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A Multi-Stage Strategy to Decipher the Pharmacodynamic Material Basis of Qiliqiangxin Capsules for Heart Failure Therapy
Jiekai Hua a,b 1, Jianwei Zhang b 1, Sijia Wu b,c 1, Qingyin Feng a,b, Guosheng Fu b, Chunhui Li d, Ying Chen b, Sijie Liu b, Jie Shen b , Shuling Wang a, Wei Liu a,b *
Affiliations:
a School of Pharmacy, Hangzhou Normal University; Key Laboratory of Elemene Class Anti-Cancer Chinese Medicines, Engineering Laboratory of Development and Application of Traditional Chinese Medicines; Collaborative Innovation Center of Traditional Chinese Medicines of Zhejiang Province, Hangzhou Normal University, Hangzhou, Zhejiang 311121, China.
b Department of Pharmacy, The NATCM Third Grade Laboratory of Traditional Chinese Medicine Preparations, Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Road, Shanghai, 201203, China
c Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, The MOE Key Laboratory for Standardization of Chinese Medicines, 1200 Cailun Road, Shanghai 201203, China
d Institute of Liver Diseases, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine
Background: Qiliqiangxin Capsules (QLQX) is the first Chinese medicine with clinically evidence-based medical confirmation demonstrating clear efficacy for heart failure (HF). However, no study has comprehensively elucidated the pharmacodynamic material basis of QLQX.
Methods: Comprehensive qualitative characterization of QLQX was performed using ultra-high-performance liquid chromatography coupled with quadrupole-Orbitrap mass spectrometry (UHPLC-Q-Orbitrap-MS). Concurrently, quantitative analysis was conducted on representative compounds in QLQX and intestinal contents. Furthermore, a robust and fully validated liquid chromatography–tandem mass spectrometry (LC-MS/MS) method was established for the simultaneous quantification of analytes with high exposure in multi-phase pharmacokinetic and tissue distribution researches (ileum, portal vein blood, liver, peripheral blood, heart, and kidney) in rats. Angiotensin-converting enzyme (ACE) inhibition assay was performed to identify components with potential anti-HF activity.
Results: A total of 161 compounds were characterized in QLQX, and 42 constituents were quantified, among which 33 exhibited complete intestinal absorption–time profiles. 18 compounds with high exposure were selected for pharmacokinetic and tissue distribution assessment; among these, 15, 12, 15, 12, and 12 compounds were detected in the ileum, plasma, liver, heart, and kidney, respectively. Most compounds showed substantially higher concentrations in portal vein blood than in peripheral blood, and tissue abundance consistently followed the gradient ileum > liver > heart/kidney. Based on their exposure characteristics, enzyme activity validation assay was conducted, demonstrating that hesperidin, ferulic acid, chlorogenic acid, formononetin, calycosin 7-O-glucoside, talatisamine, fuziline, ononin, methylnissolin-3-O-glucoside, and alisol B, exhibited ACE inhibitory activity and could be regarded as potential ACEIs.
Conclusion: This study presented an innovative multi-stage strategy to identify the pharmacodynamic material basis of QLQX, systematically tracked compounds from the original prescription through the gastrointestinal tract and circulation to target tissues. This approach successfully identified key bioactive compounds in QLQX, revealing their potential as ACE inhibitors (ACEIs) and providing a solid foundation for developing novel anti-HF therapeutics.
