Pharmacokinetic variations of valproic acid in guinea pigs from birth to maturity were investigated. Male guinea pigs were classified into three groups according to age, and each group was further divided into two to three subgroups. The suckling group included three subgroups of 3, 6, and 10 days of age; the juvenile group, three subgroups of 14, 21, and 28 days of age; and the adult group, two subgroups of 42 and 56 days of age. The bile was exteriorized to exclude the factor of enterohepatic circulation during the experiment. Pharmacokinetic parameters were studied and statistically analyzed after an intravenous single dose of 20 mg/kg of sodium valproate. A significantly (p less than 0.01) longer elimination half-life (t1/2) in guinea pigs less than 10 days of age compared with other groups was observed. Total clearance (Cltot) was significantly smaller (p less than 0.01) in the suckling group than in the juvenile group. Volume of distribution at steady state (Vss) was not significantly different between the suckling and juvenile groups, but was significantly smallest (p less than 0.01) in the adult group. In vitro study showed that the blood-to-plasma concentration ratio, ranging from 0.81 to 0.84, and the plasma unbound fraction (fu), ranging from 0.24 to 0.38, of valproic acid around therapeutic levels (50-100 micrograms/ml) were not significantly different among different age groups. It is obvious that the longer t1/2 in the suckling group is not related to either fu or Vss.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗

PubMedDate not supplied

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.

Aging↗

PubMedDate not supplied

Pharmacokinetic analysis of the disposition of valproate in pregnant rats.

Kinetic analysis of valproate (VPA) disposition in pregnant rats was performed. A dose-dependent saturable plasma elimination was observed in both the control and pregnant rats. Saturation was more remarkable in the pregnant rats and this was assumed to be due to the decreased hepatic extraction by metabolism. Pharmacokinetic parameters were calculated using a two-compartment open model with a Michaelis-Menten-type elimination process from the central compartment. In the pregnant rats, the calculated values of Km and Vmax decreased significantly, by one-half of those of the control rats, whereas no significant difference was observed in distribution rate constants (k12, k21) and volumes of distribution (V1, Vdss) between two groups of rats. Furthermore, the hepatic extraction of VPA in the control and pregnant rats was investigated in order to explain nonlinear pharmacokinetics of VPA. The values of the hepatic extraction ratio in the control and pregnant rats were 39.9 and 22.4% at the steady state concentration of approximately 20 micrograms/ml, respectively. The extraction ratios in the pregnant rats were lower than those of the control rats. This fact may be one of the reasons why the elimination of VPA in the pregnant rats is more susceptible to saturation.

Animals↗

PubMedDate not supplied

Drug interaction. Effects of salicylate on pharmacokinetics of valproic acid in rats.

The effects of salicylic acid on the pharmacokinetics of valproic acid were investigated in bile-exteriorized rats. A 50 mg/kg bolus dose of sodium valproate was injected iv to Long Evans rats with and without (control) prior treatment by constant infusion of salicylate to keep it at steady state plasma level (about 250 micrograms/ml). The plasma elimination of valproic acid followed a monoexponential decline in both salicylate-treated and control rats. A significant increase (p less than 0.01) in the disposition rate constant (kel), the volume of distribution (Vd), and the total clearance (Cltot) as well as a significant decrease (p less than 0.01) in the AUC and the elimination half-life (t1/2) were observed in the salicylate-treated rats. In spite of the significantly lowered total plasma level and increased unbound fraction of valproic acid in the salicylate-treated rats, there were no significant differences in unbound valproic plasma levels and unbound valproate pharmacokinetic parameters. The biliary excretion of unchanged and conjugated valproate was not significantly different between the two groups. The in vitro plasma-unbound fractions (fu) of valproic acid were significantly increased (p less than 0.01) in the presence of salicylic acid. The apparent dissociation constant of plasma protein binding for valproic acid was increased from 0.287 to 1.204 mM in the presence of salicylic acid. These findings indicate that the pharmacokinetic changes of valproic acid in the presence of salicylic acid were consistent with the elevation in the plasma-unbound fraction of valproic acid due to displacement from plasma protein-binding sites by salicylic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗