氧化芍药苷在正常与抑郁大鼠体内代谢产物的比较研究

目的 研究氧化芍药苷在正常和抑郁大鼠血浆、尿液、粪便中代谢产物的差异，并推测其主要的代谢途径。方法 选取Wistar大鼠，复制慢性应激抑郁大鼠，分别连续ig给予正常和抑郁大鼠氧化芍药苷水溶液3 d，收集大鼠血清、尿液和粪便；利用超高效液相色谱-四级杆飞行时间质谱（UPLC-Q-TOF/MS）技术结合UNIFI分析平台鉴定氧化芍药苷在正常和抑郁模型大鼠体内的原型成分及代谢产物。结果 在正常和抑郁大鼠血浆中均检测到氧化芍药苷原型成分，且在抑郁大鼠血浆中的相对含量是正常大鼠血浆的10倍；在抑郁大鼠血浆、尿液和粪便中分别鉴定出4、13、2个代谢产物，在正常大鼠血浆、尿液和粪便中分别鉴定出1、12、3个代谢产物，其中11个共有代谢产物，主要发生的代谢途径为氧化、去饱和等I相代谢反应，甲基化、葡萄糖醛酸化、乙酰化等II相代谢反应。结论 氧化芍药苷ig给药后主要以原型成分进入体内，且抑郁大鼠血浆中原型成分的相对含量较正常大鼠高10倍；在抑郁和正常大鼠中的代谢产物有差异，其中葡萄糖醛酸化为正常大鼠体内特有的代谢途径，乙酰化为抑郁大鼠体内特有的代谢途径。推测氧化芍药苷可能是以原型成分为主发挥药效作用，通过尿液和粪便以原型或代谢产物排泄。

Comparative study on metabolites of oxypaeoniflorin in normal and depressed rats

Objective To compare the difference of oxypaeoniflorin metabolites in plasma, urine and feces between normal and depressed rats, and to deduce its main metabolic pathways. Methods Wistar rats were selected to establish the model of chronic stress depression in this experiment, and oxypaeoniflorin aqueous solution was given to normal and depressed rats respectively by gavage for 3 d. The serum, urine and feces were collected and UPLC-Q-TOF/MS combined with UNIFI analysis platform was used to identify the prototype component and metabolites of oxypaeoniflorin in normal and depressed rats. Results The prototype component of oxypaeoniflorin were detected in plasma from both normal and depressed rats, and the relative content in plasma of depressed rats was ten times higher than that in normal rats; four, 13 and two metabolites were identified in plasma, urine and feces of depression rats, and one, 12 and three in normal rats, respectively. Among them, 11 metabolites were detected in both depressed mice and normal rats. The metabolic pathways of oxypaeoniflorin include oxidation and desaturation in phase I metabolic reactions or methylation, glucuronidation and acetylation in phase II metabolic reactions. Conclusions Oxypaeoniflora enters the body mainly as a prototype after intragastric administration in rats, and the relative content of prototype components in plasma of depressed rats was ten times higher than that in normal rats. In addition, the metabolites of oxypaeoniflorin were different in depressed and normal rats, and glucuronidation metabolism occurred mainly in normal rats, whereas acetylation metabolism occurred mainly in depressed rats. Therefore, we speculated that the prototype of oxypaeoniflorin should be responsible for its therapeutic effect, which excreted as prototype or metabolite through urine and feces.