The relationship between plasma concentration of valproic acid and its anticonvulsant and behavioural effects in the rat.

The relationship between the plasma concentration of valproic acid (VPA) and anticonvulsant or neurotoxic effects was studied in the rat. Anticonvulsant activity was assessed against; (1) maximal seizures induced either by electroshock or by intravenous injection of pentylenetetrazol; and (2) kindled amygdaloid epilepsy. Drug-induced neurotoxicity was determined by the rotarod test and by observation of behaviour. In the maximal seizure tests, tonic hindlimb extension was always abolished at plasma valproic acid concentrations of 225 microgram ml-1 and above. Tonic forelimb extension was not consistently blocked until the plasma drug concentration exceeded 530 microgram ml-1. In fully-kindled rats, plasma valproic acid concentrations of 300 microgram ml-1 and above markedly reduced the duration of amygdala afterdischarge activity and the intensity of behavioural seizures produced by amygdala stimulation. Analysis of the data from individual kindled rats revealed that there was a significant correlation between the estimated plasma concentration of valproic acid and the degree of seizure protection. Impairment of rotarod performance and marked ataxia occurred at plasma valproic acid concentrations above 510 microgram ml-1 and loss of righting reflex became evident at 970 microgram ml-1. From these results, it is concluded that the plasma concentration of valproic acid is closely correlated with the anticonvulsant and neurotoxic effects observed in individual rats after acute administration of sodium valproate.