Spectrum-efficacy and pharmacodynamics-pharmacokinetics correlation of multi-index constituents in Liangfu Dripping Pills in ethanol-induced acute gastric ulcer rats.

Abstract

BACKGROUND: Liangfu Dripping Pills (LFDP) are a pharmaceutical formulation derived from the Liangfu Formula, a classic traditional Chinese medicine (TCM) prescription with well-documented clinical efficacy for the treatment of gastric ulcers. Nevertheless, the in vivo processes of its active constituents and the underlying mechanisms of its anti-ulcer effects remain to be fully elucidated. OBJECTIVE: To reveal the active ingredients and potential mechanisms of LFDP in exerting anti-acute gastric ulcer effects through spectrum-effect relationship and pharmacokinetics-pharmacodynamics (PK-PD) Model. METHODS: An ethanol-induced acute gastric ulcer model was established in rats. The spectrum-effect correlation between the differentially migrated constituents of LFDP and gastric ulcer indicators was analyzed to screen PK/PD markers. Differential pharmacokinetic characteristics were evaluated with respect to dosage and biological state (normal vs. gastric ulcer). An integrated multi-constituent PK-PD model was established, and potential regulatory pathways of LFDP were verified by immunoblotting and RT-qPCR. RESULTS: LFDP dose-dependently ameliorated gastric mucosal degeneration and necrosis in rats with ethanol-induced acute gastric ulcers. Twenty-seven plasma migrated constituents correlated closely with increased levels of EGF, NO, SOD and decreased TNF-&#x3b1;, GAS, MDA (VIP>1). The in vivo exposure levels of caryophyllene oxide, cyperenone, rhamnocitrin, and galangin-3-O-methyl ether increased in a significant dose-dependent manner. &#x3b1;-terpineol, benzylacetone, caryophyllene oxide, cyperenone, galangin, rhamnocitrin, or galangin-3-O-methyl ether in gastric ulcer rats exhibited increased absorption rate, higher exposure, slower clearance, and longer retention. Multi-indicator constituents had the smallest ECand Ke0 vs. EGF, indicating strongest affinity, slower regulation, and longer duration. LFDP significantly upregulated EGF and EGFR protein and mRNA levels in ulcerated gastric tissue (P&#xa0;<&#xa0;0.05). CONCLUSION: LFDP exerted a pronounced protective effect against ethanol-induced acute gastric ulcer, which was closely correlated with the systemic exposure of its flavonoid and volatile constituents. Multiple constituents displayed distinct pharmacokinetic profiles in healthy and gastric ulcer pathological states. The regulation of the EGF/EGFR signaling pathway represents a critical potential mechanism for LFDP to exert its protective effect against acute gastric ulcers.