Research on Q-markers of Qiliqiangxin capsule for chronic heart failure treatment based on pharmacokinetics and pharmacodynamics association

Phytomedicine. 2018 May 15:44:220-230. doi: 10.1016/j.phymed.2018.03.003. Epub 2018 Mar 21.

Abstract

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 (Emax) of astragaloside, calycosin-7-glucoside, sinapine and ginsenoside Rg1 and their peak concentration (Cmax) appeared at the same time; while the time of Emax 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 Cmax.

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.

Keywords: Angiotensin II; Chronic heart failure; Pharmacodynamics; Pharmacokinetics; Q-markers; Qiliqiangxin capsule.

MeSH terms

  • Aconitine / analogs & derivatives
  • Aconitine / analysis
  • Angiotensin II / blood
  • Animals
  • Benzofurans / analysis
  • Biomarkers / analysis*
  • Chromatography, High Pressure Liquid
  • Chronic Disease
  • Drugs, Chinese Herbal / analysis
  • Drugs, Chinese Herbal / pharmacokinetics*
  • Drugs, Chinese Herbal / standards*
  • Ginsenosides / analysis
  • Heart Failure / drug therapy*
  • Isoflavones / analysis
  • Male
  • Medicine, Chinese Traditional / methods
  • Medicine, Chinese Traditional / standards
  • Quality Control
  • Rats, Sprague-Dawley
  • Tandem Mass Spectrometry

Substances

  • Benzofurans
  • Biomarkers
  • Drugs, Chinese Herbal
  • Ginsenosides
  • Isoflavones
  • qiliqiangxin
  • ginsenoside Rb2
  • Angiotensin II
  • formononetin
  • mesaconitine
  • ginsenoside Rb1
  • salvianolic acid B
  • ginsenoside Rg1
  • Aconitine