Pharmacokinetics and enterohepatic circulation of 2-n-propyl-4-pentenoic acid in the rat.

The pharmacokinetics of 4-ene-valproic acid (4-ene-VPA), a putative hepatotoxic metabolite of the anticonvulsant valproic acid (VPA), were studied in normal and bile-exteriorized rats. A single iv bolus dose of 20 or 100 mg/kg of 4-ene-VPA was administered to each rat. Plasma decline of 4-ene-VPA was apparently monoexponential at the low dose and nonlinear at the high dose. In normal rats, 4-ene-VPA was recycled in the plasma due to enterohepatic circulation (EHC). A time lag pharmacokinetic model was used to describe the plasma profile, including the appearance of a secondary plasma peak, in normal animals receiving the low dose of 4-ene-VPA. Total apparent plasma clearance was 8.67 ml/min.kg at the low dose and 5.89 ml/min.kg at the high dose. EHC was abolished in bile-exteriorized animals. In these rats, the apparent plasma elimination half-life increased from 12.7 to 18.8 min and plasma clearance decreased from 11.4 to 7.41 ml/min.kg with a 5-fold increase in the dose. 4-ene-VPA was largely eliminated in urine and bile as conjugates. In normal rats, 22% and 28% of the low and high dose, respectively, were eliminated in urine. Approximately 29% of the low dose and 21% of the high dose were recovered in bile of the rat. Like the parent drug VPA, 4-ene VPA induced dose-dependent choleresis in the rat. The pharmacokinetics of 4-ene-VPA in the rat were similar to those reported for VPA.