本项目从解决基于质谱的非目标性代谢组学共性技术问题入手，以典型肾损伤化疗药物顺铂为研究对象，在前期研究发现的基础上，聚焦与顺铂肾损伤发生、发展密切关联的氧化应激代谢通路（包括甲硫氨酸-半胱氨酸循环、牛磺酸代谢和谷胱甘肽代谢等），采用稳定同位素衍生化标记/液质联用技术建立氧化应激代谢通路靶向分析方法，在此基础上分别筛选与肾损伤机制和毒性敏感性相关的生物标志物，构建肾毒性个体敏感性预测模型，进而运用申请者首次提出的代谢组进程动力学新策略，从个体代谢物和整体代谢组两个角度对顺铂肾损伤进行动态、整体评价。本研究将丰富和完善药物代谢组学研究理论和方法，推动其从 “粗线条表征”向“精细化描绘”、从“静态”向“动态”、 从“诊断评价”向“预警预测”的方向发展；相关研究发现也将为药物毒性机制和药物安全性预测研究提供新的思路和示范，对于推动药物早期成药性评价研究、提高临床安全用药水平具有重要意义。

Our previous non-targeted metabolomics study has revealed that the oxidative stress pathways (OSPs, including methionine-cysteine cycle, taurine pathway, glutathione pathway, etc.) were closely related to the nephrotoxicity induced by cisplatin, a typical renal injurious chemotherapy drug. In order to break through the common technical barriers in mass spectrometry based non-targeted metabolomics. In this project, focusing on OSPs, a liquid chromatography-mass spectrometry based targeted mtabolomics method will be developed using stable isotope labeling in combination. After that, the biomarkers related to the mechanism of nephrotoxicity and toxical sensitivity will be screened out for further identification, separately. A prediction model for individual sensitivity of nephrotoxicity will also be constructed. Referring to pharmacokinetics, we proposed the term “metabolomics”, aiming to evaluate the cisplatin-induced nephrotoxicity dynamically and globally at two levels i.e. the individual metabolite and global metabolome. The predictable success of this research project will rich and perfect the theory and method of pharmacometabolomics, provide new ideas and set up an example for the study of drug-induced toxicity mechanism and drug safety prediction. What’s more, it would enhance the preclinical druggability assessment and improve medication safety significantly.