基于药代动力学和药效学关联的芪苈强心胶囊治疗慢性心力衰竭的 Q 标志物研究。
Research on Q-markers of Qiliqiangxin capsule for chronic heart failure treatment based on pharmacokinetics and pharmacodynamics association.
机构信息
Tianjin Huanhu Hospital, Tianjin 300350, PR China; Tianjin University of Traditional Chinese Medicine, Tianjin 300193, PR China.
Tianjin University of Traditional Chinese Medicine, Tianjin 300193, PR China.
出版信息
Phytomedicine. 2018 May 15;44:220-230. doi: 10.1016/j.phymed.2018.03.003. Epub 2018 Mar 21.
BACKGROUND
Qiliqiangxin capsule (QLQX), composed of 11 herbs, is an effective traditional Chinese medicine (TCM) that has been widely used for treatment of chronic heart failure (CHF) in China. In the Chinese pharmacopoeia (Ch.P.) only astragaloside was described as the marker component to control the quality of QLQX, which could not reflect the overall effectiveness.
PURPOSE
The aim of this work was to investigate the quality markers (Q-markers) of QLQX based on the association of the pharmacodynamics (PD) of inhibitory effect on activated renin-angiotensin-aldosterone system (RAAS) and the pharmacokinetics (PK) of bioactive compounds according to the Q-marker theory.
METHODS
The contents of astragaloside, calycosin-7-glucoside, sinapine, ginsenoside Rb1, ginsenoside Rb2, ginsenoside Rg1, salvianolic acid A, salvianolic acid B, danshensu, rosmarinic acid, formononetin, aconitine, mesaconitine, hypaconitine, benzoylaconine, benzoylmesaconine and benzoylhypacoitine were determined by an HPLC-MS/MS method both in QLQX preparation and in the plasma of CHF rats administered intragastrically with QLQX. The effect of lowering angiotensin II (Ang II) production by QLQX was assayed by ELISA. The association between PK and PD was explored and the bioactive compounds with higher content in vitro and better exposure in vivo, which were closely related to the inhibitory effect on the activated RAAS, were identified as Q-markers of QLQX for CHF treatment.
RESULTS
The contents of 17 constituents were in the order of salvianolic acid B > danshensu > ginsenoside Rb1 > sinapine > benzoylmesaconine > astragaloside > benzoylhypacoitine > ginsenoside Rb2 > salvianolic acid A > ginsenoside Rg1 > calycosin-7-glucoside > rosmarinic acid > formononetin > benzoylaconine > hypaconitine > aconitine > mesaconitine in QLQX preparation. PK and PD association study of 14 bioactive compounds of QLQX showed the maximum effect (E) of astragaloside, calycosin-7-glucoside, sinapine and ginsenoside Rg1 and their peak concentration (C) appeared at the same time; while the time of E of ginsenoside Rb1, ginsenoside Rb2, salvianolic acid A, salvianolic acid B, danshensu, rosmarinic acid, formononetin, benzoylaconine, benzoylmesaconine and benzoylhypacoitine was delayed from the time of their C.
CONCLUSIONS
Astragaloside, calycosin-7-glucoside, sinapine and ginsenoside Rg1 are suitable as the Q-markers of QLQX for CHF treatment, which have higher content in vitro, finer exposure in vivo and a direct correlation with the inhibitory effect on activated RAAS.
背景
芪苈强心胶囊（QLQX）由 11 种草药组成，是一种在中国广泛用于治疗慢性心力衰竭（CHF）的有效中药。在中国药典（Ch.P.）中，仅描述黄芪甲苷作为控制 QLQX 质量的标记成分，这不能反映其整体疗效。
目的
本研究旨在根据药效学（PD）对激活肾素-血管紧张素-醛固酮系统（RAAS）的抑制作用和生物活性成分的药代动力学（PK）之间的关联，基于质量标志物（Q-marker）理论，探讨 QLQX 的质量标志物（Q-markers）。
方法
采用 HPLC-MS/MS 法测定 QLQX 制剂和灌胃给予 QLQX 的 CHF 大鼠血浆中黄芪甲苷、毛蕊异黄酮-7-葡萄糖苷、芥子碱、人参皂苷 Rb1、人参皂苷 Rb2、人参皂苷 Rg1、丹参酸 A、丹参酸 B、丹酚酸、迷迭香酸、芒柄花素、乌头碱、次乌头碱、新乌头碱、苯甲酰乌头碱、苯甲酰次乌头碱和苯甲酰新乌头碱的含量。采用 ELISA 法测定 QLQX 降低血管紧张素 II（Ang II）生成的作用。探讨 PK 和 PD 的相关性，并鉴定出体外含量较高、体内暴露较好，与抑制激活 RAAS 作用密切相关的生物活性成分，作为治疗 CHF 的 QLQX 的 Q 标志物。
结果
QLQX 制剂中 17 种成分的含量顺序为丹参酸 B>丹酚酸>人参皂苷 Rb1>芥子碱>苯甲酰次乌头碱>黄芪甲苷>苯甲酰新乌头碱>人参皂苷 Rb2>丹参酸 A>人参皂苷 Rg1>毛蕊异黄酮-7-葡萄糖苷>迷迭香酸>芒柄花素>苯甲酰乌头碱>新乌头碱>乌头碱>次乌头碱。QLQX 中 14 种生物活性成分的 PK 和 PD 关联研究表明，黄芪甲苷、毛蕊异黄酮-7-葡萄糖苷、芥子碱和人参皂苷 Rg1 的最大效应（E）及其峰值浓度（C）同时出现；而人参皂苷 Rb1、人参皂苷 Rb2、丹参酸 A、丹参酸 B、丹酚酸、迷迭香酸、芒柄花素、苯甲酰乌头碱、苯甲酰次乌头碱和苯甲酰新乌头碱的 E 出现时间滞后于 C。
结论
黄芪甲苷、毛蕊异黄酮-7-葡萄糖苷、芥子碱和人参皂苷 Rg1 可作为治疗 CHF 的 QLQX 的 Q 标志物，它们在体外含量较高，体内暴露较好，与抑制激活 RAAS 的作用直接相关。
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