Yu H Y, Wu M S, Shen Y Z
School of Pharmacy, College of Medicine, National Taiwan University, Taipei, R.O.C.
Biopharm Drug Dispos. 1993 May;14(4):297-312. doi: 10.1002/bdd.2510140404.
The plasma clearance and metabolic rate characteristics of valproic acid (VPA) were studied using guinea-pigs placed on various (0.08-9 mumol ml-1 = 11-1303 micrograms ml-1) steady-state plasma concentrations (Css) by constant intravenous (i.v.) infusion. The total clearance (CL) was significantly decreased at plasma concentration of 0.61 mumol ml-1 (88 micrograms ml-1). The metabolic clearance of VPA was apparently biphasic. The maximum metabolic rate (Vmax) and the Michaelis-Menten constant (Km) for the primary (Vmax1, Km1) and the secondary (Vmax2, Km2) pathways were Vmax1 = 1.52 mumol min-1 kg-1, Km1 = 0.15 mumol ml-1, Vmax2 = 24.98 mumol min-1 kg-1 and Km2 = 11.70 mumol ml-1, respectively. The Km1 value was within clinical therapeutic concentration range. The formation of conjugated VPA (cjVPA) metabolite in liver was shown to be saturable. Plasma protein binding of VPA was also nonlinear. The dose-dependent decrease in metabolic clearance was counterbalanced by the increased unbound fraction (fu), resulting in a relatively constant apparent clearance of VPA over a wide concentration range. The hepatic concentration of VPA was not significantly different from the plasma unbound concentration, again over a wide concentration range. The biliary and hepatic concentrations of VPA were not significantly different; but the concentration ratio of cjVPA in bile compared with that of VPA in liver decreased against hepatic concentration of VPA, which suggests a saturable conjugation rate. The Km value estimated from hepatic cjVPA production as a function of plasma VPA concentration was comparable with the Km1 value.(ABSTRACT TRUNCATED AT 250 WORDS)
通过静脉恒速输注，对处于不同稳态血浆浓度（Css为0.08 - 9 μmol/ml = 11 - 1303 μg/ml）的豚鼠进行研究，以了解丙戊酸（VPA）的血浆清除率和代谢率特征。当血浆浓度为0.61 μmol/ml（88 μg/ml）时，总清除率（CL）显著降低。VPA的代谢清除率明显呈双相性。初级途径（Vmax1，Km1）和次级途径（Vmax2，Km2）的最大代谢率（Vmax）和米氏常数（Km）分别为Vmax1 = 1.52 μmol·min⁻¹·kg⁻¹，Km1 = 0.15 μmol/ml，Vmax2 = 24.98 μmol·min⁻¹·kg⁻¹，Km2 = 11.70 μmol/ml。Km1值处于临床治疗浓度范围内。肝脏中结合型VPA（cjVPA）代谢物的形成表现为饱和性。VPA的血浆蛋白结合也呈非线性。代谢清除率随剂量的降低被未结合分数（fu）的增加所抵消，导致在较宽浓度范围内VPA的表观清除率相对恒定。在较宽浓度范围内，VPA的肝脏浓度与血浆未结合浓度无显著差异。VPA的胆汁浓度和肝脏浓度无显著差异；但胆汁中cjVPA与肝脏中VPA的浓度比随肝脏VPA浓度的升高而降低，这表明结合率具有饱和性。根据肝脏cjVPA生成量作为血浆VPA浓度函数估算的Km值与Km1值相当。（摘要截选至250字）
