Xenobiotica最新文献_第3页

Comprehensive metabolic profiling and enzyme kinetics of cis-2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside in normal and hyperlipidemic rats. 顺式-2,3,5,4′-四羟基二苯乙烯-2- o -β- d -葡萄糖苷在正常和高脂血症大鼠体内的综合代谢谱和酶动力学

IF 1.5 4区医学

Xenobiotica Pub Date : 2026-09-01 Epub Date: 2026-07-23 DOI: 10.1080/00498254.2026.2704708

Jiexin Qiu, Beibei Yao, Qing Yu, Jiajie Wang, Lingling Huang, Jiale Chen, Yufeng Lu, Chunying Wang

{"title":"Comprehensive metabolic profiling and enzyme kinetics of cis-2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside in normal and hyperlipidemic rats.","authors":"Jiexin Qiu, Beibei Yao, Qing Yu, Jiajie Wang, Lingling Huang, Jiale Chen, Yufeng Lu, Chunying Wang","doi":"10.1080/00498254.2026.2704708","DOIUrl":"10.1080/00498254.2026.2704708","url":null,"abstract":"Cis-2,3,5,4'-tetrahydroxystilbene-2-O-β-D-glucoside (cis-THSG), a photoisomer of the major bioactive component in Polygoni Multiflori Radix Praeparata (He-Shou-Wu), has enhanced hypolipidemic activity but is associated with idiosyncratic hepatotoxicity. Its metabolic fate under pathological conditions and key clearance enzymes remain unclear.This study aimed to compare metabolite profiles of cis-THSG in normal and hyperlipidemic rats in vivo and in vitro, identify metabolites, and characterise enzyme kinetics in rat liver microsomes (RLMs) and major CYP450 isoforms. Metabolites in plasma, urine, faeces, bile, and intestinal bacteria incubation fluids were analysed by UHPLC-Q-TOF-MS/MS. Enzymatic kinetics and CYP450 isoforms were investigated via chemical inhibition assays.A total of 27 metabolites were characterised; cis-THSG underwent rapid glucoside hydrolysis, and its aglycone underwent phase I and II reactions. Hyperlipidaemia reduced metabolites to 20 and markedly increased plasma cis-THSG and aglycone abundance. Kinetic parameters were Km 32.86 μmol/L, Vmax 0.7285 μmol/(min·mg protein), CLint 0.02217 L/(min·mg protein). Rat liver microsomal CYP isoforms analogous to human CYP3A4 and CYP2C9 mediated cis-THSG oxidative metabolism.This study provides the first comprehensive metabolite map of cis-THSG, identifies its aglycone as a potential bioactive form, and reveals a disease-related metabolic shift. CYP phenotyping offers a mechanistic basis for predicting clinical drug-drug interactions.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"709-721"},"PeriodicalIF":1.5,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148473327","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}

引用次数: 0

An LC-MS/MS method for simultaneous quantification of six components of Angelicae pubescentis radix and systematic evaluation of Angelicae pubescentis radix as a potential inhibitor of multiple cytochrome P450 enzymes. LC-MS/MS法同时定量测定短毛当归6种成分及系统评价短毛当归作为多种细胞色素P450酶抑制剂的作用。

IF 1.5 4区医学

Xenobiotica Pub Date : 2026-09-01 Epub Date: 2026-07-18 DOI: 10.1080/00498254.2026.2704711

Jia Yao, Shunjun Yang, Ying Liu, Rong Ye, Yufen Liao, Yong Guo, Rong Tan, Tiantai Wu, Yang Jin, Gangyan Yu, Chang Lin, Weiwei Li, Shiyu Zhang, Jia Yu

{"title":"An LC-MS/MS method for simultaneous quantification of six components of Angelicae pubescentis radix and systematic evaluation of Angelicae pubescentis radix as a potential inhibitor of multiple cytochrome P450 enzymes.","authors":"Jia Yao, Shunjun Yang, Ying Liu, Rong Ye, Yufen Liao, Yong Guo, Rong Tan, Tiantai Wu, Yang Jin, Gangyan Yu, Chang Lin, Weiwei Li, Shiyu Zhang, Jia Yu","doi":"10.1080/00498254.2026.2704711","DOIUrl":"10.1080/00498254.2026.2704711","url":null,"abstract":"Quantitative analytical method was developed for six coumarin constituents in Angelicae pubescentis radix (APR), and the inhibitory effect of the herb's extract on cytochrome P450 enzymes was investigated.A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous quantification of six coumarins (imperatorin, 8-methoxypsoralen, isopimpinellin, isoimperatorin, bergapten, and cnidilin) in APR. Concurrently, the inhibitory effects of its aqueous extract on multiple P450s were evaluated in rat liver microsomes using a 'Pittsburgh cocktail' approach.The method demonstrated excellent linearity (R2 > 0.999), precision, stability, repeatability (RSD < 3.0%), and recovery (95.15-102.36%). The extract exhibited significant time-dependent inhibition of CYP1A2 (residual activity 58.2%), with weaker effects on other P450s.A robust LC-MS/MS method was successfully established. The extract of APR was identified as a potent time-dependent inhibitor of CYP1A2 in rat liver microsomes (RLMs), suggesting a potential risk for metabolism-based drug interactions in rats that warrants further investigation in human systems.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"744-754"},"PeriodicalIF":1.5,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148473268","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}

引用次数: 0

Formaldehyde directly induces cytotoxicity in human lymphocytes through ROS formation, mitochondrial/lysosomal destruction and oxidative stress; analysis of the protective effects of crocin. 甲醛通过ROS形成、线粒体/溶酶体破坏和氧化应激直接诱导人淋巴细胞毒性藏红花素的保护作用分析。

IF 1.5 4区医学

Xenobiotica Pub Date : 2026-09-01 Epub Date: 2026-07-24 DOI: 10.1080/00498254.2026.2707488

Ahmad Salimi, Hanieh Delavari, Behrooz Elyasi, Leila Rezaie Shirmard, Vahed Adhami, Farnaz Abdollahi, Masumeh Naderi

{"title":"Formaldehyde directly induces cytotoxicity in human lymphocytes through ROS formation, mitochondrial/lysosomal destruction and oxidative stress; analysis of the protective effects of crocin.","authors":"Ahmad Salimi, Hanieh Delavari, Behrooz Elyasi, Leila Rezaie Shirmard, Vahed Adhami, Farnaz Abdollahi, Masumeh Naderi","doi":"10.1080/00498254.2026.2707488","DOIUrl":"10.1080/00498254.2026.2707488","url":null,"abstract":"Here we investigated the direct effect of formaldehyde, a major environmental and occupational pollutant, and cytoprotective potency of crocin as a natural compound against its toxicity in human lymphocytes, an important immune cell.For this purpose, human lymphocytes were isolated from peripheral blood and exposed to different concentrations of formaldehyde for 4 hours. Then, to investigate the protective potential of crocin, the human lymphocytes were simultaneously treated with its different concentrations in presence of formaldehyde. A set of biochemical and flow cytometric indices including cell viability, ROS production, mitochondrial membrane potential (MMP) collapse, lysosomal damage, malondialdehyde (MDA) and glutathione (GSH) levels, as indicator of oxidative stress were measured.The findings showed that formaldehyde significantly induced ROS formation, MMP collapse, lysosomal membrane destruction, lipid peroxidation and cytotoxicity. Our observations showed that simultaneous exposure of crocin with formaldehyde could not significantly reduce the toxicity parameters caused by formaldehyde.Overall, we observed that formaldehyde can cause direct toxicity via ROS formation, MMP collapse, lysosomal damages and oxidative stress in human lymphocytes and crocin with routine concentrations cannot reduce these toxicities. Therefore, reducing the toxicity of formaldehyde in lymphocytes by stronger antioxidant agents is suggested in future studies.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"755-764"},"PeriodicalIF":1.5,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148550647","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}

引用次数: 0

Oxycodone alleviates post-anaesthesia cognitive impairment in the elderly via miR-150-5p/H731 axis. 羟考酮通过miR-150-5p/H731轴缓解老年人麻醉后认知障碍

IF 1.5 4区医学

Xenobiotica Pub Date : 2026-09-01 Epub Date: 2026-08-24 DOI: 10.1080/00498254.2026.2699830

Xiaoyu Li, Hong Han, Hongzhe Li, Zitan Zhang, Yingbing Lv, Cuirong Chen

{"title":"Oxycodone alleviates post-anaesthesia cognitive impairment in the elderly via miR-150-5p/H731 axis.","authors":"Xiaoyu Li, Hong Han, Hongzhe Li, Zitan Zhang, Yingbing Lv, Cuirong Chen","doi":"10.1080/00498254.2026.2699830","DOIUrl":"10.1080/00498254.2026.2699830","url":null,"abstract":"1. Postoperative cognitive dysfunction (POCD) is a major issue in elderly surgical patients. Oxycodone (Oxy) reduced POCD risks versus other anaesthetics, but its mechanism is unknown. This study probes microRNA (miR)-150-5p's possible role.2. Preoperative and postoperative serum samples were obtained from elderly patients, categorised into the POCD and non-POCD groups after oxycodone anaesthesia. In vivo POCD mice and in vitro LPS-induced cell models were constructed, both treated with Oxy. miR-150-5p Levels were measured by RT-qPCR. ROC curve evaluated its diagnostic potential for POCD. Morris Water Maze tested spatial learning/memory in POCD mice. Flow cytometry assessed cell apoptosis.3. At baseline, miR-150-5p and Nuclear Antigen H731 (H731) levels were similar between groups; however, at 72 h post-op, the POCD group had lower miR-150-5p and higher H731. MiR-150-5p acted as a risk factor and effective biomarker for identifying elderly patients at high risk of POCD. Oxy alleviated hippocampal injury and cognitive deficits in aged POCD mice, which were reversed by miR-150-5p knockdown but restored by H731 depletion. miR-150-5p knockdown abolished Oxy-mediated protection against apoptosis, inflammation, and oxidative stress, whereas H731 silencing rescued such effects.4. miR-150-5p served as a diagnostic biomarker in elderly patients undergoing Oxy-under general anaesthesia.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"732-743"},"PeriodicalIF":1.5,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148670446","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}

引用次数: 0

In vitro and in vivo intestinal and hepatic oxidative metabolism of typical cytochrome P450 3A substrates, midazolam, nifedipine, and quinidine, in minipigs: a comparison with humans, monkeys, and dogs. 迷你猪体内和体外典型细胞色素P450 3A底物咪达唑安定、硝苯地平和奎尼丁的肠道和肝脏氧化代谢：与人类、猴子和狗的比较

IF 1.5 4区医学

Xenobiotica Pub Date : 2026-09-01 Epub Date: 2026-08-05 DOI: 10.1080/00498254.2026.2711041

Chizuka Sakai, Eriko Higashi, Shunsuke Iwano, Yohei Miyamoto, Hiroshi Yamazaki, Masashi Uchida

{"title":"In vitro and in vivo intestinal and hepatic oxidative metabolism of typical cytochrome P450 3A substrates, midazolam, nifedipine, and quinidine, in minipigs: a comparison with humans, monkeys, and dogs.","authors":"Chizuka Sakai, Eriko Higashi, Shunsuke Iwano, Yohei Miyamoto, Hiroshi Yamazaki, Masashi Uchida","doi":"10.1080/00498254.2026.2711041","DOIUrl":"10.1080/00498254.2026.2711041","url":null,"abstract":"This study evaluated intestinal and hepatic first-pass metabolism of CYP3A substrates (midazolam, nifedipine, and quinidine) in minipigs and compared results with in vivo data reported for humans, monkeys, and dogs, and with in vitro data generated herein, to investigate interspecies differences and the feasibility of human extrapolation.In vivo pharmacokinetics were assessed in minipigs following intravenous and oral administration. Intestinal and hepatic intrinsic clearance were measured using microsomes from humans, minipigs, monkeys, and dogs.Across four species, the intestinal extraction ratio (Eg) correlated more strongly with oral bioavailability (F) than did the hepatic extraction ratio (Eh), indicating that intestinal first-pass extraction mainly determines F; in vivo and in vitro-predicted Eh correlated only when dogs were excluded. Minipig first-pass metabolism resembled that of humans for midazolam but showed strong substrate dependence, with a higher F for nifedipine and a higher Eg and lower F for quinidine; monkeys and dogs likewise deviated from humans in a substrate-dependent manner.Integrating multi-species in vitro and in vivo data yielded only preliminary, exploratory correlations; quantitative extrapolation from a single species remains limited, and improving the prediction of human first-pass metabolism will require integration with human-based in vitro models.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"722-731"},"PeriodicalIF":1.5,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148621642","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}

引用次数: 0

Leucoseptoside a reverses multidrug resistance in breast cancer cells by targeting P-glycoprotein (P-gp/ABCB1) transporter. 白菌苷A通过靶向p -糖蛋白（P-gp/ABCB1）转运体逆转乳腺癌细胞的多药耐药。

IF 1.5 4区医学

Xenobiotica Pub Date : 2026-09-01 Epub Date: 2026-08-19 DOI: 10.1080/00498254.2026.2714456

Haoxue Zhang, Xiaohan Li, Bingling Xie, Fangyun Wu, Jinmei Ren, Jing Wang, Lu Wang, Tingchi Wen, Jichuan Kang, Yixin Qian

{"title":"Leucoseptoside a reverses multidrug resistance in breast cancer cells by targeting P-glycoprotein (P-gp/ABCB1) transporter.","authors":"Haoxue Zhang, Xiaohan Li, Bingling Xie, Fangyun Wu, Jinmei Ren, Jing Wang, Lu Wang, Tingchi Wen, Jichuan Kang, Yixin Qian","doi":"10.1080/00498254.2026.2714456","DOIUrl":"10.1080/00498254.2026.2714456","url":null,"abstract":"The overexpression of P-glycoprotein (P-gp) in tumour cells and its mediated drug efflux represent key mechanisms of cancer multidrug resistance (MDR). Natural compounds are attractive candidates for reversing MDR due to their multi-target activity and hypotoxicity. This study evaluated the ability of leucoseptoside A (LeuA) to reverse P-gp-mediated MDR in MCF-7/ADR cells.The MDR reversal activity of LeuA was assessed based on changes in drug sensitivity measured using the MTT assay. P-gp expression was measured by Western blotting. The intracellular accumulation of rhodamine 123 (Rh123) and adriamycin (ADR) was determined using confocal laser scanning microscopy and flow cytometry, and P-gp ATPase activity was assessed using the Pgp-Glo™ system. The binding mode and affinity of LeuA for P-gp were predicted by molecular docking.LeuA markedly enhanced the sensitivity of MCF-7/ADR cells to ADR and paclitaxel (PTX). This mechanism was achieved by inhibiting P-gp efflux rather than altering its protein expression levels. Molecular docking analysis further revealed that LeuA competitively binds to the drug-binding pocket of P-gp with a higher binding affinity than verapamil (VRP).LeuA is a potent reversal agent for P-gp-mediated MDR, promising as a natural inhibitor for cancer therapy.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"765-777"},"PeriodicalIF":1.5,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148673849","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}

引用次数: 0

Study on the regulatory effect of pomegranate peel polyphenols on rat metabolism and its mechanism mediated by gut microbiota. 石榴皮多酚对大鼠代谢的调节作用及其肠道菌群介导的机制研究。

IF 1.5 4区医学

Xenobiotica Pub Date : 2026-08-31 DOI: 10.1080/00498254.2026.2720772

Haidan Shi, Yaojie Liu, Yihang Chen, Jianke Li

{"title":"Study on the regulatory effect of pomegranate peel polyphenols on rat metabolism and its mechanism mediated by gut microbiota.","authors":"Haidan Shi, Yaojie Liu, Yihang Chen, Jianke Li","doi":"10.1080/00498254.2026.2720772","DOIUrl":"https://doi.org/10.1080/00498254.2026.2720772","url":null,"abstract":"Purpose: Pomegranate peel polyphenols (PPPs) have recognised bioactive properties, but their metabolic interactions with gut microbiota are still uncertain.Materials and methods: This investigation aimed to shed light on the metabolic regulation by PPPs and the gut microbiota's role in this process in normal SD rats. Animals were administered PPPs (300 mg/kg·bw·d) for 28 days.Results: Results showed PPPs significantly reduced rat body weight, and optimised lipid profiles. PPPs modulated the gut microbial composition by enhancing the abundance of beneficial bacterial genera (e.g. Oscillibacter, Prevotella_9) and stimulating the biosynthesis of short-chain fatty acids (SCFAs). Serum metabolomics further revealed that PPPs altered key metabolic pathways, including glycine metabolism, primary bile acid biosynthesis, and tryptophan metabolism. The correlation studies indicated that PPPs target specific gut bacterial genera (Oscillibacter, Allobaculum, Prevotella) to regulate SCFAs production and key metabolic pathways, thereby optimising the metabolic status of rats.Conclusions: These findings provide a critical scientific basis for their potential application in preventing metabolic disorders.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"1-12"},"PeriodicalIF":1.5,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148867235","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}

引用次数: 0

Inhibiting CYP2A5 enzyme in mice decreases circulating cotinine after nicotine administration and increases dopamine in the brain. 抑制小鼠体内的CYP2A5酶会减少尼古丁给药后的可替宁循环，并增加大脑中的多巴胺。

IF 1.5 4区医学

Xenobiotica Pub Date : 2026-08-19 DOI: 10.1080/00498254.2026.2720198

Lefteris C Zacharia, Sotiris Ioannou

{"title":"Inhibiting CYP2A5 enzyme in mice decreases circulating cotinine after nicotine administration and increases dopamine in the brain.","authors":"Lefteris C Zacharia, Sotiris Ioannou","doi":"10.1080/00498254.2026.2720198","DOIUrl":"10.1080/00498254.2026.2720198","url":null,"abstract":"Smoking is a public health concern, and smoking cessation methods such as nicotine replacement therapy (NRT) are often ineffective partly because they are not personalised. Smoking behaviour is related to polymorphisms of the nicotine-metabolizing enzyme P450 2A6. Accordingly, fast metabolizers are nicotine-dependent, smoke more cigarettes and have lower quitting rates compared to slow metabolizers. Thus, inhibiting the nicotine-metabolizing enzyme and prolonging the presence of nicotine in the blood could lead to enhanced NRT and/or fewer cigarettes smoked.In this study, we examined whether Ginkgo biloba (GB), its main constituent quercetin, and 8-methoxypsoralen (8-MOP) can inhibit nicotine metabolism in vivo in mice. We administered nicotine to mice in the presence or absence of the test articles and measured serum cotinine levels, brain dopamine levels and liver CYP2A5 activity.Our results indicate that 8-MOP can inhibit nicotine metabolism in vivo by 55% and increase dopamine in the brain. Chronic administration of GB and quercetin did not detectably inhibit nicotine metabolism, however, GB increased dopamine in the brain. Our results suggest that supplements or drugs that can inhibit nicotine metabolism sufficiently may help smokers reduce the number of cigarettes smoked by prolonging the presence of nicotine in the blood and dopamine in the brain.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"1-7"},"PeriodicalIF":1.5,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148762425","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}

引用次数: 0

Computational analysis of dual targeting of β₁-adrenergic and AT₁ receptors by bisoprolol fumarate and candesartan cilexetil for hypertensive modulation. 富马酸比索洛尔和坎地沙坦西列地酯对高血压调节β1-肾上腺素能和AT1受体双重靶向的计算分析。

IF 1.5 4区医学

Xenobiotica Pub Date : 2026-08-01 Epub Date: 2026-06-26 DOI: 10.1080/00498254.2026.2693908

Sana Yakoubi, Abir Alatrache

{"title":"Computational analysis of dual targeting of β1-adrenergic and AT1 receptors by bisoprolol fumarate and candesartan cilexetil for hypertensive modulation.","authors":"Sana Yakoubi, Abir Alatrache","doi":"10.1080/00498254.2026.2693908","DOIUrl":"10.1080/00498254.2026.2693908","url":null,"abstract":"This study explores a dual-action approach for hypertension management based on a co-formulated suspension containing Candesartan cilexetil (CC) - Bisoprolol fumarate (BF) system, combining FTIR characterisation with computational modelling to evaluate molecular compatibility, binding behaviour, and pharmacokinetic properties.Direct in situ FTIR-ATR spectral analysis confirmed the successful interfacial wetting and co-dispersion of both drugs within the surfactant matrix, driven by robust hydrophobic interactions and cooperative hydrogen bonding. Hirshfeld surface analysis revealed complementary intermolecular interaction patterns between BF and CC, with BF exhibiting flexible hydrogen-bond networks and CC showing directional hydrogen bonding, π-π stacking, and electrostatic interactions.These distinct yet complementary profiles suggest favourable molecular packing and potential co-formulation. Molecular docking further demonstrated balanced binding of the dual system to both β1 and AT1 receptors, with binding energies of -5.19 and -4.88 kcal/mol, respectively. Furthermore, ADMET results indicate poor gastrointestinal absorption and low oral bioavailability, mainly due to high lipophilicity, which may limit in vivo efficacy, although the compound shows an overall acceptable safety profile.In summary, while the CC-BF system appears promising as a dual-target antihypertensive strategy, further formulation improvements and experimental in vitro and in vivo validation are required to confirm its therapeutic potential.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"660-671"},"PeriodicalIF":1.5,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148303293","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}

引用次数: 0

A high-throughput LC-MS/MS method for simultaneous determination of lumateperone and its four metabolites in human plasma: application to a clinical trial. 高通量lC-MS/mS同时测定人血浆中lumateperone及其四种代谢物的方法：在临床试验中的应用

IF 1.5 4区医学

Xenobiotica Pub Date : 2026-08-01 Epub Date: 2026-07-23 DOI: 10.1080/00498254.2026.2704032

Hongjie Ding, Bingda Wu, Rui Wang, Chenxin Ding, Pengfei Zhang, Juefang Ding, Li Ding, Yunli Zhao

{"title":"A high-throughput LC-MS/MS method for simultaneous determination of lumateperone and its four metabolites in human plasma: application to a clinical trial.","authors":"Hongjie Ding, Bingda Wu, Rui Wang, Chenxin Ding, Pengfei Zhang, Juefang Ding, Li Ding, Yunli Zhao","doi":"10.1080/00498254.2026.2704032","DOIUrl":"10.1080/00498254.2026.2704032","url":null,"abstract":"Lumateperone is an antipsychotic metabolised to four active metabolites IC200131, IC200161, IC200565 and IC201308, which are closely related to its clinical efficacy and safety.For evaluating the clinical pharmacokinetics of lumateperone and its active metabolites in Chinese subjects, a high-throughput LC-MS/MS method was developed and validated for the simultaneous quantification of lumateperone and its four metabolites in human plasma. Chromatographic separation was achieved using an alkaline mobile phase and a bidentate silane column (Zorbax Extend-C18) with two-step gradient elution, which overcame peak tailing and carryover while enabling rapid analysis. The calibration ranges were 0.100-80.0 ng/mL for lumateperone and IC200131, 0.0400-32.0 ng/mL for IC200161 and IC201308, and 0.150-30.0 ng/mL for IC200565.The validated method was successfully applied to a pharmacokinetic study of lumateperone tosylate capsules. The clinical trial was registered at the Chinese Clinical Trial Registry (identifier: CTR20242699). Under fasting conditions, the mean Cmax values were 30.6 ng/mL for lumateperone, with corresponding AUC0-t values of 72.8 h·ng/mL. Under fed conditions, food delayed absorption and decreased Cmax for all analytes.This study reports the first comprehensive pharmacokinetic profiles of lumateperone and its four active metabolites in Chinese subjects. The validated method provides a robust foundation for pharmacokinetic research of lumateperone in humans.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"649-659"},"PeriodicalIF":1.5,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148449421","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}

引用次数: 0