Disposition of valproic acid in man.

The pharmacokinetics of valproic acid (VPA) have been studied in 6 healthy subjects following a single 600 mg dose, and after multiple doses over 12 days (1200 mg daily) of enteric-coated sodium valproate. A time lag before absorption of 1 to 2 h was observed in each subject, and then absorption was rapid, peak concentrations being recorded 3 to 4 h after administration of the dose. The plasma level decline was biphasic with a terminal half-life of 15.9 +/- 2.6 h in the single dose and 17.3 +/- 3.0 h in the multiple dose experiments. There was no evidence of dose dependent kinetics or autoinduction. Total plasma clearance was 0.0064 +/- 0.0011 l/kg X h. The apparent volume of distribution was small at 0.15 +/- 0.2 l/kg. The mean steady state plasma concentration (Css) reached after 4 days was 81.3 +/- 13.0 microgram/ml. Css observed was lower than Css predicted (99.2 +/- 14.7 microgram/ml) from single dose kinetics (p less than 0.001). The difference was probably due to a reduction in plasma protein binding at higher concentrations. VPA concentration in saliva was between 0.4 and 4.5% of the total plasma concentration and was not equal to the concentration of unbound drug in plasma (6.7 +/- 0.8% unbound). 3.2% of the dose was excreted in urine as the parent drug and 21.2% as conjugated metabolites.