Dose-dependent inhibition in plasma protein binding of valproic acid during continued treatment in guinea-pigs.

Plasma protein binding of valproic acid over a wide range of steady-state plasma concentration (11.3 +/- 2.6-1303.0 +/- 122.9 micrograms 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 micrograms mL-1, where the Cb was 152.5 +/- 26.8 micrograms mL-1. At a Css of 1303.3 +/- 122.9 micrograms mL-1 the Cb was significantly (P less than 0.05) decreased to 72.8 +/- 20.2 micrograms mL-1. Binding characteristics of valproic acid in-vitro were studied using drug-free guinea-pig plasma with added valproic acid (10-1000 micrograms 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.