Abstract

Shimotsuto is a traditional Japanese Kampo medicine used to treat gynecological diseases, such as irregular menstruation, in addition to oversensitivity to cold and chilblains. Part of the pharmacological actions of shimotsuto is traditionally considered to be exerted by an improvement effect of the blood and the circulatory system. Multiple ingredients (e.g., catalpol and paeoniflorin) contained in shimotsuto have been reported to have pharmacological activities on the blood and circulatory system, and thus been considered to contribute to the pharmacological actions of shimotsuto. However, it remains unclear whether the ingredients can be absorbed into the body following oral administration of shimotsuto. The aim in the present study was to specify shimotsuto ingredient absorbed into the systemic circulation in rats. Seven candidate active ingredients (catalpol, paeoniflorin, albiflorin, ligustilide, senkyunolide A, butylphthalide, and ferulic acid) in plasma after oral administration of shimotsuto were quantified by targeted liquid chromatography–tandem mass spectrometry (LC–MS/MS) analysis. This study also performed nontargeted LC–MS/MS analysis of plasma following administration of constituent crude drugs of shimotsuto to find extensively blood-absorbed ingredients of shimotsuto. Among detected peaks in the nontargeted analysis, two peaks could be identified as bergapten and 8-debenzoylpaeoniflorin, subsequently their concentrations in shimotsuto-treated rat plasma were quantified. These pharmacokinetic studies indicated that catalpol showed the highest plasma concentration following administration of shimotsuto, followed by 8-debenzoylpaeoniflorin. This study suggests that all nine ingredients are absorbed into the blood following oral administration of shimotsuto and possibly contribute to its pharmacological action.

Graphic abstract

中文翻译：

---

日本传统汉方药shimotsuto药治疗大鼠妇科疾病的药代动力学研究

摘要

Shimotsuto是一种传统的日本Kampo药物，除了对冷和雪白过敏症外，还用于治疗妇科疾病，例如月经不调。传统上认为shimotsuto的部分药理作用是通过改善血液和循环系统来发挥的。据报道，shimotsuto中包含的多种成分（例如，梓醇和pa药苷）对血液和循环系统具有药理活性，因此被认为有助于shimotsuto的药理作用。然而，尚不清楚口服Shimottsuto后这些成分是否可以吸收到体内。本研究的目的是确定被吸收到大鼠全身循环中的Shimotsuto成分。通过靶向液相色谱-串联质谱分析法（LC-MS / MS）定量测定了Shimottsuto口服后血浆中的七种候选活性成分（梓醇，pa药苷，白花青素，li本内酯，山豆酚A，丁基邻苯二甲酸酯和阿魏酸）。这项研究还对施用shimotsuto的原料药进行了血浆非血浆LC-MS / MS分析，以发现shimotsuto的大量血液吸收成分。在非目标分析中检测到的峰中，可以鉴定出两个峰，分别是佛手柑和8-去苯甲酰pa药苷，然后对它们在Shitsutsuto处理的大鼠血浆中的浓度进行定量。这些药代动力学研究表明，在施用shimotsuto之后，其后是8-debenzoylpaeoniflorin，catalpol显示出最高的血浆浓度。

图形摘要