Effect of dose on the kinetic behaviour of valproic acid: modifications in plasma protein binding

A study was made of the kinetic behaviour of valproic acid (VPA) given as a single dose to 9 healthy adult volunteers receiving three different doses of the drug (Group A, 1000 mg; Group B, 2000 mg and Group C, 3000 mg), according to a compensated cross-over design. Blood samples were withdrawn at programmed times, determining the total and free plasma levels of VPA with an immunoenzymatic technique (EMIT). The time course of the plasma levels was fitted to a two-compartmental kinetic model. Of all the pharmacokinetic parameters studied, statistically significant differences were only found in the area under the curve, normalized with dose, both of the total (AUC/D)T and free (AUC/C)L plasma levels. The differences found in this parameter, which globally describes the kinetic behaviour of a drug, were only observed in the individuals receiving the dose of 3000 mg. Regarding Vd, although there were no statistically significant differences among the three groups, tended to increase in Group C. This can be attributed to the significant increase undergone by the free fraction of VPA (FL), determined the relationship between the AUC of free and total plasma levels, as the dose administered is increased. The increase in the free fraction of drug with dose is due to the fact that VPA binding to plasma proteins becomes saturated when the total drug levels surpass 100 micrograms/ml. Assuming Michaelian-type kinetics for plasma protein binding, a relationship was established between the FL and total VPA plasma levels.(ABSTRACT TRUNCATED AT 250 WORDS)