title: Pharmacokinetics of free and total sodium valproate in adolescents and young adults during maintenance therapy.
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.
authors.affiliation: Department of Clinical Pharmacology, Karolinska Hospital, Stockholm, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Herngren
authors.forename: A
authors.initials: A
authors.lastname: Nergårdh
mesh_terms: D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000627:therapeutic use*; D001798:Blood Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008297:Male; D014635:Valproic Acid / Q000493:pharmacokinetics*
chemical_list: D000927:Anticonvulsants; D001798:Blood Proteins; D014635:Valproic Acid