Ren Wei, Zuo Ran, Wang Yao-Nan, Wang Hong-Jie, Yang Jian, Xin Shao-Kun, Han Ling-Yu, Zhao Hai-Yu, Han Shu-Yan, Gao Bo, Hu Hao, Hu Yuan-Jia, Bian Bao-Lin, Si Nan
Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
Capital Medical University, Beijing 100069, China.
PLoS One. 2016 Jun 9;11(6):e0156256. doi: 10.1371/journal.pone.0156256. eCollection 2016.
Huang-Lian-Jie-Du Decoction (HLJDD) is a classical Traditional Chinese Medicine (TCM) formula with heat-dissipating and detoxifying effects. It is used to treat inflammation-associated diseases. However, no systematic pharmacokinetic (PK) and pharmacodynamic (PD) data concerning the activity of HLJDD under inflammatory conditions is available to date. In the present study, the concentration-time profiles and the hepatic clearance rates (HCR) of 41 major components in rat plasma in response to the oral administration of a clinical dose of HLJDD were investigated by LC-QqQ-MS using a dynamic multiple reaction monitoring (DMRM) method. Additionally, the levels of 7 cytokines (CKs) in the plasma and the body temperature of rats were analyzed. Furthermore, a PK-PD model was established to describe the time course of the hemodynamic and anti-inflammatory effects of HLJDD. As one of the three major active constituents in HLJDD, iridoids were absorbed and eliminated more easily and quickly than alkaloids and flavonoids. Compared with the normal controls, the flavonoids, alkaloids and iridoids in inflamed rats exhibited consistently changing trends of PK behaviors, such as higher bioavailability, slower elimination, delays in reaching the maximum concentration (Tmax) and longer substantivity. The HCR of iridoids was different from that of alkaloids and flavonoids in inflamed rats. Furthermore, excellent pharmacodynamic effects of HLJDD were observed in inflamed rats. The levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1β, IL-10, and macrophage inflammatory protein-2 (MIP-2) and body temperature significantly decreased after the administration of HLJDD. Based on PK-PD modeling with the three-phase synchronous characterization of time-concentration-effect, flavonoids exhibited one mechanism of action in the anti-inflammatory process, while iridoids and alkaloids showed another mechanism of action. Taken together, the results demonstrated that HLJDD may restrain inflammation synergistically via its major constituents (alkaloids, flavonoids and iridoids). A correlation between the exposure concentration of different types of compounds and their anti-inflammatory effects in the body was shown. This study provides a comprehensive understanding of the anti-inflammatory activity of HLJDD.
黄连解毒汤（HLJDD）是一种具有清热泻火解毒功效的经典中药方剂，用于治疗炎症相关疾病。然而，目前尚无关于HLJDD在炎症条件下活性的系统药代动力学（PK）和药效学（PD）数据。在本研究中，采用液相色谱-三重四极杆质谱联用（LC-QqQ-MS）的动态多反应监测（DMRM）方法，研究了大鼠口服临床剂量HLJDD后血浆中41种主要成分的浓度-时间曲线和肝清除率（HCR）。此外，还分析了大鼠血浆中7种细胞因子（CKs）的水平和体温。此外，建立了PK-PD模型来描述HLJDD的血流动力学和抗炎作用的时间过程。作为HLJDD的三种主要活性成分之一，环烯醚萜类化合物比生物碱和黄酮类化合物更容易、更快地被吸收和消除。与正常对照组相比，炎症大鼠体内的黄酮类化合物、生物碱和环烯醚萜类化合物的PK行为呈现出一致的变化趋势，如生物利用度更高、消除更慢、达到最大浓度（Tmax）延迟和持续时间更长。炎症大鼠中环烯醚萜类化合物的HCR与生物碱和黄酮类化合物不同。此外，在炎症大鼠中观察到HLJDD具有良好的药效学作用。给予HLJDD后，肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）、白细胞介素-1β（IL-1β）、白细胞介素-10（IL-10）和巨噬细胞炎性蛋白-2（MIP-2）水平及体温显著降低。基于时间-浓度-效应三相同步表征的PK-PD建模，黄酮类化合物在抗炎过程中表现出一种作用机制，而环烯醚萜类化合物和生物碱则表现出另一种作用机制。综上所述，结果表明HLJDD可能通过其主要成分（生物碱、黄酮类化合物和环烯醚萜类化合物）协同抑制炎症。研究显示了不同类型化合物的暴露浓度与其在体内抗炎作用之间的相关性。本研究为全面了解HLJDD的抗炎活性提供了依据。
