Glycycoumarin is a representative coumarin compound with significant pharmacological activities isolated from Glycyrrhiza uralensis Fisch., Fabaceae. Studies have shown that glycycoumarin has many biological activities, such as anti-tumor, liver protection, antispasmodic, antibacterial, and antivirus. However, the poor solubility of glycycoumarin in water and the accompanying reactions of the phase I (hydroxylation) and II (glucuronidation) metabolism limit its druggability, which manifests as low absorption in the body after oral administration and low free drug concentration, ultimately leading to low bioavailability. Therefore, a comprehensive review of the pharmacological effects and pharmacokinetics of glycycoumarin is presented to provide a reference for further research and application as a therapeutic agent. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1007/s43450-022-00342-x.

Licorice (Glycyrrhiza uralensis Fisch) is a natural plant resource widely used as a food and herbal medication in China. Glycycoumarin (GCM) is a major coumarin in licorice that possesses several biological activities. However, little is known about its pharmacokinetic profile. The present study aimed to describe the oral absorption, tissue distribution, and excretion of GCM in rats. Free (parent drug) and/or total (parent drug plus the glucuronidated metabolite) GCM in biological samples was quantified before and after the hydrolysis reaction with β-glucuronidase using a reliable LC-MS/MS method. The results indicated that GCM was rapidly absorbed and transformed into its conjugated metabolites after administration. Free GCM plasma concentrations after i. v. (10 mg/kg) administration quickly decreased with an average t1/2,λz of 0.71 h, whereas the total GCM concentration reduced slowly with a t1/2, λz of 2.46 h. The area under the curve of glucuronidated metabolites was approximately four-times higher than that of free GCM. Presumably, because of hepatic and/or intestinal tract first-pass metabolism, GCM exhibited a poor bioavailability of 9.22%, as estimated from its total plasma concentration. Additionally, GCM was distributed rapidly and widely in various tissues except the brain. The liver had the highest concentration; further, GCM was promptly eliminated from test tissues after intraperitoneal (20 mg/kg) administration, but only a small amount of GCM was excreted via bile and urine. Overall, GCM is absorbed and rapidly transformed into its conjugated metabolites with low bioavailability; further, it is distributed in various tissues, except the brain. These pharmacokinetic results are helpful for better understanding the characteristics and pharmacological effects of GCM.

Network pharmacology, reverse molecular docking, and rat acute pancreatitis (AP) models were used to analyze the mechanism of protection by Qingyi II granules. The chemical components of 7 Chinese herbal medicines in Qingyi II granules were searched through the TCMSP (traditional Chinese medicine systems pharmacology database and analysis platform) database. The active ingredients were screened out in the OB (oral bioavailability) and DL (drug likeness) filters as a condition for inclusion. Then, the prediction analysis of potential targets was performed through databases. A GO (gene ontology) enrichment analysis of target proteins related to AP and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway annotation was performed using the DAVID (The Database for Annotation, Visualization, and Integrated Discovery) database. Finally, the “Herbal-Compound-Target” network was constructed using Cytoscape software. The active component structure and target name were uploaded to the Systems Dock database for reverse molecular docking. With octreotide as a positive control, Qingyi II decoction and Qingyi II granules were administered to AP rats at low, medium, and high doses. The pathological changes in the pancreas were observed using HE staining. The levels of Bcl-2, AMS, BAX, IL-2, and CASP3 in plasma were determined by an ELISA kit. Real-time PCR detected the expression of AKT1 and PIK3CA mRNA in the pancreas. The database predicted 94 active components of Qingyi II granules, 76 potential targets, and 64 signaling pathways. Twenty pathways were directly or indirectly associated with acute pancreatitis, including the TNF signaling pathway and the PI3K-AKT signaling pathway. In the reverse molecular docking experiment, the matching scores of the active components and the target were mainly between 6.0 and 7.0, with strong binding activity. Compared to the normal group, the plasma concentrations of BAX, IL-2, Bcl-2, AMS, and CASP3 in the model group were significantly increased ( P < 0.05 ). Compared with the model group, the low-dose group of Qingyi II granules only significantly reduced IL-2 levels and had no effect on other indicators. The other groups could significantly reduce the levels of AMS, BAX, and CASP3 ( P < 0.05 ). Compared with the model group, the octreotide group and Qingyi II granules high-dose group significantly increased the Bcl-2 level ( P < 0.05 ), and there was no statistical difference in other drug-administered groups. Compared with the normal group, the expression of AKT1 and PIK3CA in the pancreas of the model group was significantly higher. Compared to the model group, the expression of PIK3CA was low in all drug-administered groups. In addition to the low-dose group, the other drug-administered groups significantly reduced the expression of AKT1. Qingyi can reduce the levels of AMS, BAX, IL-2, and CASP3 and increase the levels of Bcl-2. This mechanism may be related to the PI3K- AKT signaling pathway.