M Hanano

Changes in Pharmacokinetics of Valproic Acid in Guinea Pigs from Birth to Maturity

Summary: 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 fürther divided into two to three subgrups. 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 < 0.01) longer elimination half‐life (t1/2) in guinea pigs <10 days of age compared with other groups was observed. Total clearance (Cltot) was significantly smaller (p < 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 grups, but was significantly smallest (p < 0.01) in the adult group. In vitro study showed that the blood‐to‐plasma concentraction 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 μg/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. Therefore, lwo metabolic capacity, i. e., low intrinsic clearance, which was estimated from Cltot and fu, might be the mechanism for the long t1/2 of valproic acid in the suckling stage of guinea pigs.