DOSE-DEPENDENT DISTRIBUTION VOLUMES OF TOTAL AND UNBOUND VALPROATE IN GUINEA-PIGS: CONSEQUENCE OF NON-LINEAR PLASMA PROTEIN BINDING
✍ Scribed by Hsui-Ying Yu; Yu-Zen Shen
- Publisher
- John Wiley and Sons
- Year
- 1996
- Tongue
- English
- Weight
- 475 KB
- Volume
- 17
- Category
- Article
- ISSN
- 0142-2782
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✦ Synopsis
The response of steady-state distribution volume (V,, for total and Vdssu for unbound drug) of valproate (VPA) to dose-dependent plasma protein binding was studied in guinea-pigs. Various steady-state plasma concentrations of VPA were achieved by intravenous constant infusion. The concentrations of VPA in plasma (Css for total and Cuss for unbound drug) and various tissues (C,) were determined. The Vd,, and the Vd, were estimated based upon the apparent tissue-to-plasma concentration ratio of VPA. The results showed that the plasma unbound fraction V;) of VPA increased significantly with dose. The V, , was significantly increased with, while the Vd,,, was significantly decreased against the increasing dose. The increase in Vd,, with dose indicated an increase in tissue-to-plasma concentration ratio, which may be attributed to the increase in distribution of unbound drug from plasma to tissues subsequent to non-linear plasma protein binding. The decrease in Vdm against the increasing dose indicated a decrease in tissue-to-unbound plasma concentration ratio, which suggests that the extravascular distribution of unbound VPA might be capacity limited and the tissue binding of VPA negligible.