Yu H Y
Ther Drug Monit. 1984;6(4):414-23. doi: 10.1097/00007691-198412000-00006.
Steady-state serum levels of total and unbound valproic acid as well as unbound fraction in epileptic children were studied in a clinical setting. Valproic acid binding parameters were analyzed and compared with in vitro findings. Daily dose of sodium valproate ranging from 29 to 73 mg/kg/day were administered per os. Considerable variation in total and unbound concentrations and unbound fractions within and between subjects was observed. In subjects evaluated in this study, serum level of total and unbound valproic acid ranged from 279 to 1,196 mumol/L and from 37 to 410 mumol/L, respectively. The unbound fraction ranged from 10.32 to 48.39%. In vivo binding parameters obtained from clinical material were as follows: association constant, Ka = 4.984 L/mmol; total binding sites, NP = 1.451 mmol/L, where P is the molar concentration of albumin; number of binding sites per molecule of albumin, N = 2.48. Using spiked sera, binding parameters of Ka = 8.032 L/mmol, NP = 1.262 mmol/L, and N = 1.86 were found in the in vitro study. The association constant obtained from in vivo and in vitro studies were not significantly different (p greater than 0.05) from each other. The unbound fraction of valproic acid was concentration dependent even within the therapeutic range. An equation for estimating unbound concentration (Cf') or unbound fraction (fp') from total concentration (Ct) of valproic acid is derived. The ratio of observed unbound fraction to the estimated unbound fraction (fp/fp') was used to evaluate the variation in valproate serum binding of that clinical sample. Nine samples from hospitalized patients whose medication and diet were closely supervised showed an fp/fp' ratio very close to 1 (mean +/- SD 1.04 +/- 0.24). It is suggested that a clinical sample showing a value of fp/fp' greater than 1.76 (mean + 3 SD) should be evaluated for the cause of the decrease in serum binding and for the associated pharmacokinetic alterations. Therefore, in clinical monitoring of valproate, determination of both total and unbound drug levels was preferable to determination of either one alone. Furthermore, an understanding of the unbound fraction of valproic acid would significantly contribute to the effective management of epileptic patients.
在临床环境中研究了癫痫患儿丙戊酸的稳态血清总水平、游离水平以及游离分数。分析了丙戊酸的结合参数，并与体外研究结果进行比较。口服丙戊酸钠的日剂量范围为29至73mg/kg/天。观察到受试者体内以及受试者之间丙戊酸的总浓度、游离浓度和游离分数存在相当大的差异。在本研究评估的受试者中，丙戊酸的血清总水平和游离水平分别为279至1196μmol/L和37至410μmol/L。游离分数范围为10.32%至48.39%。从临床材料获得的体内结合参数如下：缔合常数，Ka = 4.984L/mmol；总结合位点，NP = 1.451mmol/L，其中P是白蛋白的摩尔浓度；每个白蛋白分子的结合位点数，N = 2.48。在体外研究中，使用加标血清发现结合参数为Ka = 8.032L/mmol、NP = 1.262mmol/L和N = 1.86。体内和体外研究获得的缔合常数彼此之间无显著差异（p大于0.05）。即使在治疗范围内，丙戊酸的游离分数也与浓度相关。推导了一个根据丙戊酸总浓度（Ct）估算游离浓度（Cf'）或游离分数（fp'）的方程。观察到的游离分数与估算的游离分数之比（fp/fp'）用于评估该临床样本中丙戊酸血清结合的变化。来自住院患者的9个样本，其用药和饮食受到密切监测，显示fp/fp'比值非常接近1（平均值±标准差1.04±0.24）。建议对显示fp/fp'值大于1.76（平均值+3标准差）的临床样本进行血清结合降低原因及相关药代动力学改变的评估。因此，在丙戊酸的临床监测中，同时测定总药物水平和游离药物水平比单独测定其中任何一个更可取。此外，了解丙戊酸的游离分数将显著有助于癫痫患者的有效管理。
