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A novel pharmacokinetics-pharmacodynamics strategy for effective components exploration combined with metabolomics
Xia Gao1, MingKe Yin2, Jing Liu2
1State Key Laboratory of Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture (Jiangsu Kanion Pharmaceutical Co. Ltd & Nanjing University of Chinese Medicine), Nanjing 210000, China; Nanjing University of Chinese Medicine, Nanjing 222001, China; Jiangsu Kanion Modern Chinese Medicine Institute, Nanjing 210023, China.
Abstract:
Traditional Chinese medicine (TCM) is characterized by its complex and diverse components, difficult to identify the effective components. In this study, a pharmacokinetics (PK)-pharmacodynamics (PD) strategy, integrating chemical component profile, PK, metabolomics, and proteomics, was developed to explore the effective components of Xingbei Zhike granule (XBZKG) in treating post-infection cough (PIC). The quality consistency of XBZKG was confirmed by evaluating 78 components across 20 batches. And its good curative effect against PIC was verified through measurements of cough latency, cough frequency, and biochemical assays. Meanwhile, XBZKG was found to ameliorate PIC-induced metabolic disturbances, particularly in amino acid metabolism. Interestingly, the pathological state of PIC itself altered the absorption and metabolism of XBZKG in rats. Among ten components, ephedrine, pseudoephedrine, and amygdalin fitted good dose-effect models with three PD indicators, with the PIC pathological state appearing to enhance their efficacy. Spearman correlation analysis further revealed that 15 components alleviated PIC-induced amino acid imbalances, and some structurally similar components exhibited synergistic effects. Integrative proteomic and metabolomic analysis identified 28 potential pathway of XBZKG in the treatment of PIC, mainly related to inflammation. Finally, in vitro cellular assays confirmed 15 components exert good anti-inflammatory activity. This study provides a reproducible strategy for identifying effective components in TCM and offers new insights into its multi-component, multi-target, and multi-pathway therapeutic mechanisms.
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