Metabolic difference of potentially toxic components from Psoraleae Fructus and Euodiae Fructus in Sishen formula by different compatibilities and physiologies

Compatibility attenuation is an effective strategy to ensure the safety of traditional Chinese medicine (TCM). Mechanistic elucidation is essential, however, no consensus reaches on the scientific connotation of compatibility attenuation in Sishen formula (SSF). Given TCM metabolism is closely associated with its toxicological consequences, this study was designed to systematically decipher and compare the holistic metabolic differences of potential toxicants derived from Psoraleae Fructus (PF) and Euodiae Fructus (EF) within SSF. In total, 23 potential toxicants from PF and EF were identified through a comprehensive literature review. Using ultra-high performance liquid chromatography/ion-mobility quadrupole time-of-flight mass spectrometry and ultra-high performance liquid chromatography/triple quadrupole-linear ion trap mass spectrometry, the metabolic difference of target components among differentiated compatibility and physiological state was elucidated by integrating serum metabolomics and poly-pharmacokinetics analyses. Holistically, the compatibility could suppress the transformation of potential toxicants, whereas irritable bowel syndrome (IBS) state exhibited a promoting effect. Myristicae Semen (MyS) or Schisandrae Chinensis Fructus (SCF) increased the exposure of toxicants from PF, while EF demonstrated an opposing effect. SCF promoted the exposure of toxicants from EF, which could be mitigated by Ershen formula. The IBS mice exhibited greater exposure to potential toxicants and their metabolites from PF (compared to the sham operation group), yet SSF alleviated this effect. Furthermore, potential toxicants in the SSF group tended to exhibit reduced metabolic transformation, decreased exposure, enhanced tissue distribution, and facilitated excretion. Collectively, these findings provide novel insights into the metabolic mechanisms underlying SSF detoxification and offer valuable safety recommendation in clinical use. • Metabolic profiles of PF, EF, and related herb-pairs were deciphered and compared. • Effect of compatibility and IBS for the potential toxicants’ metabolism was unveiled. • IBS state may be more susceptible to PF and its metabolites. • The chemical mechanism of SSF compatibility attenuation was tentatively proposed.