Core effective components identifying strategy of Xingbei Zhike granule: integrating multi-component quantification, tissue distribution, oral bioavailability, and antitussive effect.

Ethnopharmacological Relevance: Xingbei Zhike granule (XBZK), a widely used Chinese patent medicine consisting of nine herbal medicines, is clinically used to clear lung qi, relieve cough, and reduce phlegm and is commonly prescribed for cough associated the syndromes of external cold and internal heat. However, its core effective components remain unclear.

Aim Of Study: This study aims to develop a new strategy, integrating content proportion, tissue targeting, bioavailability, and pharmacodynamic contribution, to explore the core effective components for precise quality control of traditional Chinese medicine (TCM), using Xingbei Zhike granule (XBZK) as a model.

Materials And Methods: Two sensitive and accurate methods were developed and validated for component quantification, tissues distribution analysis, and OB studies of XBZK using Ultra-performance liquid chromatography with triple quadrupole mass spectrometry (UPLC-TQ-MS/MS). Then, the main compounds were quantified in XBZK and tissues, especially the lung and trachea from XBZK-administered rats. The antitussive effect of two mixtures of the identified main components was compared with that of XBZK.

Results: XBZK demonstrated stable quality via content evaluation of 26 components in 18 batches of preparations, with little fluctuation in the top ten components. Seven effective components were distributed in different tissues, especially target tissues (lung and trachea). Four components showed a stable distribution ratio between plasma and target tissues. Amygdalin, with the highest content, exhibited the lowest OB, while enoxolone, present at the lowest, possessed the highest OB. The mixtures of the main effective components demonstrated a similar efficacy to XBZK at 1 h post-administration. Further, based on the exposure ratio in plasma and concentration ratio in target tissues of each component, amygdalin, ephedrine, pseudoephedrine, and enoxolone were identified as the core effective components of XBZK, and glycyrrhizic acid, the precursor of enoxolone in vivo, should became its core quality control.

Conclusions: This research proposes a multi-dimensional core effective component determination standard of "exposure - distribution - effect", with successful application in XBZK, breaking the limitation of the traditional "content-only" approach in TCM quality control research, and providing a replicable model for TCM quality control research.