Dose-dependent distribution volumes of total and unbound valproate in guinea-pigs: consequence of non-linear plasma protein binding.

The response of steady-state distribution volume (Vdss for total and Vdssu for unbound drug) of valproate (VPA) to dose-dependent plasma protein binding was studied in guinea-pigs. Various steady-state plasma concentrations of VPA were achieved by intravenous constant infusion. The concentrations of VPA in plasma (Css for total and C(uss) for unbound drug) and various tissues (CT) were determined. The Vdss and the Vdssu were estimated based upon the apparent tissue-to-plasma concentration ratio of VPA. The results showed that the plasma unbound fraction (fu) of VPA increased significantly with dose. The Vdss was significantly increased with, while the Vdssu was significantly decreased against the increasing dose. The increase in Vdss with dose indicated an increase in tissue-to-plasma concentration ratio, which may be attributed to the increase in distribution of unbound drug from plasma to tissues subsequent to non-linear plasma protein binding. The decrease in Vdssu against the increasing dose indicated a decrease in tissue-to-unbound plasma concentration ratio, which suggests that the extravascular distribution of unbound VPA might be capacity limited and the tissue binding of VPA negligible.