Yu H Y, Shen Y Z
School of Pharmacy, National Taiwan University, Taipei, Republic of China.
Biopharm Drug Dispos. 1996 Apr;17(3):237-47. doi: 10.1002/(SICI)1099-081X(199604)17:3<237::AID-BDD950>3.0.CO;2-R.
The response of steady-state distribution volume (Vdss 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 C(uss) for unbound drug) and various tissues (CT) were determined. The Vdss and the Vdssu were estimated based upon the apparent tissue-to-plasma concentration ratio of VPA. The results showed that the plasma unbound fraction (fu) of VPA increased significantly with dose. The Vdss was significantly increased with, while the Vdssu was significantly decreased against the increasing dose. The increase in Vdss 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 Vdssu 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.
在豚鼠中研究了丙戊酸（VPA）的稳态分布容积（总药物的Vdss和游离药物的Vdssu）对剂量依赖性血浆蛋白结合的反应。通过静脉恒速输注达到不同的VPA稳态血浆浓度。测定了血浆中VPA的浓度（总药物的Css和游离药物的C(uss)）以及各种组织中的浓度（CT）。基于VPA的表观组织与血浆浓度比估算Vdss和Vdssu。结果表明，VPA的血浆游离分数（fu）随剂量显著增加。Vdss随剂量显著增加，而Vdssu随剂量增加显著降低。Vdss随剂量增加表明组织与血浆浓度比增加，这可能归因于非线性血浆蛋白结合后游离药物从血浆向组织分布的增加。Vdssu随剂量增加而降低表明组织与游离血浆浓度比降低，这表明游离VPA的血管外分布可能受容量限制，且VPA的组织结合可忽略不计。
