Current drug metabolism最新文献

{"title":"Avapritinib Carries the Risk of Drug Interaction <i>via</i> Inhibition of UDP-Glucuronyltransferase (UGT) 1A1.","authors":"Xin Lv, Zhen Wang, Zhe Wang, Hang Yin, Yangliu Xia, Lili Jiang, Yong Liu","doi":"10.2174/0113892002288312240521092054","DOIUrl":"10.2174/0113892002288312240521092054","url":null,"abstract":"<p><strong>Background: </strong>Avapritinib is the only drug for adult patients with PDGFRA exon 18 mutated unresectable or metastatic gastrointestinal stromal tumor (GIST). Although avapritinib has been approved by the FDA for four years, little is known about the risk of drug-drug interactions (DDIs) via UDP-glucuronyltransferases (UGTs) inhibition.</p><p><strong>Objective: </strong>The aim of the present study was to systematically evaluate the inhibitory effects of avapritinib against UGTs and to quantitatively estimate its potential DDIs risk <i>in vivo</i>.</p><p><strong>Methods: </strong>Recombinant human UGTs were employed to catalyze the glucuronidation of substrates in a range of concentrations of avapritinib. The kinetics analysis was performed to evaluate the inhibition types of avapritinib against UGTs. The quantitative prediction of DDIs was done using <i>in vitro-in vivo</i> extrapolation (IVIVE).</p><p><strong>Results: </strong>Avapritinib had a potent competitive inhibitory effect on UGT1A1. Quantitative prediction results showed that avapritinib administered at clinical doses might result in a 14.85% increase in area under the curve (AUC) of drugs primarily cleared by UGT1A1. Moreover, the Rgut value was calculated to be 18.44.</p><p><strong>Conclusion: </strong>Avapritinib has the potential to cause intestinal DDIs <i>via</i> the inhibition of UGT1A1. Additional attention should be paid when avapritinib is coadministered with UGT1A1 substrates.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"197-204"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141157928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disposition Kinetics of Cathinone and its Metabolites after Oral Administration in Rats.","authors":"Fahad Y Sabei, Ibrahim Khardali, Mohamed A Al-Kasim, Emad Sayed Shaheen, Magbool Oraiby, Ahmad Alamir, Banji David, Saeed Alshahrani, Abdulmajeed M Jali, Mohammed Attafi, Mohammed Y Albeishy, Ibraheem Attafi","doi":"10.2174/0113892002300638240513065512","DOIUrl":"10.2174/0113892002300638240513065512","url":null,"abstract":"<p><strong>Background: </strong>Cathinone is a natural stimulant found in the Catha edulis plant. Its derivatives make up the largest group of new psychoactive substances. In order to better understand its effects, it is imperative to investigate its distribution, pharmacokinetics, and metabolic profile. However, the existing literature on cathinone remains limited.</p><p><strong>Objective: </strong>This study aimed to investigate the disposition kinetics and metabolic profile of cathinone and its metabolite cathine through a single oral dose of cathinone administration in rats.</p><p><strong>Methods: </strong>Cathinone and cathine concentrations were identified and quantified using ion trap liquid chromatography- mass spectrometry (LC-IT/MS). The metabolic profile in the serum, brain, lung, liver, kidney, and heart was analyzed at specific time points (0, 0.5, 2.5, 6, 12, 24, 48, and 72 hours) using the ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF/MS) method.</p><p><strong>Results: </strong>The highest concentration of cathinone was found in the kidney (1438.6 μg/L, which gradually decreased to 1.97 within 48 h and disappeared after 72 h. Cathinone levels in the lungs, liver, and heart were 859, 798.9, and 385.8 μg/L, respectively, within half an hour. However, within 2.5 hours, these levels decreased to 608.1, 429.3, and 309.1 μg/L and became undetectable after 24 h. In the rat brain, cathinone levels dropped quickly and were undetectable within six hours, decreasing from 712.7 μg/L after 30 min. In the brain and serum, cathine reached its highest levels at 2.5 hours, while in other organs, it peaked at 0.5 hours, indicating slower conversion of cathinone to cathine in the brain and serum.</p><p><strong>Conclusion: </strong>This study revealed a dynamic interplay between cathinone disposition kinetics and its impact on organ-specific metabolic profiles in rats. These results have significant implications for drug development, pharmacovigilance, and clinical practices involving cathinone. Investigating the correlation between the changes in biomarkers found in the brain and the levels of cathinone and cathine is essential for informed decision- making in medical practices and further research into the pharmacological properties of cathinone.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"220-226"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140944368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent Advances in Hepatic Metabolic Regulation by the Nuclear Factor Rev-erbɑ.","authors":"Qi Zhang, Yutong Chen, Jingqi Li, Haishan Xia, Yongbin Tong, Yuyu Liu","doi":"10.2174/0113892002290055240212074758","DOIUrl":"10.2174/0113892002290055240212074758","url":null,"abstract":"<p><p>Rev-erbɑ (NR1D1) is a nuclear receptor superfamily member that plays a vital role in mammalian molecular clocks and metabolism. Rev-erbɑ can regulate the metabolism of drugs and the body's glucose metabolism, lipid metabolism, and adipogenesis. It is even one of the important regulatory factors regulating the occurrence of metabolic diseases (e.g., diabetes, fatty liver). Metabolic enzymes mediate most drug metabolic reactions in the body. Rev-erbɑ has been recognized to regulate drug metabolic enzymes (such as Cyp2b10 and Ugt1a9). Therefore, this paper mainly reviewed that Rev-erbɑ regulates I and II metabolic enzymes in the liver to affect drug pharmacokinetics. The expression of these drug metabolic enzymes (up-regulated or down-regulated) is related to drug exposure and effects/ toxicity. In addition, our discussion extends to Rev-erbɑ regulating some transporters (such as P-gp, Mrp2, and Bcrp), as they also play an essential role in drug metabolism. Finally, we briefly describe the role and mechanism of nuclear receptor Rev-erbɑ in lipid and glucose homeostasis, obesity, and metabolic disorders syndrome. In conclusion, this paper aims to understand better the role and mechanism of Rev-erbɑ in regulating drug metabolism, lipid, glucose homeostasis, obesity, and metabolic disorders syndrome, which explores how to target Rev-erbɑ to guide the design and development of new drugs and provide scientific reference for the molecular mechanism of new drug development, rational drug use, and drug interaction.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"2-12"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139971187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hydrogen Peroxide Induces Ethanol-inducible CYP2E1 <i>via</i> the NF-kB-classical Pathway: CYP2E1 mRNA Levels are not High in Alcoholic Hepatitis.","authors":"Akiyoshi Tamura, Ferbian Milas Siswanto, Takumi Yoshimura, Ami Oguro, Susumu Imaoka","doi":"10.2174/0113892002305174240805064406","DOIUrl":"10.2174/0113892002305174240805064406","url":null,"abstract":"<p><strong>Aims: </strong>The aim of the present study is to elucidate the mechanism of CYP2E1 induction as a causative factor of Alcoholic Hepatitis (AH) and its relationship with inflammation.</p><p><strong>Background: </strong>Chronic alcohol consumption induces CYP2E1, which is involved in the development of Alcoholic Hepatitis (AH). However, the mechanisms underlying the induction of CYP2E1 by alcohol remain unclear. Therefore, we herein investigated the induction of drug-metabolizing enzymes, particularly CYP2E1, by hydrogen peroxide (H₂O₂), the concentration of which is elevated under inflammatory conditions.</p><p><strong>Objective: </strong>The mechanisms underlying the induction of CYP2E1 by H₂O₂ were examined with a focus on Keap1, a target factor of H₂O₂.</p><p><strong>Methods: </strong>We assessed changes in the expression of drug-metabolizing enzymes in the human hepatoma cell line, Hep3B, following treatment with H₂O₂, and evaluated changes in the expression of the NF-kB-related factor RelA(p65) after the knockdown of Keap1, a regulator of Nrf2 expression by reactive oxygen species. We also performed a promoter analysis using the upstream region of the CYP2E1 gene. We herein used the GSE89632 series for non-alcoholic hepatitis (NASH) and the GSE28619 series for AH.</p><p><strong>Results: </strong>The induction of CYP2E1 by H₂O₂ was significantly stronger than that of other drugmetabolizing enzymes. On the other hand, the knockdown of Keap1, a target of H₂O₂, markedly increased RelA(p65), an NFkB factor. Furthermore, the overexpression of RelA(p65) strongly induced the expression of CYP2E1. Four candidate p65-binding sequences were identified upstream of the CYP2E1 gene, and promoter activity assays showed that the third sequence was responsive to the overexpression of RelA(p65). We used the GSE89632 series for NASH and the GSE28619 series for AH in the present study. The expression of CYP2E1 mRNA in the liver was significantly lower in AH patients than in HC patients, but was similar in HC patients and NASH patients.</p><p><strong>Conclusion: </strong>We herein demonstrated that the expression of CYP2E1 was induced by H₂O₂. The overexpression of RelA(p65) also induced CYP2E1 mRNA expression, whereas H₂O₂ did not after the knockdown of RelA. These results suggest that H₂O₂ acts on Keap1 to upregulate RelA (p65) in the NFkB system. One of the mechanisms underlying the induction of CYP2E1 was dependent on the H₂O₂-Keap1-RelA axis. The results of the database analysis revealed that the expression of CYP2E1 in the liver was significantly lower in AH patients than in NASH patients, suggesting that CYP2E1 is not the main cause of AH; however, CYP2E1 may exacerbate the pathogenesis of AH.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"307-316"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141916270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of <i>UGT1A</i> Gene Polymorphisms with BKV Infection in Renal Transplantation Recipients.","authors":"Jingwen Yuan, Shuang Fei, Zeping Gui, Zijie Wang, Hao Chen, Li Sun, Jun Tao, Zhijian Han, Xiaobing Ju, Ruoyun Tan, Min Gu, Zhengkai Huang","doi":"10.2174/0113892002282727240307072255","DOIUrl":"10.2174/0113892002282727240307072255","url":null,"abstract":"<p><strong>Background: </strong>BK virus (BKV) infection is an opportunistic infectious complication and constitutes a risk factor for premature graft failure in kidney transplantation. Our research aimed to identify associations and assess the impact of single-nucleotide polymorphisms (SNPs) on metabolism-related genes in patients who have undergone kidney transplantation with BKV infection.</p><p><strong>Material/methods: </strong>The DNA samples of 200 eligible kidney transplant recipients from our center, meeting the inclusion criteria, have been collected and extracted. Next-generation sequencing was used to genotype SNPs on metabolism-associated genes (CYP3A4/5/7, UGT1A4/7/8/9, UGT2B7). A general linear model (GLM) was used to identify and eliminate confounding factors that may influence the outcome events. Multiple inheritance models and haplotype analyses were utilized to identify variation loci associated with infection caused by BKV and ascertain haplotypes, respectively.</p><p><strong>Results: </strong>A total of 141 SNPs located on metabolism-related genes were identified. After Hardy-Weinberg equilibrium (HWE) and minor allele frequency (MAF) analysis, 21 tagger SNPs were selected for further association analysis. Based on GLM results, no confounding factor was significant in predicting the incidence of BK polyomavirus-associated infection. Then, multiple inheritance model analyses revealed that the risk of BKV infection was significantly associated with rs3732218 and rs4556969. Finally, we detect significant associations between haplotype T-A-C of block 2 (rs4556969, rs3732218, rs12468274) and infection caused by BKV (P = 0.0004).</p><p><strong>Conclusion: </strong>We found that genetic variants in the UGT1A gene confer BKV infection susceptibility after kidney transplantation.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"188-196"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140174062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety Aspects of Herb Interactions: Current Understanding and Future Prospects.","authors":"Subhajit Hazra, Preet Amol Singh","doi":"10.2174/0113892002289753240305062601","DOIUrl":"10.2174/0113892002289753240305062601","url":null,"abstract":"<p><strong>Background: </strong>The use of herbal medicines is on the rise throughout the world due to their perceived safety profile. However, incidences of herb-drug, herb-herb and herb-food interactions considering safety aspects have opened new arenas for discussion.</p><p><strong>Objective: </strong>The current study aims to provide comprehensive insights into the various types of herb interactions, the mechanisms involved, their assessment, and historical developments, keeping herbal safety at the central point of discussion.</p><p><strong>Methods: </strong>The authors undertook a focused/targeted literature review and collected data from various databases, including Science Direct, Wiley Online Library, Springer, PubMed, and Google Scholar. Conventional literature on herbal remedies, such as those by the WHO and other international or national organizations.</p><p><strong>Results: </strong>The article considered reviewing the regulations, interaction mechanisms, and detection of herb-herb, herb-drug and herb-food interactions in commonly used yet vital plants, including <i>Glycyrrhiza glabra, Mentha piperita, Aloe barbadensis, Zingiber officinale, Gingko biloba, Withania somnifera, etc</i>. The study found that healthcare professionals worry about patients not informing them about their herbal prescriptions (primarily used with conventional treatment), which can cause herb-drug/herb-food/herb-herb interactions. These interactions were caused by altered pharmacodynamic and pharmacokinetic processes, which might be explained using <i>in-vivo, in-vitro, in-silico</i>, pharmacogenomics, and pharmacogenetics. Nutrivigilance may be the greatest method to monitor herb-food interactions, but its adoption is limited worldwide.</p><p><strong>Conclusion: </strong>This article can serve as a lead for clinicians, guiding them regarding herb-drug, herb-food, and herb-herb interactions induced by commonly consumed plant species. Patients may also be counseled to avoid conventional drugs, botanicals, and foods with a restricted therapeutic window.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"28-53"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140119027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Where will Medicines that Serve the Global South and Economically Disadvantaged People Come From?","authors":"Ming Hu","doi":"10.2174/138920022501240507141919","DOIUrl":"https://doi.org/10.2174/138920022501240507141919","url":null,"abstract":"","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":"25 1","pages":"1"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141491227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of High-altitude Hypoxia on Drug Metabolism and Pharmacokinetics of Sedative-hypnotic Drugs and Regulatory Mechanism.","authors":"Lu Tian, Guiqin Liu, Junjun Han, Xiangyang Li","doi":"10.2174/0113892002318723240802100729","DOIUrl":"10.2174/0113892002318723240802100729","url":null,"abstract":"<p><p>Sedative hypnotics effectively improve sleep quality under high-altitude hypoxia by reducing central nervous system excitability. High-altitude hypoxia causes sleep disorders and modifies the metabolism and mechanisms of drug action, impacting medication therapy's effectiveness. This review aims to provide a theoretical basis for the treatment of central nervous system diseases in high-altitude areas by summarizing the progress and mechanism of sedative-hypnotics in hypoxic environments, as well as the impact of high-altitude hypoxia on sleep.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"416-424"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141897014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prediction of Protein-Drug Interactions, Pharmacophore Modeling, and Toxicokinetics of Novel Leads for Type 2 Diabetes Treatment.","authors":"Anuradha Mehra, Amit Mittal, Prakhar Kumar Vishwakarma","doi":"10.2174/0113892002321919240801065905","DOIUrl":"10.2174/0113892002321919240801065905","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Small heterocyclic compounds have been crucial in pioneering advances in type 2 diabetes treatment. There has been a dramatic increase in the pharmacological development of novel heterocyclic derivatives aimed at stimulating the activation of Glucokinase (GK). A pharmaceutical intervention for diabetes is increasingly targeting GK as a legitimate target. Diabetes type 2 compromises Glucokinase's function, an enzyme vital for maintaining the balance of blood glucose levels. Medicinal substances strategically positioned to improve type 2 diabetes management are used to stimulate the GK enzyme using heterocyclic derivatives.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Objective: &lt;/strong&gt;The research endeavor aimed to craft novel compounds, drawing inspiration from the inherent coumarin nucleus found in nature. The goal was to evoke the activity of the glucokinase enzyme, offering a tailored approach to mitigate the undesired side effects typically associated with conventional therapies employed in the treatment of type 2 diabetes.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Coumarin, sourced from nature's embrace, unfolds as a potent and naturally derived ally in the quest for innovative antidiabetic interventions. Coumarin was extracted from a variety of botanical origins, including Artemisia keiskeana, Mallotus resinosus, Jatropha integerrima, Ferula tingitana, Zanthoxylum schinifolium, Phebalium clavatum, and Mammea siamensis. This inclusive evaluation was conducted on Muybridge's digital database containing 53,000 hit compounds. The presence of the coumarin nucleus was found in 100 compounds, that were selected from this extensive repository. Utilizing Auto Dock Vina 1.5.6 and ChemBioDraw Ultra, structures generated through this process underwent docking analysis. Furthermore, these compounds were accurately predicted online log P using the Swiss ADME algorithm. A predictive analysis was conducted using PKCSM software on the primary compounds to assess potential toxicity.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Using Auto Dock Vina 1.5.6, 100 coumarin derivatives were assessed for docking. Glucokinase (GK) binding was significantly enhanced by most of these compounds. Based on superior binding characteristics compared with Dorzagliatin (standard GKA) and MRK (co-crystallized ligand), the top eight molecules were identified. After further evaluation through ADMET analysis of these eight promising candidates, it was confirmed that they met the Lipinski rule of five and their pharmacokinetic profile was enhanced. The highest binding affinity was demonstrated by APV16 at -10.6 kcal/mol. A comparison between the APV16, Dorzagliatin and MRK in terms of toxicity predictions using PKCSM indicated that the former exhibited less skin sensitization, AMES toxicity, and hepatotoxicity.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;Glucokinase is most potently activated by 100 of the compound leads in the database of 53,000 compounds that contain the coumarin nucleus. APV12, with its hi","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"355-380"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141897016","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An Efficient Integrated Strategy for Comprehensive Metabolite Profiling of Sakurasosaponin from Aegiceras corniculatum in Rats.","authors":"Xiangying Wang, Xiao Yang, Erwei Hao, Jinling Xie, Zhengcai Du, Jiagang Deng, Xiaotao Hou, Wei Wei","doi":"10.2174/0113892002299923240801092101","DOIUrl":"10.2174/0113892002299923240801092101","url":null,"abstract":"<p><strong>Objective: </strong>Sakurasosaponin, a primary bioactive saponin from Aegiceras corniculatum, shows potential as an anti-cancer agent. However, there is a lack of information on its in vivo metabolism. This study aims to profile the in vivo metabolites of sakurasosaponin in rat feces, urine, and plasma after oral administration. An efficient strategy using ultra-high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry was developed, which combined metabolic prediction, multiple mass defects filtering, and highresolution extracted ion chromatograms for rapid and systematic analysis.</p><p><strong>Methods: </strong>Firstly, a theoretical list of metabolites for sakurasosaponin was developed. This was done by considering the metabolic pathways of saponins. Next, the multiple mass defects filtering method was employed to identify potential metabolites in feces and urine, using the unique metabolites of sakurasosaponin as multiple mass defects filtering templates. Subsequently, a high-resolution extracted ion chromatogram was used to quickly determine the metabolites in rat plasma post-identification in feces and urine. Lastly, the analysis of accurate mass, typical neutral loss, and diagnostic ion of the candidate metabolites was carried out to confirm their structural elucidation, and metabolic pathways of sakurasosaponin in vivo were also proposed.</p><p><strong>Results: </strong>In total, 30 metabolites were provisionally identified in feces, urine, and plasma. Analysis of metabolic pathways revealed isomerization, deglycosylation, oxidation, hydroxylation, sulfate conjugation, glucuronide conjugation, and other related reactions as the primary biotransformation reactions of sakurasosaponin in vivo.</p><p><strong>Conclusion: </strong>The findings demonstrate that the designed research strategy effectively minimizes matrix interference, prevents the omission of low-concentration metabolites, and serves as a foundation for the discovery of active metabolites of sakurasosaponin.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"340-354"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141897012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}