ADMET and DMPK最新文献

{"title":"Imipramine solubility-pH profiles: self-aggregation <i>vs.</i> common-ion effect.","authors":"Olivera S Marković, Miloš P Pešić, Alex Avdeef, Abu T M Serajuddin, Tatjana Ž Verbić","doi":"10.5599/admet.3128","DOIUrl":"10.5599/admet.3128","url":null,"abstract":"<p><strong>Background and purpose: </strong>The pH-dependent solubility of imipramine, a tricyclic antidepressant, and its hydrochloride salt was investigated in phosphate buffers and chloride-containing aqueous media using the pH-ramp shake-flask method. It was reported that aggregation of imipramine in acidic media and its partial degradation in alkaline media complicate the determination of its solubility. This was further investigated with modified methods.</p><p><strong>Experimental approach: </strong>For imipramine solubility studies, the computer program <i>p</i>DISOL-X was used to design experiments, process data, and refine the equilibrium constants. Isolated solid precipitates under various conditions were characterized using thermogravimetric analysis, differential scanning calorimetry, powder X-ray diffraction, and elemental analysis. The critical micelle concentration of imipramine hydrochloride was determined in 0.10 mol L^-1 NaH₂PO₄ and in 0.15 mol L^-1 NaCl by conductometric titrations.</p><p><strong>Key results: </strong>A detailed analysis of imipramine pH-solubility profiles reveals complex equilibria in the aqueous phase, as well as various solid-phase transformations. Intrinsic solubility of imipramine, solubility products of imipramine hydrochloride and imipramine phosphate salts, and aggregation constants (trimer, heptamer, and cationic complex with phosphate ions) were determined. Solid state characterization results are in accordance with pDISOL-X analysis.</p><p><strong>Conclusion: </strong>These findings, along with our previous solubility studies of desipramine and nortriptyline, suggest that even subtle structural variations can lead to significant differences in the aqueous media behaviour of tricyclic antidepressants. This type of information can be valuable in the early stages of drug discovery, in formulation optimization experiments, as well as in <i>in vitro</i> and <i>in vivo</i> studies.</p>","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"14 ","pages":"3128"},"PeriodicalIF":5.1,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12994603/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147479563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Y-Co metal-organic framework for sensitive electrochemical determination of doxorubicin hydrochloride.","authors":"Somayeh Mir, Niloufar Akbarzadeh Torbati, Vahid Amani, Somayeh Tajik, Hadi Beitollahi","doi":"10.5599/admet.3141","DOIUrl":"10.5599/admet.3141","url":null,"abstract":"<p><strong>Background and purpose: </strong>Cancer represents a major challenge to public health; therefore, identifying doxorubicin hydrochloride (DOX·HCl) as an important chemotherapy drug holds considerable significance.</p><p><strong>Experimental approach: </strong>An electrochemical sensing strategy was designed for DOX·HCl determination by using Y-Co bimetallic metal-organic framework (Y-Co MOF) modified carbon paste electrode (CPE). The Y-Co-MOF was successfully prepared via the solvothermal method.</p><p><strong>Key results: </strong>Characterizations using field emission scanning electron microscopy, transmission electron microscopy, X-ray diffraction, Fourier transform infrared spectroscopy and energy-dispersive X-ray spectroscopy with elemental mapping images were used to evaluate the morphological features, crystalline structure, functional groups, and elemental composition of the Y-Co-MOF. From cyclic voltammetric studies, well-defined redox peaks of DOX·HCl with improved response peak currents at lower overpotentials were observed on the surface of Y-Co MOF/CPE compared to the unmodified CPE. This indicated that the as-prepared modified CPE has a strong and efficient redox capability toward DOX·HCl. Under the optimized parameters and conditions, the linear response range from differential pulse voltammetry measurements for DOX·HCl were 0.0025 to 100.0 μM, with a low limit of detection of 0.001 μM. Finally, the ability of the designed sensing platform to determine the amounts of DOX·HCl in the injection sample was studied and it has been observed a high and efficient ability with satisfactory values of recovery and relative standard deviation.</p><p><strong>Conclusion: </strong>This analytical approach offers a useful means for the analysis of pharmaceutical formulations, providing potential advantages in cancer therapy.</p>","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"13 6","pages":"3141"},"PeriodicalIF":4.3,"publicationDate":"2025-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12755315/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145888231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Precision therapeutics in non-scarring alopecia: a systemic genomic and pathway-based framework for targeted interventions.","authors":"Rinky Kapoor, Depti Bellani, Raji Patil, Debalina Bose, Madhuri Pola, Prashant Anilkumar Singh, Mamata Mishra, Debraj Shome","doi":"10.5599/admet.3030","DOIUrl":"10.5599/admet.3030","url":null,"abstract":"<p><strong>Background and purpose: </strong>Non-scarring alopecia, principally androgenetic alopecia and alopecia areata is highly prevalent and psychologically burdensome; androgenetic alopecia is androgen-driven, whereas alopecia areata is autoimmune. This review synthesizes genetic architecture and pathway biology to outline a precision framework for targeted interventions.</p><p><strong>Experimental approach: </strong>We reviewed full-text studies from the past decade across PubMed, Web of Science and Google Scholar, applying explicit inclusion/exclusion criteria; emphasis was placed on Genome wide association studies and Next generation sequencing findings, immune and androgen-axis biology, environmental modifiers, and therapeutic evidence (conventional, targeted, and regenerative), alongside artificial Intelligence-enabled diagnostics.</p><p><strong>Key results: </strong>Androgenetic alopecia risk converges on androgen-receptor signalling and related loci, with perifollicular inflammation and oxidative stress as modifiers; finasteride remains a cornerstone therapy. Alopecia areata reflects polygenic immune dysregulation (<i>e.g.</i> Human leukocyte antigen/cytokine axes) with Janus Kinase-pathway inhibition yielding robust regrowth; across phenotypes, wingless-related integration sit/β-catenin and stem-cell programs are central targets. Regenerative options (Protein Rich Plasma, stem-cell/exosome approaches) and artificial Intelligence-assisted stratification are emerging adjuncts.</p><p><strong>Conclusion: </strong>A pathway-guided, genotype and phenotype-informed strategy, targeting the androgen axis for androgenetic alopecia, immune circuits for alopecia areata, and adding regenerative or microenvironmental therapies where indicated-promises earlier diagnosis and more durable, individualized outcomes, especially as genome-wide association study/next-generation sequencing and artificial Intelligence tools are integrated into care.</p>","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"14 ","pages":"3030"},"PeriodicalIF":5.1,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12994595/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147479474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Poly(lactic-co-glycolic acid) nanoparticles and microparticles for peptide delivery: release mechanisms and controlling factors.","authors":"Mohammadmahdi Eshaghi, Marzieh Dehghani, Azam Abedi, Mehrdad Moosazadeh Moghaddam, Ramezan Ali Taheri","doi":"10.5599/admet.3091","DOIUrl":"10.5599/admet.3091","url":null,"abstract":"<p><strong>Background and purpose: </strong>Therapeutic peptides offer high potency but are limited by rapid degradation, poor bioavailability, and the need for frequent dosing. Poly(lactic-co-glycolic acid) (PLGA) nanoparticles and microparticles are effective carriers that protect peptides and enable controlled release. This review summarizes the mechanisms governing peptide release from PLGA particles and identifies formulation factors critical for optimizing therapeutic performance.</p><p><strong>Approach: </strong>A comprehensive analysis of polymer characteristics, particle design parameters, peptide physicochemical properties, and formulation strategies was conducted using data from recent studies. Release mechanisms, including diffusion, polymer degradation, and erosion, were examined alongside manufacturing methods. The review also evaluates clinical PLGA-based peptide products to highlight translational relevance.</p><p><strong>Key results: </strong>Peptide release profiles are strongly influenced by PLGA molecular weight, lactide:glycolide ratio, particle size, end-group chemistry, drug loading, and excipients. Lower polymer molecular weight, higher glycolide content, and smaller particle dimensions accelerate release, whereas cationic peptides experience electrostatic retention within degrading matrices. Additives such as PEG, magnesium salts, and chitosan coatings effectively modulate burst release and stability. PLGA systems typically display triphasic release profiles governed by diffusion and erosion. Several PLGA microparticle-based peptide depots have achieved clinical success, although no nanoparticle-based products have yet reached the market due to manufacturing and regulatory challenges.</p><p><strong>Conclusion: </strong>PLGA nano- and microparticles provide versatile, tunable platforms for sustained peptide delivery. Understanding the interplay between polymer properties, particle architecture, and peptide characteristics is essential for designing next-generation long-acting formulations with improved efficacy and clinical translation.</p>","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"14 ","pages":"3091"},"PeriodicalIF":5.1,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12994588/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147479540","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Electrochemical detection of chloramphenicol using gadolinium tungstate with sulphur-doped carbon nitride nanocomposite.","authors":"Trishul Alanahally Mallu, Gagankumar Sakleshpur Kumar, Santhosh Arehalli Shivamurthy, Nalini Seetharamaiah, Manoj Kumar Basavarajappa, Sandeep Shadakshari","doi":"10.5599/admet.3015","DOIUrl":"10.5599/admet.3015","url":null,"abstract":"<p><strong>Background and purpose: </strong>Chloramphenicol (CAP) is a broad-spectrum antibiotic whose unregulated presence in pharmaceuticals and food products raises significant health concerns, underscoring the need for rapid, reliable detection methods. This study aimed to develop a sensitive and economical electrochemical sensing platform based on a novel gadolinium tungstate (Gd₂(WO₄)₃) and sulphur-doped graphitic carbon nitride (S-g-C₃N₄) nanocomposite for the efficient determination of CAP.</p><p><strong>Experimental approach: </strong>The Gd₂(WO₄)₃/S-g-C₃N₄ nanocomposite was synthesized via a simple co-precipitation method and characterized using XRD, XPS, EDS, and TEM to confirm structural and morphological integration. A glassy carbon electrode modified with the composite was evaluated by cyclic and linear sweep voltammetry, along with analyses of interference, repeatability, stability, and real samples in eye-drop formulations and milk.</p><p><strong>Key results: </strong>The modified electrode exhibited significantly enhanced electrocatalytic oxidation of CAP compared with bare and individually modified electrodes, demonstrating high sensitivity, good selectivity against common interferents, and strong operational stability and reproducibility. A low detection limit was achieved, and the electrode effectively quantified CAP in real matrices with satisfactory recovery.</p><p><strong>Conclusion: </strong>The findings establish the Gd₂(WO₄)₃/S-g-C₃N₄ nanocomposite as an efficient sensing material, offering a reliable, stable, and cost-effective platform for routine monitoring of antibiotic residues. While minor optimization may further expand its applicability, the study advances electrochemical sensing by introducing a robust nanocomposite with improved analytical performance for CAP detection.</p>","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"13 6","pages":"3015"},"PeriodicalIF":4.3,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12755314/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145888241","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TiO₂-embedded molecularly imprinted polymer as electrochemical sensor for ultrasensitive determination of glycopyrronium bromide.","authors":"Zehra Dogan, Ensar Piskin, Ahmet Cetinkaya, Esen Bellur Atici, Sibel A Ozkan","doi":"10.5599/admet.3102","DOIUrl":"10.5599/admet.3102","url":null,"abstract":"<p><strong>Background and purpose: </strong>The precise quantification and quality evaluation of glycopyrronium bromide (GLB), a long-acting muscarinic antagonist widely used in the treatment of chronic obstructive pulmonary disease, requires the development of advanced analytical methodologies capable of achieving high sensitivity, accuracy, and selectivity to ensure therapeutic efficacy and formulation integrity. This study aims to overcome the limitations of conventional methods by developing a rapid, cost-effective method for determining GLB.</p><p><strong>Experimental approach: </strong>To achieve this, titanium dioxide nanoparticles (TiO₂ NPs) were initially applied onto a glassy carbon electrode surface to provide an enhanced surface area and increased conductivity. Subsequently, a TiO₂ nanoparticle-supported molecularly imprinted polymer (MIP) film was synthesized via photopolymerization using GLB as the template molecule, 4-amminobenzoic acid (4-ABA) as the functional monomer, ethylene glycol dimethacrylate as the crosslinking agent, and 2-hydroxyethyl methacrylate (HEMA) as the basic monomer.</p><p><strong>Key results: </strong>The optimized GLB/4-ABA@TiO₂ NPs/MIP- sensor demonstrated outstanding analytical performance, achieving ultra-low picomolar detection limits. The system exhibited superior selectivity (confirmed by high imprinting factor), excellent repeatability and reproducibility, and satisfactory stability. It was successfully applied to the accurate measurement of GLB in both commercial serum and pharmaceutical formulations.</p><p><strong>Conclusion: </strong>The designed nanomaterial-embedded MIP-based electrochemical system presented here offers a highly successful, sensitive, and selective method for GLB determination. The work significantly advances knowledge in the field of analytical medicine and drug monitoring by providing a fast, robust alternative for routine clinical and quality-control tracking of GLB.</p>","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"13 6","pages":"3102"},"PeriodicalIF":4.3,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12755310/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145888226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intranasal carvacrol nanoemulsion: Stroke imaging and neuroprotective study.","authors":"Hitendra Mahajan, Ghanashyam Girnar","doi":"10.5599/admet.2967","DOIUrl":"10.5599/admet.2967","url":null,"abstract":"<p><strong>Background and purpose: </strong>Cerebral ischemia causes neuronal damage due to restricted blood flow and presents significant challenges for brain-targeted drug delivery because of the blood-brain barrier. The purpose of this study is to formulate and evaluate an intranasal oil-in-water nanoemulsion of carvacrol, a neuroprotective agent, for direct nose-to-brain delivery in treating cerebral ischemia.</p><p><strong>Experimental approach: </strong>Nanoemulsions were developed using high-pressure homogenization and optimized by adjusting surfactant mixture ratios and homogenization cycles. Characterization included droplet size (<200 nm), polydispersity index, zeta potential, drug content, transmission electron microscopy (TEM), and drug release profiles. Intranasal suitability was assessed through <i>in vitro</i>, <i>ex vivo</i> and <i>in vivo</i> studies, including pharmacokinetics, single photon emission computed tomography (SPECT) imaging, and evaluation in a middle cerebral artery occlusion rat model.</p><p><strong>Key results: </strong>The optimized nanoemulsion showed sustained release, enhanced nasal permeation, and significantly improved brain bioavailability (<i>C</i> _max = 67.79 ng mL^-1 intranasal <i>vs.</i> 49.71 ng mL^-1 intravenous). Lower systemic exposure and high targeting indices (DTE: 1317 %; DTP: 92.40 %) confirmed efficient brain delivery. SPECT imaging validated localized uptake, and the ischemia model demonstrated strong neuroprotective efficacy.</p><p><strong>Conclusion: </strong>Intranasal carvacrol-loaded nanoemulsion is a promising non-invasive strategy for cerebral ischemia treatment, enabling effective brain targeting and significant therapeutic benefit.</p>","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"14 ","pages":"2967"},"PeriodicalIF":5.1,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12994602/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147479476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Liposome-mediated gene delivery: A comprehensive review of biophysical parameters, lipid composition and targeting strategies.","authors":"Erfan Jafari Saleh, Mohammad Satari, Behnam Hajipour-Verdom","doi":"10.5599/admet.3065","DOIUrl":"10.5599/admet.3065","url":null,"abstract":"<p><strong>Background and purpose: </strong>Gene therapy has emerged as a transformative strategy for treating genetic and acquired disorders, but its clinical success relies heavily on the development of safe, efficient, and target-specific delivery vectors.</p><p><strong>Experimental approach: </strong>The paper systematically analysed published evidence on liposome composition, physicochemical behaviour, targeting strategies, and their applications in delivering diverse nucleic acids, with emphasis on the structure-function relationships of lipid components and the impact of biophysical parameters on transfection efficiency.</p><p><strong>Key results: </strong>Current findings demonstrate that the molecular architecture of cationic, neutral, and anionic lipids, particularly variations in head groups, linkers, and hydrophobic tails, strongly dictates liposome stability, cellular uptake, and cargo release. Biophysical attributes such as vesicle size, zeta potential, membrane fluidity, fusion capacity, and PEGylation were identified as major determinants of in vivo fate. Active targeting through ligands, including antibodies, peptides, folate, and aptamers, enhances cell-specific delivery, while combinatorial approaches with physical enhancement techniques such as sonoporation and electroporation further improve nucleic acid transport.</p><p><strong>Conclusion: </strong>By integrating structural, functional, and application-based insights, this review highlights key design principles for optimizing next-generation liposomal vectors, although challenges remain in achieving consistent in vivo performance and clinical translation. The work advances the field by offering a unified framework to guide rational engineering of liposomal platforms for gene therapy.</p>","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"14 ","pages":"3065"},"PeriodicalIF":5.1,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12994598/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147479561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypotension and antiphlogistic potential of empagliflozin ocular film: swelling and release kinetics.","authors":"Tanisha Das, Subrata Mallick, Sourajit Parida, Mouli Das, Rakesh Swain, Sk Habibullah","doi":"10.5599/admet.2941","DOIUrl":"10.5599/admet.2941","url":null,"abstract":"<p><strong>Background and purpose: </strong>Empagliflozin (EMP) is a sodium-glucose cotransporter 2 (SGLT2) inhibitor used for the management of type 2 diabetes mellitus. The danger of glaucoma in type 2 diabetes mellitus patients is known to be reduced using SGLT2 inhibitors. Empagliflozin is also believed to reduce the level of inflammatory markers. The present work has been undertaken for monitoring intraocular pressure and anti-inflammatory activity using the empagliflozin ocular film formulation. The effect of colloidal silicon dioxide upon the dynamics of swelling and drug release performance was also studied.</p><p><strong>Experimental approach: </strong>Hydroxypropyl methylcellulose-based ocular film of empagliflozin was prepared, including silicon dioxide in different ratios as 1:0.00, 1:0.01, 1:0.02, 1:0.04, and 1:0.06 (namely, EMA0, EMA1, EMA2, EMA3 and EMA4, respectively) using casting and solvent evaporation. Swelling and drug release studies of the films were conducted in phosphate buffer solution (pH 7.4), and the kinetic mechanisms of swelling and drug release were evaluated. Intraocular pressure was measured after application of the film in the normotensive rabbit eye. Moreover, the anti-inflammatory effect was assessed using a rabbit ocular carrageenan-induced inflammation model.</p><p><strong>Key results: </strong>Swelling behaviour followed Fickian mechanism in the order: EMA3<EMA2<EMA0<EMA4<EMA1, and partial relaxation with EMA3. Films containing silicon dioxide showed faster release than those without it (EMA0), following a diffusion pattern. The silicon dioxide-loaded film (EMA3) showed significantly lowered intraocular pressure and promising ocular anti-inflammation with favourable binding affinities of EMP to Interleukin-1β, Interleukin 6 and tumour necrosis factor-α. A good correlation between intraocular pressure and drug release was also established.</p><p><strong>Conclusion: </strong>A hydroxypropyl methylcellulose-based ocular film containing empagliflozin and silicon dioxide could be used to manage intraocular pressure and inflammation in a controlled manner in patients with type 2 diabetes mellitus.</p>","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"14 ","pages":"2941"},"PeriodicalIF":5.1,"publicationDate":"2025-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12994604/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147479565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elucidating CYP2D6-driven metabolism and hepatotoxic bioactivation of metoprolol in plateable human and animal hepatocytes.","authors":"Jiang Pu, Mei Yang, Min Zhang, Ruiqi Gao, Yue Xiao, Lingyu Liu, Chuanjing Zhang, Wennuo Xu, Kaifang Li, Wanyong Feng","doi":"10.5599/admet.2961","DOIUrl":"10.5599/admet.2961","url":null,"abstract":"<p><strong>Background and purpose: </strong>As a classic β-blocker with low systemic clearance, metoprolol has been linked to rare but clinically significant hepatotoxicity, yet its hepatic metabolic fate remains poorly characterized.</p><p><strong>Experimental approach: </strong>Metoprolol was incubated individually in plateable human and animal hepatocytes, and recombinant cytochrome <i>(</i>CYP) P450 enzymes, followed by sample processing for cytotoxicity assessment, stability analysis, phenotyping and metabolite identification studies.</p><p><strong>Key results: </strong><i>In vitro</i> cytotoxicity assessment revealed distinct species-specific responses to metoprolol exposure. Metoprolol showed no observable cytotoxicity across the tested concentration range (0 to 500 μM) in human hepatocytes, whereas it was cytotoxic only at a concentration of 500 μM in rat hepatocytes. Metabolic characterization showed low intrinsic clearance in human hepatocytes (0.56±0.12 μL min^-1 <i>per</i> million cells) over a 72-hour incubation. Comprehensive mass spectrometer analysis identified 22 metabolites across four species (rat, dog, monkey, and human) and fifteen metabolites were identified as the new ones, with CYP2D6-mediated biotransformation pathways (including mono-oxygenation, <i>O</i>-demethylation, and oxidation) accounting for the generation of four major metabolites (M1, M10, M13, M17). Notably, species-specific metabolism was observed for s-hydroxy-metoprolol (M10). It served as the predominant metabolite in rat hepatocytes and underwent subsequent bioactivation to a reactive glutathione (GSH) conjugate. Inhibition studies with 1-aminobenzotriazole (a non-specific CYP inhibitor) confirmed the CYP-dependent nature of this hepatotoxic metabolic pathway.</p><p><strong>Conclusion: </strong>The sustained metabolic activity of plateable hepatocytes facilitated a comprehensive metabolic profiling of metoprolol, including direct observation of GSH-mediated bioactivation. Integrating with cytotoxicity data, these findings offered crucial insights into its hepatic adverse effects.</p>","PeriodicalId":7259,"journal":{"name":"ADMET and DMPK","volume":"13 5","pages":"2961"},"PeriodicalIF":4.3,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12662248/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145647049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}