Abstract
The pharmacokinetics of total and free valproic acid (VPA) in plasma and whole blood was investigated in seven adolescents and young adults (mean age 17.3 years) during a dosage interval at steady state. The concentration curves of VPA in whole blood after an oral morning dose (mean 8.2 mg/kg body wt.) closely followed those in plasma but at a reduced level. The apparent volume of distribution (Vd) of total VPA was 0.150-0.197 l/kg body wt. and of free VPA 0.911-1.58 l/kg body wt., which indicates considerable distribution of unbound VPA as well as drug binding to extravascular proteins. The terminal half-life of free VPA (6.4-6.7 h) was significantly shorter (P less than 0.05) than the half-life of total VPA (10.4-11.9 h). The binding of VPA in plasma was concentration dependent and fluctuated considerably within the individual dosage intervals. Concentrations of unbound VPA in plasma water of whole blood varied to a corresponding degree, since distribution to blood cells was low (mean 2.2%). It is concluded that there are substantial differences in the pharmacokinetics of free and total VPA. This may contribute to the well-known poor correlation between dose, plasma concentrations and effect of VPA.
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