Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, China.
Department of Pharmacy, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Basic Clin Pharmacol Toxicol. 2018 Nov;123(5):628-634. doi: 10.1111/bcpt.13049. Epub 2018 Jul 19.
This study was aimed at identifying genetic and non-genetic risk factors for valproic acid (VPA)-induced hyperammonaemia in Chinese paediatric patients with epilepsy. A total of 210 epileptic patients, treated with VPA as monotherapy, were enrolled and classified into hyperammonaemia and control groups according to their blood ammonia level (cut-off value 50 μmol/L). Serum concentrations of VPA and its major metabolites were simultaneously determined by ultrahigh-performance liquid chromatography-tandem mass spectrometry. Six single nucleotide polymorphisms in the candidate genes, CYP2C9, CYP2A6, CYP2B6 and CPS1, were analysed by a matrix-assisted laser desorption ionization-time of flight mass spectrometry method or nested PCR. Significant differences in age, aspartate transaminase level and the incidence of liver injury were observed between patients of hyperammonaemia and control groups. Genotype distributions of CYP2C93, CYP2A64 and CPS1 4217C>A allelic variants were also significantly different between the two groups. According to multiple regression analysis, a significant negative correlation was detected between age and the blood ammonia level, while liver injury, the concentration-dose ratio (CDR) of VPA and 2-propyl-4-pentenoic acid (4-ene VPA), and the presence of CYP2A64 or CPS1 4217C>A showed positive correlations with the blood ammonia level. In addition, the risk factors for hyperammonaemia identified by logistic regression analysis were as follows: a younger age (odds ratio [OR] = 0.85; 95% confidence interval [CI] = 0.76-0.96; p = 0.007), occurrence of liver injury (OR = 4.60; 95% CI = 1.27-16.74; p = 0.021), higher CDR of 4-ene VPA (OR = 1.08; 95% CI = 1.03-1.14; p = 0.001), and carrying mutant alleles of CYP2C93 (OR = 3.42; 95% CI = 1.15-10.19; p = 0.028), CYP2A6*4 (OR = 3.23; 95% CI = 1.40-7.48; p = 0.006) and CPS1 4217C>A (OR = 3.25; 95% CI = 1.52-6.94; p = 0.002). Our findings indicated that multiple genetic and non-genetic risk factors that were identified can be used to predict the development of VPA-induced hyperammonaemia in Chinese paediatric patients with epilepsy.
本研究旨在确定中国儿科癫痫患者丙戊酸（VPA）诱导高氨血症的遗传和非遗传风险因素。共纳入 210 例接受 VPA 单药治疗的癫痫患者，根据血氨水平（截断值 50μmol/L）将其分为高氨血症组和对照组。采用超高效液相色谱-串联质谱法同时测定 VPA 及其主要代谢物的血清浓度。采用基质辅助激光解吸电离飞行时间质谱法或巢式 PCR 分析候选基因 CYP2C9、CYP2A6、CYP2B6 和 CPS1 中的 6 个单核苷酸多态性。高氨血症组和对照组患者的年龄、天冬氨酸转氨酶水平和肝损伤发生率存在显著差异。两组 CYP2C93、CYP2A64 和 CPS1 4217C>A 等位基因分布也存在显著差异。根据多元回归分析，年龄与血氨水平呈显著负相关，而肝损伤、VPA 浓度-剂量比（CDR）和 2-丙基-4-戊烯酸（4-ene VPA）以及 CYP2A64 或 CPS1 4217C>A 的存在与血氨水平呈正相关。此外，逻辑回归分析确定的高氨血症危险因素如下：年龄较小（比值比[OR] = 0.85；95%置信区间[CI] = 0.76-0.96；p = 0.007）、发生肝损伤（OR = 4.60；95%CI = 1.27-16.74；p = 0.021）、4-ene VPA 的 CDR 较高（OR = 1.08；95%CI = 1.03-1.14；p = 0.001）和携带 CYP2C93 突变等位基因（OR = 3.42；95%CI = 1.15-10.19；p = 0.028）、CYP2A6*4（OR = 3.23；95%CI = 1.40-7.48；p = 0.006）和 CPS1 4217C>A（OR = 3.25；95%CI = 1.52-6.94；p = 0.002）。我们的研究结果表明，鉴定出的多种遗传和非遗传危险因素可用于预测中国儿科癫痫患者 VPA 诱导高氨血症的发生。
