Application of the two-compartment open model with Michaelis-Menten elimination kinetics to valproic acid in the bile-exteriorized rat.

The concentration profile of valproic acid (VPA) in bile-exteriorized rats given an i.v. bolus of 15 mg sodium valproate (NaVPA) per kg has been previously shown to exhibit a limited distribution phase and first-order elimination kinetics (two-compartment open model). At a higher dose of 150 mg NaVPA/kg, the initial elimination was non-linear (capacity-limited). Using an 'iterative modified Euler integration technique,' the results have been fitted to a pharmacokinetic model which allows for both two-compartment redistribution of drug as well as saturable Michaelis-Menten elimination kinetics. A combined pharmacokinetic model of this type has not been previously described.