To reveal the pharmacokinetic process of narirutin, naringin, and honokiol in normal and different courses of liver-stagnation and spleen-deficiency syndrome depressive rats after intragastric administration of Zhi-Zi-Hou-Po decoction (ZZHPD), a rapid ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) method was proposed in this study. Chronic unpredictable mild stress (CUMS) rat was employed as the depression model. Acetonitrile solution containing 0.1% acetic acid and methyl alcohol-water (50 : 50, ) was chosen as the protein precipitant and redissolve solution severally; a Shim-pack GISS C₁₈ column coupled with 0.1% aqueous acetic acid-acetonitrile in gradient elution was employed to separate the mixed constituents in plasma. The WinNonLin software (version 6.1) was chosen as the analytical tool for the pharmacokinetic parameters. The results indicated that compared with rats in the control group, the sucrose preference, scores in the open-field test, and the concentration of 5-HT in plasma of rats in CUMS and CUMS + ZZHPD treatment groups were lower, while the immobility time in the forced swimming test of rats in these two groups was longer, which implied that the depression model was successful. These behavioral and biochemical indexes of rats above in the CUMS + ZZHPD treatment group were improved after oral administration of ZZHPD, which indicated that the antidepressant effect of ZZHPD was definite. The UHPLC-MS/MS method was stabilized, sensitive, and exclusive, and the extraction recovery and matrix effect of three analytes were all above 89%. The T_max, AUC, and C_max of three ingredients in CUMS-induced depression rats were significantly larger than control rats, while these pharmacokinetic parameters in CUMS + ZZHPD treatment rats were decreased significantly compared with CUMS-induced depression rats, which may relate with the changes in physiological function of the gastrointestinal tract and liver in CUMS-induced liver-stagnation and spleen-deficiency syndrome depressive rats. This study provided important information for the clinical rational use of ZZHPD in antidepressant treatment.

中文翻译：

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栀子厚朴汤灌胃后三种主要活性成分在肝郁脾虚证抑郁大鼠正常及不同病程中的药代动力学比较研究


揭示柚皮苷、柚皮苷、和厚朴酚在肝郁脾虚证抑郁大鼠正常及不同疗程中给予栀子厚朴汤（ZZHPD）后的药代动力学过程。本研究提出了液相色谱-串联质谱（UHPLC-MS/MS）方法。采用慢性不可预测轻度应激(CUMS)大鼠作为抑郁模型。含0.1%乙酸和甲醇-水（50：50， )分别作为蛋白沉淀剂和复溶液；采用 Shim-pack GISS C ₁₈柱与 0.1% 乙酸-乙腈水溶液梯度洗脱相结合，分离血浆中的混合成分。选择 WinNonLin 软件（版本 6.1）作为药代动力学参数的分析工具。结果表明，与对照组大鼠相比，CUMS和CUMS+ZZHPD治疗组大鼠的蔗糖偏好、旷场试验得分和血浆5-HT浓度较低，而不动时间较低。这两组大鼠在强迫游泳试验中的时间较长，这表明抑郁模型是成功的。 CUMS+ZZHPD治疗组大鼠上述行为及生化指标在口服ZZHPD后均得到改善，表明ZZHPD的抗抑郁作用是明确的。 UHPLC-MS/MS方法稳定、灵敏、专属，3种分析物的提取回收率和基质效应均在89%以上。 CUMS致抑郁大鼠中三种成分的T _max 、AUC和C _max均显着大于对照大鼠，而CUMS+ZZHPD治疗组大鼠的这些药代动力学参数较CUMS致抑郁大鼠显着降低，这可能与CUMS致肝郁脾虚证抑郁大鼠胃肠道及肝脏生理功能的变化该研究为临床合理使用ZZHPD抗抑郁治疗提供了重要信息。