Compatibility mechanism of Atractylodis Macrocephalae Rhizoma and Glycyrrhizae Radix et Rhizoma in colitis treatment: Integrating pharmacokinetics, metabolomics, and network pharmacology.

Atractylodis Macrocephalae Rhizoma (AM) and Glycyrrhizae Radix et Rhizoma (GR) are important traditional herb medicines with multiple activities, which are usually used as a herb pair (AG) to cure ulcerative colitis (UC) in clinical practices for thousands of years. However, their compatibility mechanism is not yet clear. The purpose of this study was to reveal the compatibility mechanism of AM and GR in the treatment of UC by the multidisciplinary approach integrating metabolomics, pharmacokinetics, and network pharmacology. Pharmacodynamics (PD) analysis demonstrated that AM and GR could significantly reduce colonic damage and inflammatory response in UC mice, while AG showed stronger efficacies. Dissolution rates of seven main active ingredients in AG (atractylenolide I, atractylenolide III, liquiritin, isoliquiritin, glycyrrhizic acid, glycyrrhetinic acid, and isoliquiritigenin) were markedly increased. Pharmacokinetic (PK) analysis further showed that AUC(0-t) and MRT(0-t) of these ingredients were significantly increased in the AG group. Furthermore, the disorder of plasma metabolic profiles in UC mice could be notably reversed by AG, which mainly modulated arachidonic acid metabolism pathways. Network pharmacology (NP) results showed that 43 targets related to UC might be modulated by seven main active ingredients in AG. Molecular docking and RT-qPCR analysis further confirmed that AG could notably inhibit the expression of PTGS2. Compared with AM and GR, their compatibility could notably improve pathological symptoms of UC mice, which might be related to the increased dissolution rate of the active ingredients in vitro and in vivo exposure. And the potential mechanism of the AG herb pair might regulate the arachidonic acid metabolism pathway by inhibiting the expression of PTGS2.