Dose-dependent pharmacokinetics of valproate in guinea pigs of different ages

The dose-dependence of sodium valproate (VPA) pharmacokinetics in relation to age was studied using guinea pigs. Sodium valproate in doses of 20, 200, and 600 mg/kg was administered by rapid intravenous infusion to male guinea pigs 3, 21, and 42 days old. Serum levels of VPA were determined by gas chromatography. Pharmacokinetic parameters were calculated based upon a two-compartment model. The area under the plasma concentration-time curve (AUC) increased out of proportion at the 600 mg/kg dose level in all groups. Other pharmacokinetic changes were as follows: in 3-day-old guinea pigs, the slow disposition rate constant (beta), the elimination rate constant from central compartment (K10), and the total clearance (Clt) were significantly decreased and the beta phase half-life (t 1/2) and the volume of central compartment (V1) were significantly increased at the 600 mg/kg dose level. In 21-day-old guinea pigs, beta and K10 were significantly decreased and t1/2 and V1 were significantly increased at doses of both 200 mg/kg and 600 mg/kg. In 42-day-old guinea pigs, however, only V1 and the volume of distribution at steady-state (Vss) showed significant increase after increasing doses. The extraction ratio (E) and the clearance of unbound drug (Clu), which were calculated based on unbound plasma levels, indicate that the dose-dependent kinetics of VPA are probably due to saturation of metabolism and that the metabolic capacity for VPA in the newborn group is the smallest among all groups.