Can the serum protein binding of valproic acid limit the hepatic elimination?

In the previous study, we determined the in vivo binding parameters of valproic acid to serum proteins in seven healthy young adults at steady-state. In this study, we determined the effects of serum protein binding on hepatic elimination with the use of observed data obtained from our previous study of valproic acid. A regression analysis between the binding parameters and the pharmacokinetic parameters was performed. In addition, the relationship between each pharmacokinetic parameter was also analyzed. The order of association constant (K) for valproic acid-serum protein was 10(-2) l/mumol. No significant correlation was found between the binding parameters and the rate of elimination. On the other hand, the average unbound serum concentration was found to be a significantly negative correlation with the unbound (intrinsic) clearance (p = 0.0082). The product of association constant and concentration of free protein (P) correlated positively with the unbound clearance (p = 0.0233) and negatively with the average unbound and total serum concentrations (p = 0.0021 and p = 0.0029, respectively). The results indicate that the membrane permeability of valproic acid is high and that the increase of unbound clearance accompanies directly the decrease of the average unbound and total serum concentrations. Consequently, the KP values are proportional to the unbound clearance due to the rapid changes of the concentration of free protein. Therefore, the dissociation of the valproic acid-serum protein complex is not a rate-limiting factor for hepatic elimination and hence the serum protein binding cannot limit the ability of the liver to extract drug from blood.