Rationality of the ethanol precipitation process in modern preparation production of Zishui‐Qinggan decoction evaluated by integrating UPLC‐QTOF‐MS/MS‐based chemical profiling/serum pharmacochemistry and network pharmacology

Introduction Zishui‐Qinggan decoction (ZQD) is a classical traditional Chinese medicine formula (TCMF) for alleviating menopausal symptoms (MPS) induced by endocrine therapy in breast cancer patients. In the production of TCMF modern preparations, ethanol precipitation (EP) is a commonly but not fully verified refining process. Objectives Chemical profiling/serum pharmacochemistry and network pharmacology approaches were integrated for exploring the rationality of the EP process in the production of ZQD modern preparations. Material and methods Ultra‐performance liquid chromatography–quadrupole time‐of‐flight tandem mass spectrometry (UPLC‐QTOF‐MS/MS) was applied to identify the chemical profiles and absorbed components of ZQD. Network pharmacology was used to identify targets and pathways related to MPS‐relieving efficacy. Results The chemicals of ZQDs without/with EP process (referred to as ZQD‐W and ZQD‐W‐P, respectively) were qualitatively similar with 89 and 87 components identified, respectively, but their relative contents were different; 51 components were detectable in the serum of rats orally administered with ZQD‐W, whereas only 19 were detected in that administered with ZQD‐W‐P. Key targets, such as AKT1, and pathways, such as the PI3K‐Akt signalling pathway, affected by ZQD‐W and ZQD‐W‐P were similar, while the neuroactive ligand–receptor interaction pathway among others and the MAPK signalling pathway among others were specific pathways affected by ZQD‐W and ZQD‐W‐P, respectively. The specifically absorbed components of ZQD‐W could combine its specific key targets. Conclusion The EP process quantitatively altered the chemical profiles of ZQD, subsequently affected the absorbed components of ZQD, and then affected the key targets and pathways of ZQD for relieving MPS. The EP process might result in variation of the MPS‐relieving efficacy of ZQD, which deserves further in vivo verification. The ethanol precipitation process quantitatively altered the chemical profiles of ZQD, subsequently affected the absorbed components of ZQD, and then affected the key targets and pathways of ZQD for relieving MPS. The ethanol precipitation process might result in variation of MPS‐relieving efficacy of ZQD, which deserves further in vivo verification.