oxcarbazepine (OCBZ, Trileptal) and its main human monohydroxy metabolite (MHD) protected mice and rats against generalized tonic-clonic seizures induced by electroshock with ED50 values between 13.5 and 20.5 mg/kg p.o. No tolerance toward this anticonvulsant effect was observed when rats were treated with OCBZ or MHD daily for 4 weeks. The therapeutic indices were 4 (OCBZ) and > 6 (MHD) for sedation (observation test, mice and rats) and 8 (MHD) or 10 (OCBZ) for motor impairment (rotorod test, mice). Both compounds were less potent in suppressing chemically induced seizures and did not significantly influence rat kindling development. At doses of 50 mg/kg p.o. and 20 mg/kg i.m. and higher, OCBZ and, to a lesser extent, MHD protected Rhesus monkeys from aluminum-induced chronically recurring partial seizures. In vitro, OCBZ and MHD suppressed sustained high-frequency repetitive firing of sodium-dependent action potentials in mouse neurons in cell culture with equal potency (medium effective concentration 5 x 10(-8) M/L). This effect is probably due in part to a direct effect on sodium channels. Patch-clamp studies on rat dorsal root ganglia cells revealed that up to a concentration of 3 x 10(-4) M, MHD did not significantly interact with L-type calcium currents, whereas OCBZ diminished them by about 30% at the concentration of 3 x 10(-4) M. In biochemical investigations, no brain neurotransmitter or modulator receptor site responsible for the anticonvulsant mechanism of action of OCBZ and MHD was identified.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

“…Exposure to the active metabolite is considerably greater than the parent drug and it is somewhat less protein-bound (Dickinson Patsalos et al, 1990). Although the mechanism of action may not be definitively proven, both compounds block sodium channels in vitro with equivalent potency (Schmutz et al, 1994). Considering the relative potency, plasma exposure, and free fraction values, and assuming equivalent brain penetrability, it can be estimated that the metabolite carries 17-times the in vivo activity of the parent drug.…”

Population pharmacokinetics modeling of oxcarbazepine to characterize drug interactions in Chinese children with epilepsy

“…In humans, the formation of MHD is stereoselective, with the two enantiomeres formed in a ratio of 80% (S-MHD) to 20% (R-MHD) [4][5][6][7][8] . It has been demonstrated that the two enantiomers have similar antiepileptic efficacy and tolerability [9] . Usually, the pharmacokinetics and disposition of the racemate were investigated [4] .…”

Oxcarbazepine

“…In the electroshock test in mice, the factors for OXC and MHD are 4 and >6, respectively, for sedation. In the rotorod test, the factors are 10 and 8, respectively, for motor impairment (2). In acute toxicity studies across multiple species, extremely high doses of oral OXC were tolerated and no compound-related deaths were noted in subchronic toxicity studies at a daily dose of 600-3,000 mgkg.…”

“…M, respectively) limited repetitive neuronal firing elicited by intracellularly applied depolarizing currents at stable membrane potentials (Em -49 to -55 mV) (1)(2)(3). These effects were seen at concentrations much lower than plasma concentrations in patients treated with OXC.…”