Drug-induced enzyme activity inhibition and CYP3A4 genetic polymorphism significantly shape the metabolic characteristics of furmonertinib.

This study aimed to elucidate the impact of variations in liver enzyme activity, particularly CYP3A4, on the metabolism of furmonertinib. An in vitro enzyme incubation system was established for furmonertinib using liver microsomes and recombinant CYP3A4 baculosomes, with analytes detected by LC-MS/MS. The pharmacokinetic characteristics of furmonertinib were studied in vivo using Sprague-Dawley rats. It was found that telmisartan significantly inhibited the metabolism of furmonertinib, as demonstrated by a significant increase in the AUC of furmonertinib when co-administered with telmisartan, compared to the furmonertinib-alone group. Mechanistically, it was noncompetitive in rat liver microsomes, while it was mixed competitive and noncompetitive in human liver microsomes and CYP3A4. Considering the genetic polymorphism of CYP3A4, the study further investigated its effect on the kinetics of furmonertinib. The results showed that compared to CYP3A4.1, CYP3A4.29 had significantly increased activity in catalyzing furmonertinib, whereas CYP3A4.7, 9, 10, 12, 13, 14, 18, 23, 33, and 34 showed markedly decreased activity. The inhibitory activity of telmisartan varied in CYP3A4.1 and CYP3A4.18, with IC50 values of 8.56 ± 0.90 µM and 27.48 ± 3.52 µM, respectively. The key loci affecting the inhibitory effect were identified as ARG105, ILE301, ALA370, and LEU373. Collectively, these data would provide a reference for the quantitative application of furmonertinib.

The impact of CYP3A4 genetic polymorphism on crizotinib metabolism and drug-drug interactions.

To elucidate the impact of CYP3A4 activity inhibition and genetic polymorphism on the metabolism of crizotinib. Enzymatic incubation systems for crizotinib were established, and Sprague-Dawley rats were utilized for in vivo experiments. Analytes were quantified using LC-MS/MS. Upon screening 122 drugs and natural compounds, proanthocyanidins emerged as inhibitor of crizotinib metabolism, exhibiting a relative inhibition rate of 93.7%. The IC50 values were 24.53 ± 0.32 µM in rat liver microsomes and 18.24 ± 0.12 µM in human liver microsomes. In vivo studies revealed that proanthocyanidins markedly affected the pharmacokinetic parameters of crizotinib. Co-administration led to a significant reduction in the AUC(0-t), Cmax of PF-06260182 (the primary metabolite of crizotinib), and the urinary metabolic ratio. This interaction is attributed to the mixed-type inhibition of liver microsome activity by proanthocyanidins. CYP3A4, being the principal metabolic enzyme for crizotinib, has its genetic polymorphisms significantly influencing crizotinib's pharmacokinetics. Kinetic data showed that the relative metabolic rates of crizotinib across 26 CYP3A4 variants ranged from 13.14% (CYP3A4.12, 13) to 188.57% (CYP3A4.33) when compared to the wild-type CYP3A4.1. Additionally, the inhibitory effects of proanthocyanidins varied between CYP3A4.12 and CYP3A4.33, when compared to the wild type. Our findings indicate that proanthocyanidins coadministration and CYP3A4 genetic polymorphism can significantly influence crizotinib metabolism.

Astragalus Polysaccharide Alleviates Ulcerative Colitis by Regulating the Balance of mTh17/mTreg Cells through TIGIT/CD155 Signaling.

The balance between memory Th17 cells (mTh17) and memory Treg cells (mTreg) plays a key role in the pathogenesis of ulcerative colitis (UC), and TIGIT signaling is involved in the differentiation of mTh17/mTreg cells. Astragalus polysaccharide (APS) has good immunomodulatory and anti-inflammatory effects. Here, the regulatory effects and potential mechanisms of APS on mTh17/mTreg cells in UC are explored. A UC model was induced with dextran sulfate sodium (DSS) and treated simultaneously with APS (200 mg/kg/day) for 10 days. After APS treatment, the mice showed a significant increase in colonic length and a significant decrease in colonic weight, colonic weight index and colonic weight/colonic length, and more intact mucosa and lighter inflammatory cell infiltration. Notably, APS significantly down-regulated the percentages of Th17 (CD4+CCR6+), cmTh17 (CD4+CCR7+CCR6+) and emTh17 (CD4+CCR7-CCR6+) cells and significantly up-regulated the percentages of cmTreg (CD4+CCR7+Foxp3+) and emTreg (CD4+CCR7-Foxp3+) cells in the mesenteric lymph nodes of the colitis mice. Importantly, APS reversed the expression changes in the TIGIT molecule on mTh17/mTreg cells in the colitis mice with fewer CD4+CCR6+TIGIT+, CD4+CCR7-CCR6+TIGIT+ and CD4+CCR7-CCR6+TIGIT+ cells and more CD4+Foxp3+TIGIT+, CD4+CCR7-Foxp3+TIGIT+ and CD4+CCR7-Foxp3+TIGIT+ cells. Meanwhile, APS significantly inhibited the protein expression of the TIGIT ligands CD155, CD113 and CD112 and downstream proteins PI3K and AKT in the colon tissues of the colitis mice. In conclusion, APS effectively alleviated DSS-induced UC in mice by regulating the balance between mTh17/mTreg cells, which was mainly achieved through regulation of the TIGIT/CD155 signaling pathway.

Integrating network pharmacology and experimental verification to explore the mucosal protective effect of Chimonanthus nitens Oliv. Leaf Granule on ulcerative colitis.

ETHNOPHARMACOLOGICAL RELEVANCE: Chimonanthus nitens Oliv. Leaf Granule (COG) is a commonly used clinical preparation of traditional Chinese medicine for the treatment of cold, but there are folk reports that it can treat diarrhea and other gastrointestinal diseases. Therefore, the mechanism of COG in the treatment of ulcerative colitis with diarrhea as the main symptom needs to be studied. AIM OF THE STUDY: Combined network pharmacology and experimental validation to explore the mechanism of COG in the treatment of ulcerative colitis. MATERIALS AND METHODS: First, the main components of COG were characterized by liquid chromatography-mass spectrometry (LC-MS); subsequently, a network pharmacology approach was used to screen the effective chemical components and action targets of COG to construct a target network of COG for the treatment of ulcerative colitis (UC). The protein-protein interaction network (PPI) and literature reports were combined to identify the potential targets of COG for the treatment of UC. Finally, the predicted results of network pharmacology were validated by animal and cellular experiments. RESULTS: 19 components of COG were characterized by LC-MS, among which 10 bioactive components could act on 377 potential targets of UC. Key therapeutic targets were collected, including SRC, HSP90AA1, PIK3RI, MAPK1 and ESR1. KEGG results are enriched in pathways related to oxidative stress. Molecular docking analysis showed good binding activity of main components and target genes. Animal experiments showed that COG significantly relieved the colitis symptoms in mice, regulated the Treg/Th17 balance, and promoted the secretion of IL-10 and IL-4, along with the inhibition of IL-1ß and TNF-α. Additionally, COG reduced the apoptosis of colon epithelial cells, and significantly improved the levels of SOD, MAO, GSH-px, and inhibited MDA, iNOS, eNOS in colon. Also, it increased the expression of tight junction proteins such as ZO-1, Claudin1, Occludin and E-cadherin. In vitro experiments, COG inhibited the oxidative stress and inflammatory injury of HCT116 cells induced by LPS. CONCLUSIONS: Combining network pharmacology and in vitro and in vivo experiments, COG was verified to have a good protective effect in UC, which may be related to enhancing antioxidation in colon tissues.

Ginsenoside Rg1 Alleviates Ulcerative Colitis in Obese Mice by Regulating the Gut Microbiota-Lipid Metabolism-Th1/Th2/Th17 Cells Axis.

Ginsenoside Rg1 (G-Rg1) has various pharmacological properties including antiobesity, immunomodulatory, and anti-inflammatory effects. This study aimed to explore the therapeutic effects and underlying mechanisms of G-Rg1 on colitis complicated by obesity. The results indicate that G-Rg1 effectively alleviates colitis in obese mice and improves serum lipid levels and liver function. Importantly, G-Rg1 improved the composition of gut microbiota in obese mice with colitis, with increases in alpha diversity indexes Sobs, Ace, and Chao, a significant down-regulation of the relative abundance of Romboutsia, and a significant up-regulation of Rikenellaceae_RC9_gut_group, Lachnospiraceae_NK4A136_group, Enterorhabdus, Desulfovibrio, and Alistipes. Meanwhile, G-Rg1 improved lipid metabolism in the colonic contents of obese mice with colitis. Additionally, G-Rg1 significantly reduced the percentages of helper T (Th)1, Th17, central memory T (TCM), and effector memory T (TEM) cells in obese mice with colitis while significantly increasing Naïve T and Th2 cells. In conclusion, G-Rg1 could be a promising therapeutic option for alleviating obesity complicated by colitis through regulation of the gut microbiota and lipid metabolism as well as Th1/Th2/Th17 cell differentiation.