In recent years, depression occurs frequently. Given the long duration of the disease and the high risk of recurrence, the treatment of depression requires long-term medication. Zhi-Zi-Hou-Po Decoction (ZZHPD) has been used in clinical treatment of depression and related diseases for many years, and the potential toxic damage caused by its long-term use has gradually emerged. Existing research methods that expose toxicity by a one-time administration of large doses cannot provide a reference for clinical safe drug use. In this study, the potential toxicity of ZZHPD in repeated administration was studied by urinary metabolomics with nondestructive sampling. Based on ultra-high performance liquid chromatography-quadruple-Exactive Orbitrap mass spectrometry (UHPLC-Q-Exactive Orbitrap-MS) and chemometrics, 33 differential biomarkers, such as 3-hydroxybutyric acid, indole sulfuric acid, hippuric acid and citric acid, were screened and dynamically tracked. The changes of some endogenous substances showed obvious time dependence. Further analysis of these time-dependent components in combination with network pharmacology revealed that the potential hepatotoxicity and nephrotoxicity of ZZHPD were related to the disorders of amino acid metabolism, energy metabolism, lipid metabolism, nucleotide metabolism and gut microflora metabolism pathway. This study can better grasp the occurrence and development of drug toxicity, and provide reference for rational and safe drug use and potential toxicity prevention of ZZHPD.

中文翻译：

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基于UHPLC-Q-Exactive Orbitrap-MS的动态尿液代谢组学研究Zhi-Zi-Hou-Po汤的潜在毒性机制。

近年来，抑郁症经常发生。考虑到疾病的持续时间长和复发风险高，抑郁症的治疗需要长期的药物治疗。智子活宝汤（ZZHPD）已被广泛用于抑郁症和相关疾病的临床治疗，长期使用引起的潜在毒性损害已逐渐显现。现有的通过一次大剂量给药暴露毒性的研究方法不能为临床安全用药提供参考。在这项研究中，ZZHPD在重复给药中的潜在毒性是通过无损取样的尿液代谢组学研究的。基于超高效液相色谱-四重-主动Orbitrap质谱（UHPLC-Q-Exactive Orbitrap-MS）和化学计量学，共33种生物标志物，如3-羟基丁酸，吲哚硫酸，马尿酸和柠檬酸等被筛选并动态跟踪。某些内源性物质的变化表现出明显的时间依赖性。结合网络药理学进一步分析这些时间依赖性成分，发现ZZHPD的潜在肝毒性和肾毒性与氨基酸代谢，能量代谢，脂质代谢，核苷酸代谢和肠道菌群代谢途径的疾病有关。本研究可更好地掌握药物毒性的发生和发展，为合理安全使用药物和预防ZHZPD的潜在毒性提供参考。某些内源性物质的变化表现出明显的时间依赖性。结合网络药理学进一步分析这些时间依赖性成分，发现ZZHPD的潜在肝毒性和肾毒性与氨基酸代谢，能量代谢，脂质代谢，核苷酸代谢和肠道菌群代谢途径的疾病有关。本研究可更好地掌握药物毒性的发生和发展，为合理安全使用药物和预防ZHZPD的潜在毒性提供参考。某些内源性物质的变化表现出明显的时间依赖性。结合网络药理学进一步分析这些时间依赖性成分，发现ZZHPD的潜在肝毒性和肾毒性与氨基酸代谢，能量代谢，脂质代谢，核苷酸代谢和肠道菌群代谢途径的疾病有关。本研究可更好地掌握药物毒性的发生和发展，为合理安全使用药物和预防ZHZPD的潜在毒性提供参考。核苷酸代谢和肠道菌群代谢途径。本研究可更好地掌握药物毒性的发生和发展，为合理安全使用药物和预防ZHZPD的潜在毒性提供参考。核苷酸代谢和肠道菌群代谢途径。本研究可更好地掌握药物毒性的发生和发展，为合理安全使用药物和预防ZHZPD的潜在毒性提供参考。