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 (V_dss for total and V_dssu 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 (C_ss for total and C_uss for unbound drug) and various tissues (C_T) were determined. The V_dss and the V_dssu were estimated based upon the apparent tissue-to-plasma concentration ratio of VPA. The results showed that the plasma unbound fraction (f_u) of VPA increased significantly with dose. The V_dss was significantly increased with, while the V_dssu was significantly decreased against the increasing dose. The increase in V_dss 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 V_dssu 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.