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 stea dy-state. In this study, we determined the effects of serum protein bi nding on hepatic elimination with the use of observed data obtained fr om our previous study of valproic acid. A regression analysis between the binding parameters and the pharmacokinetic parameters was performe d. In addition, the relationship between each pharmacokinetic paramete r was also analyzed. The order of association constant (K) for valproi c acid-serum protein was 10(-2) 1/mu mol. No significant correlation w as found between the binding parameters and the rate of elimination. O n 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 concen tration of free protein (P) correlated positively with the unbound cle arance (p = 0.0233) and negatively with the average unbound and total serum concentrations (p = 0.0021 and p = 0.0029, respectively). The re sults indicate that the membrane permeability of valproic acid is high and that the increase of unbound clearance accompanies directly the d ecrease of the average unbound and total serum concentrations. Consequ ently, 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 b inding cannot limit the ability of the liver to extract drug from bloo d.