The gastric-emptying and satiety effects of semaglutide may lead to its misuse by athletes in weight-class sports, especially as the approved oral formulation is more convenient than subcutaneous injections. This study aimed to establish a simple ultrahigh-performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS) method for monitoring semaglutide abuse based on urinary metabolites U6 and U7, and elucidate the urinary excretion profile of the oral formulation. Multidimensional optimization determined three key factors for reliable trace detection (recovery > 90%), with enhanced hydrophobic interactions dominating the enrichment process: (i) the adsorbent, (ii) the loading pH, and (iii) the washing solvent. Orbitrap-HRMS operating in dual acquisition modes enabled both specific identification and retrospective analysis. Systematic qualitative and quantitative validation was performed, and a single oral microdose of semaglutide (3 mg) was administered to a healthy volunteer, followed by continuous urine collection for 1 week. The optimized method provided satisfactory sensitivity (limit of detection of 0.03 ng/mL) and quantitative performance (linearity range: 0.1–20 ng/mL, R 2 > 0.995; accuracy > 85%) for both U6 and U7. Excretion profiling of 25 postdose samples showed that U6 and U7 were first detectable at 21 h, peaked at 0.15 and 0.10 ng/mL, respectively, and remained detectable for up to 28 h. Additionally, five abundant metabolites of the absorption enhancer salcaprozate sodium were identified (detection window up to 7 days), serving as sensitive screening indicators for oral semaglutide. These findings demonstrate the effectiveness of the developed method and provide the first perspective on the urinary excretion profile of oral semaglutide.
Juan Tao,Xinrui Lu,Yuning Wei,Jiayi Feng,Jinlong Yang,Jianping Qi
Oral delivery of peptide therapeutics remains challenging due to gastrointestinal degradation, poor epithelial permeability, and extremely low bioavailability. To address these limitations, we developed an enteric solid formulation based on sorbic acid–choline ionic liquids (ILs) for the oral delivery of semaglutide (Sema), a glucagon-like peptide-1 (GLP-1) analogue. The IL-based enteric system was designed to enhance peptide stability, reduce gastric degradation, and promote intestinal absorption. In vitro studies demonstrated strong resistance to acidic conditions and pH-responsive release in simulated intestinal fluid. In vivo imaging further revealed prolonged intestinal retention of the IL-loaded enteric particles. Pharmacokinetic evaluation showed a 2.3-fold increase in maximum plasma concentration compared to the reference Rybelsus. In type 2 diabetes mellitus (T2DM) mice, the formulation achieved glucose-lowering efficacy comparable to subcutaneous Sema administration, with additional improvements in hepatic histology. Importantly, repeated-dose studies indicated favorable systemic and gastrointestinal tolerability under the tested conditions. Collectively, these results demonstrate that IL-based enteric formulation enhances oral peptide exposure while maintaining safety, offering a promising strategy for noninvasive T2DM management.
Yanyu Zhai,Kaili Lu,Yuan Yuan,Ziyao Zhang,Lixia Xue,Fei Zhao,Xiaofeng Xu,Hongmei Wang
BackgroundAlzheimer's disease (AD) causes cognitive function disorder and has become the preeminent cause of dementia. Glucagon-like peptide-1 (GLP-1) receptor agonists, semaglutide, have shown positive effects on promoting the cognitive function. However, research about the mechanism of semaglutide as a therapeutic intervention in AD is sparse.ObjectiveThis study was to investigate the therapeutic efficacy of semaglutide in a transgenic mouse model of AD pathology and explored the detailed mechanism by semaglutide modulated neuroinflammatory processes.MethodsMale amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice were treated with semaglutide or vehicle for 8 weeks. Morris water maze test was used to assess the therapeutic efficacy of semaglutide on recognition function. Pathology analysis was performed to detect the deposition of amyloid plaques. High-throughput sequencing analysis was applied to specify the mechanism. Microglia and astrocyte activation were assessed with immunofluorescent staining. Inflammation cytokine levels were evaluated with enzyme-linked immunosorbent assay (ELISA). Related proteins and pathway were evaluated with western blot.ResultsSemaglutide treatment attenuated Aβ accumulation and enhanced cognitive function in APP/PS1 transgenic mice. Through transcriptomic profiling, immunohistochemical staining, and ELISA, semaglutide was substantiated to inhibit the overactivation of microglia and astrocytes, as well as to curtail the secretion of inflammatory mediators. Furthermore, semaglutide robustly activated AMP-activated protein kinase (AMPK) and suppressed the toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling cascade, thus reducing the Aβ deposition and dampening the inflammatory cascade.ConclusionsThe results demonstrated that semaglutide mitigated neuroinflammation and decelerated the advance of AD in APP/PS1 transgenic mice.
危险品化学品经营许可证（带存储）