Pharmacokinetics of valproic acid in guinea-pigs with biliary abnormality

To explore whether biliary cannulation, biliary obstruction or gall bladder obstruction could alter the disposition of valproic acid, guinea-pigs were subjected to common bile duct cannulation or ligation, gall bladder-neck ligation or sham surgery as a control. They were then given an intravenous (i.v.) dose of sodium valproate (50 mg kg-1) and the pharmacokinetics of valproic acid in each group were compared. In the cannulated group, significant decreases (P less than 0.05) in the area under the elimination curve (AUC), the volume of distribution at steady-state (Vdss) and the mean residence time (MRT) were observed. Significant increases (P less than 0.05) in the elimination rate constant (kz) and total clearance (CLtot) of valproic acid were noted. In the biliary obstructed guinea-pigs, the Vdss was significantly decreased (P less than 0.05). In the gall bladder obstructed guinea-pigs, there was a secondary peak of valproate plasma concentration, and the kz was significantly decreased. The biliary excretion of unchanged and conjugated valproic acid was 2.0 +/- 0.7 (s.e.m.) and 19.7 +/- 3.6 (s.e.m.)% of dose, respectively, and was almost completely reabsorbed in the enterohepatic recycling. Urinary excretion of unchanged and conjugated valproic acid, as well as non-conjugate metabolic clearance of valproic acid, were not significantly different among the four groups. The results suggest that the pharmacokinetics of valproic acid in guinea-pigs are particularly sensitive to interruption of the enterohepatic cycle. Biliary obstruction may elevate plasma concentrations owing to the decreased Vdss of valproic acid. Gall bladder obstruction may cause fluctuation of valproate plasma concentrations. The data indicate that the apparent total clearance of valproic acid is significantly less than the intrinsic clearance owing to enterohepatic recycling.