Nonlinear elimination and cholerteic effect of valproic acid in the monkey

Five adult cynomolgus monkeys (Macaca fascicularis) were each given doses of 15 and 150 mg/kg of sodium valproate on separate occasions through indwelling arterial or venous catheters. Timed samples of blood (0-1440 min) and urine were collected for measurement of free and conjugated valproic acid (VPA). In all animals a brief distribution (alpha) phase, complete by 10 to 15 min, was followed by a biphasic decline in concentration of the drug. The times required for the concentration of VPA in blood at 25 min to decline by 50% were 42.4 +/- 2.6 (S.E.) min and 94 +/- 7.5 (S.E.) min at the 15 and 150 mg/kg doses, respectively. The terminal half-lives (T 1/2) were 345 +/- 46 (S.E.) min and 428 +/- 56 (S.E.) min at the low and high dose, respectively. In contrast to our earlier studies in the rat, surgical exteriorization of the bile did not alter the elimination profile of VPA from the blood of the monkey. Only 3 to 7% of the administered dose of the drug appeared as conjugated VPA in the bile (c.f. 60% in the rat), thereby confirming that enterohepatic circulation of VPA was of minor importance in determining the pattern of elimination of the drug from blood in the monkey. Urinary excretion of conjugated VPA in intact and bile-exteriorized monkeys totaled 56 and 52% of the 15 mg/kg dose and 60 and 63% of the 150 mg/kg dose, respectively. In monkeys, as in rats, sodium valproate caused a dose-dependent, immediate choleretic reponse, the duration of which followed the blood concentration of the drug.