バルプロ酸単独服用患者における血清蛋白との結合

Abstract

Valproic acid is highly bound to serum protein, mainly albumin. Valproic acid exhibits concentration-dependent protein binding, which partly accounts for considerable variability in the unbound fraction, even within the therapeutic range. Therefore, valproic acidprotein interaction and determination of the corresponding binding parameters should be considered. In the present study, we investigated the binding characteristics in epileptic adults and children under valproic acid chronic monotherapy, and determined the binding parameters of valproic acid to serum protein.There was a curvilinear relationship between total and unbound concentrations orunbound fraction, using a second-degree polynomial equation. The unbound fraction increased curvilinearly in proportion to the increase in total concentration . Averages of unbound fraction obtained from adults and children were not significantly different from each other (P>0.05). The unbound fraction ranged from 4.1 to 16 .7% (adults), and from 5.6 to 16.7% (children). There were marked about three-fold variations of unbound fraction in both adults and children.On the other hand, as the Scatchard plot was shown to be linear in both adults and children, valproic acid was bound to only one class of binding sites on the protein molecule. The binding parameters calculated by Scatchard plot were as follows: association constants (Ka) were 1. 14×104l/mol (adults) and 1.44×104l/mol (children), total number of binding sites (n (Pt)) was 1.36×10-3mol/l (adults) and 1. 20×10-3mol/l (children). There was no significant difference in the two parameters between adults and children (P>0 .05). Therefore, we determined the binding parameters from all samples (n=96) by using Langmuir plot. These results showed that dissociation constant (Kd) was 3 .89×10-5mol/l, total number of binding sites (n (Pt)) was 8.46×10-4 mol/l.These results suggested that valproic acid had the same binding characteristics in both adults and children. The molecular interaction between valproic acid and serum albumin involved one class of binding sites within the investigated range.