Study on the pharmacodynamic material basis and mechanism of stereochemically defined active constituents from Notopterygium incisum Against RA based on PK-PD modeling and untargeted metabolomics.

In this study, the pharmacodynamic material basis and mechanisms of Notopterygium incisum in the treatment of rheumatoid arthritis (RA) were investigated, with special emphasis on the stereochemistry of its active constituents. A pharmacokinetic-pharmacodynamic (PK-PD) model and untargeted metabolomics were applied in an adjuvant-induced arthritis (AIA) rat model. Plasma constituent concentrations and inflammatory cytokine levels were monitored at multiple time points after administration. PK-PD relationships for 11 stereochemically defined active constituents were established using the Sigmoid-Emax model, yielding biologically plausible parameters describing constituent disposition-effect relationships. Untargeted metabolomics identified 8 significantly altered metabolites associated with inflammatory status, involving amino acid, glycerophospholipid, and purine metabolism, among other pathways. Notopterygium incisum effectively alleviated inflammation and synovial lesions in AIA rats. Four constituents-isoimperatorin, bergapten, (-)-notopterol, and (+)-notopterol-were identified as primary therapeutic agents, modulating inflammatory cytokines and regulating multiple metabolic pathways. These findings provide a mechanistic rationale for the anti-RA potential of Notopterygium incisum and support its further development as a therapeutic agent.