Kodama Y, Kuranari M, Teraoka I, Fujii I, Takeyama M
Department of Clinical Pharmacy, Oita Medical University, Japan.
Int J Clin Pharmacol Ther Toxicol. 1993 Nov;31(11):529-32.
In the previous study, we determined the in vivo binding parameters of valproic acid to serum proteins in seven healthy young adults at steady-state. In this study, we determined the effects of serum protein binding on hepatic elimination with the use of observed data obtained from our previous study of valproic acid. A regression analysis between the binding parameters and the pharmacokinetic parameters was performed. In addition, the relationship between each pharmacokinetic parameter was also analyzed. The order of association constant (K) for valproic acid-serum protein was 10(-2) l/mumol. No significant correlation was found between the binding parameters and the rate of elimination. On the other hand, the average unbound serum concentration was found to be a significantly negative correlation with the unbound (intrinsic) clearance (p = 0.0082). The product of association constant and concentration of free protein (P) correlated positively with the unbound clearance (p = 0.0233) and negatively with the average unbound and total serum concentrations (p = 0.0021 and p = 0.0029, respectively). The results indicate that the membrane permeability of valproic acid is high and that the increase of unbound clearance accompanies directly the decrease of the average unbound and total serum concentrations. Consequently, the KP values are proportional to the unbound clearance due to the rapid changes of the concentration of free protein. Therefore, the dissociation of the valproic acid-serum protein complex is not a rate-limiting factor for hepatic elimination and hence the serum protein binding cannot limit the ability of the liver to extract drug from blood.
在之前的研究中，我们测定了7名健康年轻成年人在稳态时丙戊酸与血清蛋白的体内结合参数。在本研究中，我们利用先前对丙戊酸研究获得的观测数据，测定了血清蛋白结合对肝脏清除的影响。对结合参数和药代动力学参数进行了回归分析。此外，还分析了各药代动力学参数之间的关系。丙戊酸 - 血清蛋白的缔合常数（K）顺序为10^(-2) l/μmol。未发现结合参数与消除速率之间存在显著相关性。另一方面，发现平均未结合血清浓度与未结合（内在）清除率呈显著负相关（p = 0.0082）。缔合常数与游离蛋白浓度（P）的乘积与未结合清除率呈正相关（p = 0.0233），与平均未结合和总血清浓度呈负相关（分别为p = 0.0021和p = 0.0029）。结果表明丙戊酸的膜通透性较高，未结合清除率的增加直接伴随着平均未结合和总血清浓度的降低。因此，由于游离蛋白浓度的快速变化，KP值与未结合清除率成正比。所以，丙戊酸 - 血清蛋白复合物的解离不是肝脏清除的限速因素，因此血清蛋白结合不会限制肝脏从血液中提取药物的能力。
