Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore.
College of Pharmacy, Shenzhen Technology University, Shenzhen 518118, China.
Int J Mol Sci. 2022 Jun 25;23(13):7083. doi: 10.3390/ijms23137083.
The immediate and delayed metabolic changes in rats treated with valproate (VPA), a drug used for the treatment of epilepsy, were profiled. An established approach using dried blood spots (DBS) as sample matrices for gas chromatography/mass spectrometry-based metabolomics profiling was modified using double solvents in the extraction of analytes. With the modified method, some of the previously undetectable metabolites were recovered and subtle differences in the metabolic changes upon exposure to a single dose of VPA between males and female rats were identified. In male rats, changes in 2-hydroxybutyric acid, pipecolic acid, tetratriacontane and stearic acid were found between the control and treatment groups at various time points from 2.5 h up to 24 h. In contrast, such differences were not observed in female rats, which could be caused by the vast inter-individual variations in metabolite levels within the female group. Based on the measured DBS drug concentrations, clearance and apparent volume of distribution of VPA were estimated and the values were found to be comparable to those estimated previously from full blood drug concentrations. The current study indicated that DBS is a powerful tool to monitor drug levels and metabolic changes in response to drug treatment.
本文对用做抗癫痫药物的丙戊酸钠（VPA）处理的大鼠的即时和延迟代谢变化进行了分析。本研究通过在提取分析物时使用双溶剂对已建立的使用干血斑（DBS）作为气相色谱/质谱代谢组学分析样本基质的方法进行了改进。采用改进后的方法，回收了一些以前无法检测到的代谢物，并确定了雄性和雌性大鼠单次暴露于 VPA 时代谢变化的细微差异。在雄性大鼠中，在 2.5 小时至 24 小时的不同时间点，在对照组和治疗组之间发现了 2-羟基丁酸、哌可酸、二十四烷和硬脂酸的变化。相比之下，在雌性大鼠中未观察到这种差异，这可能是由于雌性大鼠中代谢物水平的个体间差异很大所致。基于测量的 DBS 药物浓度，估算了 VPA 的清除率和表观分布容积，并且发现这些值与以前从全血药物浓度估算的值相当。本研究表明，DBS 是监测药物水平和药物治疗反应代谢变化的有力工具。
