目的 研究炮制与配伍对四逆散中主要有效成分在抑郁模型大鼠血浆、胆汁、尿液及粪便中代谢成分的差异。方法 建立慢性不可预期温和应激（chronic unpredictable mild stress，CUMS）抑郁大鼠模型，造模结束后分别ig柴胡、白芍、柴胡-白芍药对、四逆散及含醋炙柴胡和醋炙白芍的四逆散提取物，并在连续ig 7 d后收集24 h尿液及粪便，再次ig收集血浆及胆汁。采用超高效液相色谱-四极杆飞行质谱（UPLC-Q-TOF/MS）技术对血浆、胆汁、尿液及粪便样本进行检测，并结合PeakView^TM和MetabolitePilot^TM软件进行鉴定分析。结果 依据代谢途径和离子碎片信息，推测柴胡皂苷a、柴胡皂苷b₂、柴胡皂苷c、柴胡皂苷d、芍药苷、芍药内酯苷、苯甲酰芍药苷、氧化芍药苷、橙皮苷、橙皮素、柚皮苷、甘草苷、甘草酸以及甘草素在抑郁模型大鼠体内主要以原型、脱糖、脱氧、去甲基化、氧化、甲基化、葡萄糖醛酸化、硫酸化等形式存在。最终在柴胡组中鉴定了27种代谢产物，在白芍组中鉴定了30种代谢产物，在柴胡-白芍药对组中鉴定了52种代谢产物，在四逆散组中鉴定了118种代谢产物，在含醋炙柴胡和醋炙白芍的四逆散组中鉴定了168个代谢产物。结论 在抑郁模型大鼠体内，配伍前后的“单味药-药对-复方”和炮制前后的“生品-醋炙品”的代谢产物存在较大差异。即经醋炙及配伍后，14种主要活性成分的原型及其代谢产物的分布更为广泛，且醋炙在一定程度上促进了某些成分参与肝肠循环，进一步为四逆散抗抑郁作用的药效物质研究奠定基础，同时也为阐明炮制与配伍机制提供科学依据。

Objective To investigate the differences of the metabolites of the main effective constituents contained in Sini Powder (四逆散, SNP) in plasma, bile, urine, and feces of depressive rats by processing and compatibility. Methods The depressive rat model was established by chronic unpredictable mild stress (CUMS). After modeling, the extracts of Chaihu (Bupleuri Radix, BR), Baishao (Paeoniae Radix Alba, PRA), the herb-pair of Bupleuri Radix-Paeoniae Radix Alba (BR-PRA), SNP, and SNP containing vinegar-processed Bupleuri Radix (vpBR) and vinegar-processed Paeoniae Radix Alba (vpPRA) were ig administered, respectively. Urine and feces for 24 h were collected after continuously intragastric administration for seven days, and plasma and bile were collected after intragastric administration again. The technique of ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was applied to detect the samples of plasma, bile, urine, and feces, and PeakView^TM and MetabolitePilot^TM softwares were used for identification and analysis. Results According to the metabolic pathway and ion fragment information, it was speculated that saikosaponin a, saikosaponin b₂, saikosaponin c, saikosaponin d, paeoniflorin, albiflorin, benzoylpaeoniflorin, oxypaeoniflorin, hesperidin, hesperetin, naringin, liquiritin, glycyrrhizic acid, and liquiritigenin were mainly metabolized in vivo to prototype, deglycosylation, deoxidation, demethylation, oxidation, methylation, glucuronidation, sulfation, and other forms in depressive rats. Finally, 27, 30, 52, 118, and 168 metabolites were identified in the BR group, the PRA group, the BR-PRA herb-pair group, the SNP group, and the group of SNP containing vpBR and vpPRA, respectively. Conclusion There were large differences in metabolites between the “individual herb-herb pair-herbal formula” before and after compatibility and the “crude products-vinegar-processed products” before and after processing in depressive rats. That is to say, the prototypes and metabolites of 14 main active constituents had more extensive distribution after vinegar-processing and compatibility, and vinegar-processing promoted the participation of some constituents in hepatoenteral circulation to a certain extent, which further laid the foundation for investigating the antidepressant substantial basis of SNP, and also provide the scientific evidence for clarifying the mechanism of processing and compatibility.

R283.6

国家自然科学基金面上项目（81673600）；江苏省研究生科研创新计划（KYCX20_1604）；江苏省研究生科研创新计划（KYCX18_1637）