A Strategy of Screening Drug Combination From Traditional Chinese Medicine Based on Biomimetic Extracted Substances: Bufei Yishen Formula as a Case

ABSTRACT Introduction Traditional Chinese medicine (TCM) comprises complex matrices with largely unidentified constituents, which has resulted in clinical insecurity and difficulty in quality control. Substantial efforts have been made to screen drug combinations to replace TCM formulas; however, these methods fail to consider biotransformation among phytochemicals. Objective A “biomimetic extracted substances (BESs)” based strategy was proposed—which fully considers in vivo processes—to identify anti–chronic obstructive pulmonary disease (COPD) combinations from Bufei Yishen formula (BYF). Methods BES of each BYF ingredient was prepared via sequential coculture with artificial gastric juice, intestinal fluid, intestinal flora, and liver S9, with the compositions identified by UHPLC‐Q Exactive MS. Cytotoxicity and effects on IL‐6 secretion were analyzed in LPS‐induced macrophages to compare BYF ingredients and their BESs, screening for optimal anti‐COPD combinations. Therapeutic effects were evaluated in a smoking‐induced rat COPD model. Results Twenty‐six metabolites were identified in the BESs of five BYF ingredients from different metabolic sites. Bionic extraction reduced cytotoxicity and changed the anti‐inflammatory efficacy of BYF ingredients. Based on BES activity, nobiletin and icariin showed the highest anti‐inflammatory activity. In the COPD model, their combination significantly alleviated lung injury and inflammatory responses. Combined with metabolic analysis, the efficacy of nobiletin may be attributed to its prototype component, whereas icariin may be attributed to its deglycosylated metabolites. Conclusion BESs more closely mimics the cytotoxicity and bioactivity of TCM after metabolism. Screening based on BES thus improves consistency between in vitro and in vivo results. Using this strategy, nobiletin and icariin were identified as a potentially effective combination within BYF for alleviating COPD.