Mechanism of action of valproate

Abstract

The anticonvulsant action of valproate differs according to the test system studied (acute animal model, chronic drug therapy) partly because of differences in pharmacokinetic and metabolic phenomena. In man, circulating valproate is largely (95%) plasma protein bound, and is eliminated slowly (t 1 2 ) = 6–16 hr ). In rodents and dogs, protein binding is less, and elimination faster ( t 1 2 1–2 hr ). Omega and beta oxidation occurs in man; intermediate metabolites (including succinyl-CoA) may be biochemically and pharmacologically active. Valproate produces a marked cerebral accumulation of acid metabolites of monoamine transmitters (HVA and 5HIAA). Enhancement of GABA-mediated inhibition remains an interesting hypothesis. Evidence is available for selective synaptic accumulation of GABA (and decrease of aspartate), but there is not yet evidence for enhanced physiological release of GABA (or decreased release of dicarboxylic amino acids). Kinetic studies on GABA-transaminase inhibition suggest that valproate, 20–50 mM, is needed to block brain GABA metabolism at this step. The effects of inhibition of succinic semialdehyde dehydrogenase or reductase by valproate on GABA-mediated synaptic inhibition need to be established.