Dose-dependent Inhibition in Plasma Protein Binding of Valproic Acid During Continued Treatment in Guinea-pigs

Abstract

Abstract Plasma protein binding of valproic acid over a wide range of steady-state plasma concentration (11·3 α 2·6–130·3–0 α 122·9 μg mL−1: s.e.m., n = 5) in guinea-pigs has been studied. Valproic acid was given by intravenous constant infusion. At steady-state the plasma protein binding of valproic acid was analysed. Nonlinear binding was observed. Unbound fraction (fu) of valproic acid increased from 25 to 95% with the increase of steady-state plasma concentration (Css). The plasma protein-bound drug concentration (Cb) of valproic acid increased initially with Css but decreased after the Css exceeded 345·0 μg mL−1, where the Cb was 152·5 α 26·8 μg mL−1. At a Css of 1303·3 α 122·9 μg mL−1 the Cb was significantly (P < 0·05) decreased to 72·8 α 20·2 μg mL−1. Binding characteristics of valproic acid in-vitro were studied using drug-free guinea-pig plasma with added valproic acid (10–1000 μg mL−1). The binding behaviour was also nonlinear in-vitro. The fu increased from 14 to 79% with the increase of valproate concentrations. No decrease in Cb was observed throughout the range. The study demonstrated that binding characteristics of valproic acid in-vivo and in-vitro are not parallel. The results suggest that valproic acid may produce or induce plasma protein binding competitors; metabolites of valproic acid may be implicated.