Background

Primary dysmenorrhea (PDM) is one of the most common gynaecological disorders among women, which seriously affects women's life quality due to its high incidence rate. Guizhi Fuling capsule (GZFLC), a well-known traditional Chinese medical prescription, has been widely used to treat gynecological blood stasis syndromes such as PDM. However, its mechanisms of action and combination were still unknown.

Purpose

The aim of this study was to develop a pharmacokinetic-pharmacodynamic (PK-PD) model to assess time-concentration-effect relationships for anti-dysmenorrhea effect of GZFLC and provide better understanding for mechanisms of action and combination of GZFLC.

Study design and methods

The PDM rats model was induced by oxytocin exposure following estradiol benzoate pretreatment. Gallic acid (GA), amygdalin (AMY), albiflorin (ALB), prunasin (PA) and cinnamic acid (CA) were evaluated as bioactive ingredients for investigating PK processes. GA, AMY, ALB and PA exhibited appropriate PK parameters and were selected as the PK markers to map the anti-dysmenorrhea effect of GZFLC. A PK-PD model was established on the basis of GA, AMY, ALB and PA plasma concentrations vs. the values of two ratios (PGE₂/PGF_2α and 6-Keto-PGF_1α/TXB₂), by a two-compartment PK model with a simple E_max model to explain the time delay between the drug plasma concentrations of PK markers and the anti-dysmenorrhea effect.

Results

The PDM rat model has been successfully established. Compared with the normal treated group, the bioactive ingredients in PDM treated group exhibited significant changing trends of PK behaviors, such as better absorption and distribution, slower elimination and delays in reaching the maximum concentration (T_max). The analysis of PK-PD parameters indicated that the active metabolites and prototypes of bioactive ingredients in GZFLC were inclined to regulate the activity of prostacyclin synthetase and thromboxane synthetase to control the production of TXA₂ and PGI₂ so as to treat PDM. As the main effective medicinal materials for the treatment of PDM in GZFLC prescription Persicae Semen, Moutan Cortex and Paeonia lactiflora Pall, Persicae Semen played the most important role, while the role of Paeonia lactiflora Pall was the weakest.

Conclusion

The PK-PD model results provided scientific basis for clarifying compatibility mechanisms of GZFLC prescription and a better understanding for biosynthetic mechanisms of four prostaglandins (PGE₂, PGF_2α, 6-Keto-PGF_1α and TXB₂) in the treatment of PDM by GZFLC. Investigations on the relationship between the effects and the bioactive ingredients are of benefit to explore the mechanisms of action and combination for traditional Chinese medical prescriptions (TCP) and facilitate the development of future clinical applications of TCP.

中文翻译：

---

药代动力学模型研究桂枝Fu灵胶囊对痛经大鼠的痛经作用

背景

原发性痛经（PDM）是女性中最常见的妇科疾病之一，由于其高发率，严重影响了女性的生活质量。桂枝Fu灵胶囊（GZFLC）是一种著名的中药处方，已被广泛用于治疗妇科血瘀综合征，如PDM。但是，其作用机理和结合机理尚不清楚。

目的

这项研究的目的是开发一种药代动力学-药效学（PK-PD）模型，以评估GZFLC的痛经作用的时间-浓度-效应关系，并提供对GZFLC的作用机理和组合的更好的理解。

研究设计和方法

在苯甲酸雌二醇预处理后，通过催产素暴露来诱导PDM大鼠模型。没食子酸（GA），苦杏仁苷（AMY），白花素（ALB），甜菜碱（PA）和肉桂酸（CA）被评估为研究PK过程的生物活性成分。GA，AMY，ALB和PA表现出适当的PK参数，并被选作PK标记以绘制GZFLC的痛经作用。甲PK-PD模型成立GA，AMY，ALB和PA的基础上的血浆浓度与两个比率的值（PGE ₂ / PGF _2α和6-酮PGF _1α / TXB ₂），由双隔室具有简单E _max的PK模型 模型解释药物血浆中PK标记物浓度与抗痛经作用之间的时间延迟。

结果

PDM大鼠模型已成功建立。与正常治疗组相比，PDM治疗组的生物活性成分表现出PK行为的显着变化趋势，例如更好的吸收和分布，更慢的消除和达到最大浓度（T _max）的延迟。PK-PD参数的分析表明，GZFLC中的活性代谢物和生物活性成分的原型倾向于调节前列环素合成酶和血栓烷合成酶的活性，从而控制TXA ₂和PGI _2的产生，从而治疗PDM。GZFLC处方波斯精液，牡丹皮和牡丹皮中的PDM作为治疗PDM的主要有效药物。e药、,药的作用最重要，而Pa药的作用最弱。

结论

的PK-PD模型的结果用于澄清GZFLC处方的兼容性机制提供了科学基础和四个前列腺素的生物合成机构（PGE更好地理解₂，PGF _2α，6-酮PGF _1α和TXB ₂在由GZFLC治疗PDM的） 。研究效果与生物活性成分之间的关​​系有助于探索中药处方（TCP）的作用机理和组合机理，并有助于TCP的未来临床应用的发展。