Disposition and pharmacokinetics of valproic acid in rats.

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Abstract
The initial decline in blood concentration of valproic acid (VPA) was followed by a first-order process in rats given the drug intravenously (i.v.) (60 mg/kg) or orally (80 mg/kg), but later a secondary increase in drug concentration, resulting from enterohepatic circulation of free and conjugated drugs, was observed. In order to describe the blood concentration pattern of VPA with its pronounced secondary peak, a pharmacokinetic model consisting of central, bile and intestinal compartments was applied. Inclusion in the model of n segments (n=4 in the i.v. dose and n=5 in the oral) of gut lumen for drug transfer from the bile compartment to the absorption compartment improved the agreement between observed and predicted plasma VPA levels. Measurements of the extent of biliary excretion and reabsorption of VPA from bile in bile duct-cannulated rats were done to calculate some parameters. The pharmacokinetic model was justified by the good agreement with observed data obtained after i.v. and oral administrations of VPA in rats. This model was considerably superior to a standard two-compartment pharmacokinetic model.