Li Zhihong, Gao Weiqi, Liu Guifen, Chen Weihong
*Department of Health Statistics, School of Public Health, Shanxi Medical University; and †Department of Pharmacy, Shanxi Da Yi Hospital, Affiliated Da Yi Hospital of Shanxi Medical University, Taiyuan, China.
Ther Drug Monit. 2017 Aug;39(4):450-456. doi: 10.1097/FTD.0000000000000424.
Valproic acid (VPA) has been widely used in Chinese patients after craniotomy. Many studies have focused on the influencing factors of VPA serum concentration, but conclusions are sometimes paradoxical. Furthermore, the concentration of VPA in the cerebrospinal fluid (CSF) has been rarely reported. In the present study, VPA CSF concentrations were measured, and the potential factors influencing serum concentration and CSF distribution of VPA were investigated. In addition, the functional relationship between serum and CSF concentration was explored.
Subjects were patients who underwent craniotomy and were administrated with VPA and had a lumbar puncture. Serum and CSF VPA concentrations were measured by use of the Abbott i1000 system. CYP2C9 (430 C>T, 1075 A>C, 1076 T>C, 1080 C>G), UGT1A6 (541 A>G, 552 A>C), UGT2B7 (211 G>T, 802 C>T), and ABCB1 (1236 C>T, 2677 G>T/A, 3435 C>T) genotypes were determined by direct sequencing. Information, such as age, gender, and height, was collected, and their effect on serum and CSF VPA concentrations was investigated by univariate analysis and multiple linear regression analysis.
First, the concomitant use of carbapenems (β' = -0.422) and UGT1A6 (552 AA → AC) (β' = -0.249) had a significant negative correlation with the weight-adjusted VPA serum concentration (C:W ratio), whereas CYP2C9 (1075 AA → AC) (β' = 0.186) and gender (female compared with male) (β' = 0.322) showed a positive correlation with VPA serum C:W ratio. The coefficient of determination (R) was only 0.348. Second, the relationship between the serum concentration and the CSF square root of the concentration (R = 0.705) had a better linear fit. Third, serum VPA concentration (β' = 0.810), concomitant use of glycerol fructose (β' = 0.160), and age (≥65 compared with <65) (β' = 0.118) showed a positive correlation (R = 0.748) with the variability of square root of the concentration of the CSF.
In Chinese patients, after craniotomy, female patients with 1 or more of CYP2C9 (1075 AC) and UGT1A6 (552 AA) genotypes required a lower VPA dosage compared with male patient. There was a better-fitted linear relationship between VPA serum and the square root of CSF concentrations. CSF VPA concentrations were relatively stable, with only age and the use of glycerol fructose having a small influence.
丙戊酸（VPA）在中国开颅术后患者中已被广泛使用。许多研究聚焦于VPA血清浓度的影响因素，但结论有时相互矛盾。此外，脑脊液（CSF）中VPA的浓度鲜有报道。在本研究中，测量了VPA脑脊液浓度，并调查了影响VPA血清浓度和脑脊液分布的潜在因素。此外，还探索了血清与脑脊液浓度之间的函数关系。
研究对象为接受开颅手术并服用VPA且进行了腰椎穿刺的患者。使用雅培i1000系统测量血清和脑脊液VPA浓度。通过直接测序确定CYP2C9（430 C>T、1075 A>C、1076 T>C、1080 C>G）、UGT1A6（541 A>G、552 A>C）、UGT2B7（211 G>T、802 C>T）和ABCB1（1236 C>T、2677 G>T/A、3435 C>T）基因的基因型。收集年龄、性别和身高信息等，并通过单因素分析和多元线性回归分析研究它们对血清和脑脊液VPA浓度的影响。
首先，碳青霉烯类药物的联合使用（β' = -0.422）和UGT1A6（552 AA → AC）（β' = -0.249）与体重校正的VPA血清浓度（C:W比值）呈显著负相关，而CYP2C9（1075 AA → AC）（β' = 0.186）和性别（女性与男性相比）（β' = 0.322）与VPA血清C:W比值呈正相关。决定系数（R）仅为0.348。其次，血清浓度与脑脊液浓度的平方根之间的关系（R = 0.705）具有更好的线性拟合。第三，血清VPA浓度（β' = 0.810）、甘油果糖的联合使用（β' = 0.160）和年龄（≥65岁与<65岁相比）（β' = 0.118）与脑脊液浓度平方根的变异性呈正相关（R = 0.748）。
在中国开颅术后患者中，具有1种或更多CYP2C9（1075 AC）和UGT1A6（552 AA）基因型的女性患者与男性患者相比，所需的VPA剂量较低。VPA血清浓度与脑脊液浓度的平方根之间存在拟合较好的线性关系。脑脊液VPA浓度相对稳定，仅年龄和甘油果糖的使用有较小影响。
