Physiologically based pharmacokinetics of valproic acid in rabbits

Abstract

Protein-binding parameters of valproic acid (VPA) in rabbit serum were determined. Due to the non-linear binding, the binding percentage decreased from 91 to 41% when the serum concentration of VPA rose from 10 to 1000 μg/ml. The hepatic clearance of VPA as unbound drug followed Michaelis-Menten kinetics. A physiologically based pharmacokinetics model was adopted to interpret the overall disposition of VPA in rabbits which incorporated the non-linear plasma protein binding and non-linear intrinsic hepatic clearance. The predicted plasma and tissue concentrations were found to be in good agreement with the observed concentrations. The reason why the plasma concentration versus time curves appear to be apparently parallel in spite of remarkable changes in the unbound concentration among three different doses could be explained by the association effects in which an increase in the total plasma concentration may produce a decrease in intrinsic hepatic clearance consistent with Michaelis-Menten kinetics resulting in an increase in the unbound fraction of VPA in plasma.