Current drug metabolism最新文献

{"title":"Interconnected Metabolic and Cellular Pathways in Drug-Induced Hepatotoxicity: Translational Safety Implications.","authors":"Sushant Jain, Avijit Mazumder, Bhavani Pentela","doi":"10.2174/0113892002497372260809213500","DOIUrl":"https://doi.org/10.2174/0113892002497372260809213500","url":null,"abstract":"<p><p>Drug-induced liver injury remains a principal trigger of acute hepatic failure, late-stage drug attrition, and post-marketing withdrawal, reflecting persistent limitations in mechanistic prediction and translational safety assessment. Owing to its central role in xenobiotic biotransformation, the liver is highly vulnerable to metabolic bioactivation and reactive intermediate formation. This review presents a metabolism-centered; systems level framework that integrates Phase-I and Phase-II enzymatic processes with downstream cellular stress responses governing hepatocellular fate. Cytochrome 450-mediated oxidation and subsequent conjugative pathways determine the balance between detoxification and electrophilic burden; disruption of this equilibrium initiates oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, bile-acid transport impairment, immune-inflammatory activation, and regulated cell death. Emphasis is placed on the dynamic crosstalk among these pathways, which explains interindividual variability, idiosyncratic susceptibility and preclinical-clinical discordance. Emerging insights from network toxicology, transcriptomics, metabolomics and computational modelling have enhanced mechanistic resolution beyond conventional biomarkers. Concurrently, advanced experimental systems including three-dimensional hepatic cultures, organoids, micro-physiological liver-on-chip platforms, humanized animal models and integrative in vitro-in silico approaches are improving translational fidelity. Collectively, this synthesis advances a cohesive mechanistic perspective and highlights integrative strategies to strengthen early risk stratification, mechanistically informed evaluation and predictive safety assessment in drug development.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148863782","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":"Jujuboside A: Distribution, Pharmacological Effects, Pharmacokinetics, and Alternative Production Strategies.","authors":"Xingjie Tao, Chenxi Yu, Xiaoxiao Wang, Jinrui Liu, Junbo Xie","doi":"10.2174/0113892002484035260803070627","DOIUrl":"https://doi.org/10.2174/0113892002484035260803070627","url":null,"abstract":"<p><p>This study summarizes the chemical features, pharmacological effects, pharmacokinetic profiles, and current limitations arising from the limited natural distribution of Jujuboside A (JuA). Since demand for JuA is increasing while natural resources are scarce, our review focuses is its biosynthetic pathway and production challenges. Recent advances and perspectives on alternatives for production are also discussed, such as directed glycosylation based on structurally related homologs, metabolic pathway regulation of sour jujuba (Ziziphus jujububa var. spinosa (Bunge) Hu ex H.F.Chou), microbial cell factory development, and plant callus culture. This review summarizes the pharmacological activities, pharmacokinetics, and biosynthesis of JuA, and discusses current limitations and potential production strategies. Collectively, these insights highlight the pharmacological potential of JuA and provide a theoretical basis for future mechanistic studies and sustainable large-scale production.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148863818","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":"Progress of Framework Nucleic Acids in Tumor Diagnosis and Therapy.","authors":"Mengting Liu, Tiantian Wu, Qifeng Zhang, Huiyong Zhu","doi":"10.2174/0113892002461750260727104653","DOIUrl":"https://doi.org/10.2174/0113892002461750260727104653","url":null,"abstract":"<p><strong>Introduction: </strong>Framework Nucleic Acids (FNAs) are precisely self-assembled two- or three-dimensional nucleic acid architectures renowned for their excellent programmability, monodisperse structures, and near-atomic precision. These distinctive properties enable FNAs to function as versatile nanocarriers for targeted biomarker recognition, efficient co-delivery of therapeutics and imaging agents, and stimuli-responsive release within the tumor microenvironment, driving rapid advances in framework nucleic acid-based nanomaterials for tumor theranostics in recent years.</p><p><strong>Methods: </strong>We extensively searched bibliographic databases using keywords such as \"framework nucleic acids\", \"FNA\", \"DNA nanostructures,\" and \"tumor theranostics\". Based on the literature retrieved, we summarized the design and functionalization strategies of FNA-based nanomaterials, reviewed their applications in various tumor therapeutic modalities, and discussed the major challenges for clinical translation.</p><p><strong>Results: </strong>FNAs exhibited excellent application prospects across diverse tumor therapeutic modalities. They markedly enhanced targeted drug delivery and therapeutic efficacy in chemotherapy, enabled efficient gene silencing in gene therapy, strengthened antitumor immune responses in immunotherapy, and significantly improved precision in tumor imaging and phototherapy. Collectively, these advantages position FNAs as a highly promising and versatile platform for precision tumor theranostics.</p><p><strong>Discussion: </strong>We have further provided a comprehensive discussion of the multifaceted challenges that continue to impede the clinical translation of Framework Nucleic Acid (FNA)-based nanomaterials despite their considerable preclinical promise in tumor theranostics, as well as an in-depth outlook on their future potential in this evolving field.</p><p><strong>Conclusion: </strong>This review summarizes the remarkable potential of Framework Nucleic Acids (FNAs) as an intelligent nanoplatform for tumor diagnosis and therapy. Nevertheless, several critical challenges persist for clinical translation, including long-term biosafety, scalable manufacturing, and efficient in vivo delivery. Future efforts to address these barriers are expected to accelerate the clinical implementation of FNAs in precision oncology.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2026-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148808323","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":"Integrated Multi-Omics Reveals BCAA Metabolic Remodeling Associated with the Antifibrotic Effects of Ku-Cai-Gao in Liver Fibrosis.","authors":"Xinjian Guo, Hui Gao, Xiaomei Zhang, Yue Feng, Yu Bai, Yin Li, Jing Yan, Huanhuan Wang, Yanhua Liu, Jingtao Li, Fanrong Liu","doi":"10.2174/0113892002480918260723105428","DOIUrl":"https://doi.org/10.2174/0113892002480918260723105428","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Introduction: &lt;/strong&gt;Ku-Cai-Gao (KCG) is a traditional Chinese medicinal preparation with both therapeutic and dietary functions. Preliminary clinical observations suggest that KCG may alleviate liver fibrosis-related manifestations and improve liver function, but whether its antifibrotic effects involve hepatic amino acid metabolic remodeling remains unclear. This study investigated the hepatoprotective pathways of KCG using an integrated multi-omics strategy.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;A carbon tetrachloride (CCl4)-induced mouse model of liver fibrosis was established and treated with KCG. KCG constituents were profiled by ultra-performance liquid chromatography-tandem mass spectrometry. Liver histopathology and collagen deposition were evaluated, and serum transaminases, oxidative stress markers, and inflammatory cytokines were measured. Fibrosis- and apoptosis-related proteins were assessed by immunohistochemistry/immunofluorescence and Western blotting. Transcriptomics and proteomics were integrated to identify key pathways, with selected targets validated by reverse transcription-quantitative polymerase chain reaction and Western blotting. Targeted metabolomics assessed Branched-Chain Amino Acid (BCAA) metabolism, and 16S ribosomal RNA sequencing characterized gut microbiota changes.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;KCG markedly ameliorated CCl4-induced liver injury, as shown by improved liver morphology, reduced liver injury scores, decreased collagen deposition, and attenuation of inflammatory cell infiltration. KCG treatment reduced serum ALT, AST, ALP, and T-BIL levels, decreased MDA, IL-6, and TNF-α levels, and restored SOD activity. Histological and molecular analyses showed that KCG reduced α-SMA, collagen I, TGF-β1, PCNA, and caspase-3 expression, indicating attenuation of hepatic stellate cell activation, extracellular matrix accumulation, inflammation, and apoptosis. Integrated transcriptomic and proteomic analyses converged on the valine, leucine, and isoleucine degradation pathway, and targeted metabolomics showed decreased hepatic Branched-Chain Amino Acid (BCAA) levels after KCG treatment. These changes were accompanied by upregulation of Peroxisome Proliferator-Activated Receptor Alpha (PPARα)-related signaling. In addition, KCG treatment was associated with changes in gut microbiota composition, including alterations in Firmicutes, Bacteroidetes, and Muribaculaceae.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Discussion: &lt;/strong&gt;These findings suggest that the antifibrotic effects of KCG are associated with PPARα-related signaling, BCAA metabolic remodeling, and improvement of inflammatory and metabolic disturbances. However, the causal roles of PPARα signaling, BCAA metabolism, and gut microbiota changes require further validation.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;KCG alleviated CCl4-induced liver fibrosis in mice, and its protective effects were associated with BCAA metabolic remodeling, PPARα-related signaling, and changes in gut m","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148789392","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":"Branched-Chain Amino Acids (BCAAs): Metabolism and Their Roles In Inflammation Regulation and Disease.","authors":"Xuan Zhao, Yuyu An, Leilei Shi, Shiyu Yuan, Chaojun Han, Jiping Liu","doi":"10.2174/0113892002454247260618095436","DOIUrl":"https://doi.org/10.2174/0113892002454247260618095436","url":null,"abstract":"<p><p>Branched-chain amino acids (BCAAs)-encompassing leucine, isoleucine, and valine-constitute a class of essential amino acids indispensable for protein synthesis and a myriad of metabolic functions. Beyond their canonical roles as substrates, BCAAs are now recognised as potent signalling molecules and key regulators of immunometabolism. They exert pleiotropic effects and demonstrate a profound capacity to modulate inflammatory responses. Inflammation, an intricate biological response to harmful stimuli, is a pathogenic driver underpinning the initiation and exacerbation of numerous chronic and acute diseases. This review critically synthesises the scientific literature, systematically examining the therapeutic potential of BCAAs in mitigating inflammation-related pathologies. We delve into the mechanistic intricacies through which BCAAs exert their anti-inflammatory and immunomodulatory actions. A thorough comprehension of these mechanisms is not merely an academic exercise but a crucial prerequisite for developing effective pharmacotherapies and precision nutrition approaches, ultimately forging new paradigms for the prophylaxis and clinical management of diseases with an inflammatory component.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148390016","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":"Nucleic Acid Nanomaterials Targeting Autophagy in Bone Regeneration.","authors":"Xiao Yang, Yuehan Wang, Zhong Hu, Jinyou Geng, Yuanyuan Sun, Xiaoru Shao","doi":"10.2174/0113892002458922260601054117","DOIUrl":"https://doi.org/10.2174/0113892002458922260601054117","url":null,"abstract":"<p><p>Impairment or irreversible loss of bone tissue function remains a prevalent clinical challenge, frequently compounded by donor scarcity, perioperative infection, and immune-mediated rejection, which collectively constrain therapeutic success rates. Novel functional nanomaterials based on nucleic acids-endowed with superior biocompatibility, predictable biodegradability, negligible systemic toxicity, and an abundance of programmable modification sites-have emerged as versatile platforms in bone tissue engineering. Currently, these materials are principally exploited across four interrelated domains: sustained release, bone targeting, scaffold materials for bone regeneration, and bioimaging, all aimed at orchestrating efficient bone regeneration. Recent mechanistic investigations into nano-bio interactions reveal that autophagy, a conserved catabolic pathway in eukaryotes that maintains energetic and metabolic homeostasis, critically governs skeletal repair by directing the timely degradation of intracellular cargo and the turnover of damaged organelles. Through direct modulation of osteoclast and osteoblast differentiation, autophagy fine-tunes the coupled process of bone remodeling. Concurrently, it shapes the regenerative milieu by reprogramming immune cell responses. Consequently, targeted modulation of autophagy represents a rational and promising strategy through which nucleic acid nanomaterials can accelerate bone regeneration. This review synthesizes current knowledge on the contributions of nucleic acid nanomaterials to bone healing, delineates the regulatory functions of autophagy in skeletal regeneration, and explains how these nanomaterials exploit autophagy as a mechanistic lever to enhance bone repair.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":""},"PeriodicalIF":2.3,"publicationDate":"2026-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148270676","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":"Nicotinamide N-Methyltransferase (NNMT): A Central Regulator in Hepatocellular Carcinoma Metabolism and Therapeutic Targeting - A Systematic Review.","authors":"Shatrudhan Prajapati, Shikha Yadav, Ajay Pal Singh","doi":"10.2174/0113892002416170251209103247","DOIUrl":"https://doi.org/10.2174/0113892002416170251209103247","url":null,"abstract":"<p><strong>Introduction: </strong>The purpose of this systematic review was to assess the expression of nicotinamide N-methyltransferase (NNMT), its mechanistic value, and clinical importance in Hepatocellular Carcinoma (HCC).</p><p><strong>Methods: </strong>A search was conducted in PubMed, Scopus, Web of Science, Google Scholar, and the Cochrane Library in accordance with PRISMA guidelines. Studies published between 2010 and 2024 that evaluated NNMT expression and its functional implications in HCC were included. Data extraction, synthesis, and qualitative analysis were performed according to standardized criteria.</p><p><strong>Results: </strong>Sixty studies were included in this review. Most studies reported significantly higher NNMT overexpression in liver tumor tissue compared to non-tumor liver tissue. High NNMT levels were associated with aggressive tumor behavior, poor prognosis, and disruptions in methylation and energy metabolism. However, comparability across studies was limited due to heterogeneity in detection methods and small cohort sizes.</p><p><strong>Discussion: </strong>The findings indicate that NNMT plays a crucial role in hepatocarcinogenesis by regulating methyl-donor balance and epigenetic remodeling. Although NNMT shows strong diagnostic and therapeutic potential, the current evidence is largely preclinical, high-lighting the need for multicenter validation.</p><p><strong>Conclusion: </strong>NNMT is a promising biomarker and therapeutic target for HCC. Future research should include quantitative assessment of NNMT expression, mechanistic validation, and clinical studies exploring NNMT inhibition strategies.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148204494","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":"Unraveling the Gut Microbiota-Mediated Mechanism of Guogong Jiu for Rheumatoid Arthritis Treatment through Network Pharmacology and Metabolomics.","authors":"Zhicheng Yin, Jie Li, Xue Zhao, Jun Jia, Zhaozhou Lin, Zeping Zuo, Zijian Wang, Zhibin Wang, Jiayu Zhang","doi":"10.2174/0113892002468265260415075737","DOIUrl":"https://doi.org/10.2174/0113892002468265260415075737","url":null,"abstract":"<p><strong>Introduction: </strong>Rheumatoid Arthritis (RA) is a chronic autoimmune inflammatory disease. Guogong Jiu (GGJ) is a classical traditional Chinese medicine formula that is widely used in clinical treatment of rheumatoid arthritis. Nevertheless, the gut microbiota and metabolic mechanisms have not been fully studied. The objective of this study was to elucidate the gut microbiota-mediated mechanisms by which GGJ alleviates RA using network pharmacology, metabolomics, and experimental approaches.</p><p><strong>Methods: </strong>A rat model of collagen-induced arthritis was established to assess anti-arthritic effects systemically. The arthritis index, histopathology, inflammatory cytokines, and gut microbiota analysis (16S rRNA) were assessed for their effects. The serum and fecal metabolomics were done using UHPLC-Q-Exactive MS/MS. Moreover, network pharmacology and secondary metabolome analysis were used to identify the active herbal components, potential targets, and pathways, which were validated in Rheumatoid Arthritis Fibroblast-Like Synoviocytes (RA-FLS) as well.</p><p><strong>Results: </strong>GGJ improved the symptoms of Rheumatoid arthritis. GGJ affected pathways involved in amino acid, lipid, and energy metabolism. Moreover, the assessment of gut micro-biota revealed that GGJ helped restore microbial equilibrium by augmenting beneficial bacteria populations, including Lactobacillus and Alloprevotella, alongside diminishing Prevotella abundance. An integrated analysis identified NF-κB, MAPK, and NRF2 as key targets, which were subsequently validated at the cellular level.</p><p><strong>Discussion: </strong>The multi-omics integration reveals that GGJ exerts its therapeutic effects through coordinated regulation of the gut-joint axis, involving microbiota restoration, metabolic reprogramming, and signaling pathways. These findings provide a mechanistic basis for the clinical application of GGJ in RA.</p><p><strong>Conclusion: </strong>GGJ is effective in RA through multi-target effects involving modulation of inflammatory signaling pathways, mediation of metabolic reprogramming, and restoration of gut microbiota. The clinical application of GGJ for RA is therefore scientifically supported.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834772","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":"Cytochrome P450-derived Polyunsaturated Fatty Acid Metabolites as Modulators of Tumoral Hypoxia-induced Angiogenesis: From Mechanism to Anticancer Therapeutic Perspectives.","authors":"Carmen Torres-Zárate, Rebeca Santes-Palacios","doi":"10.2174/0113892002461017260421073832","DOIUrl":"https://doi.org/10.2174/0113892002461017260421073832","url":null,"abstract":"<p><p>Polyunsaturated Fatty Acids (PUFAs) are essential components of the human diet and physiology. Their biotransformation generates bioactive metabolites with regulatory functions in inflammation, vascular homeostasis, and tumor progression. Among these, arachidonic acid derivatives mediated by cytochrome P450 (CYP) enzymes, such as Epoxyeicosatrienoic acids (EETs) and Hydroxyeicosatetraenoic acids (HETEs), have emerged as key modulators of angiogenesis in the hypoxic tumor microenvironment. This review addresses the metabolic mechanisms that regulate the conversion of PUFAs by the CYP2C, CYP2J, and CYP4A/F families, emphasizing their role in activating signaling pathways such as VEGF/VEGFR and HIF-1, which impact cell proliferation, migration, and survival. Likewise, the therapeutic implications of modulating these PUFAs-metabolizing enzymes are analyzed, including the potential of EETs and 20-HETE analogs as pharmacological targets, with a view to developing new strategies for hypoxia-induced angiogenesis in cancer cells.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834791","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":"Chlorzoxazone-based One-Sample Method for Estimating In Vivo CYP2E1 Activity in Mice.","authors":"Cunzhen Zhang, Rui Yang, Jun Ma, Jiyao Wang, Lin Jia, Yan Fang, Qiang Wen, Na Gao, Hailing Qiao","doi":"10.2174/0113892002414713251211102027","DOIUrl":"https://doi.org/10.2174/0113892002414713251211102027","url":null,"abstract":"<p><strong>Introduction: </strong>Cytochrome P450 2E1 (CYP2E1) plays a crucial role in metabolism and disease, making it highly significant to establish a simpler, sensitive method for evaluating its in vivo activity compared to traditional pharmacokinetic (PK) parameters.</p><p><strong>Methods: </strong>A high-performance liquid chromatography-ultraviolet (HPLC-UV) method was developed and validated for determining chlorzoxazone (CZX) and its metabolite 6-hydroxy CZX (6-OH CZX) in plasma. Four mouse models with distinct CYP2E1 activity were constructed: high activity induced by isoniazid, and low activity via Q11 (a CYP2E1 inhibitor), Cyp2e1 knockout, or carbon tetrachloride (CCl₄). PK experiments were conducted, with activity changes verified by in vitro CYP2E1 protein expression and microsomal activity. Additionally, the sensitivity of PK parameters and the plasma 6-OH CZX/CZX ratio (metabolite ratio, MR) for characterizing CYP2E1 activity, as well as correlations between MR at different time points and both microsomal CYP2E1 activity and CZX half-life (t₁/₂), were analyzed.</p><p><strong>Results: </strong>The HPLC-UV method met analytical requirements in terms of specificity, linearity, and intra-day and inter-day precision. Microsomal activity and protein expression experiments confirmed the successful establishment of the four models. For CYP2E1 activity characterization, CZX t₁/₂ was more sensitive than its area under the curve (AUC) and clearance (CL); MR values at 15 and 7 minutes outperformed those at 2 minutes, with 15-minute MR showing stronger correlations with microsomal activity (r = 0.57, P = 0.007) and CZX t₁/₂ (r = 0.83, P < 0.01).</p><p><strong>Discussion: </strong>This study addresses limitations of traditional PK parameters (multiple samplings, non-metabolic interference) and existing MR methods (unclear optimal time points). The 15-min MR and CZX t₁/₂ offer simplified evaluation, with CZX's high CYP2E1 specificity enhancing translation. Limitations include focus on male C57BL/6J mice and single-point MR's inability to reflect dynamic activity.</p><p><strong>Conclusion: </strong>Four representative mouse models with distinct CYP2E1 activity were successfully constructed. CZX t₁/₂ exhibits higher sensitivity and applicability in characterizing in vivo CYP2E1 activity changes, while the 15-minute MR better represents activity changes. This research lays a foundation for characterizing CYP2E1 variations in disease and pathological processes.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":""},"PeriodicalIF":1.8,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834797","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}