Changes in pharmacokinetics of valproic acid in guinea pigs from birth to maturity

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)