Drug Metabolism Reviews最新文献

{"title":"Rare Mendelian CYP disorders: from metabolic pathways to biomarker-guided diagnosis.","authors":"Wojciech Kuban, Ewa Bromek, Renata Pukło, Anna Haduch","doi":"10.1080/03602532.2026.2743901","DOIUrl":"10.1080/03602532.2026.2743901","url":null,"abstract":"<p><p>Cytochrome P450 (CYP) enzymes are best known for xenobiotic metabolism, but many human CYPs also catalyze essential reactions in endogenous pathways governing steroidogenesis, bile acid and oxysterol turnover, vitamin D homeostasis, retinoic acid degradation, and tissue-specific lipid metabolism. Pathogenic variation in these enzymes gives rise to a distinctive class of rare Mendelian disorders in which enzyme position within a pathway predicts the dominant biochemical or tissue-restricted readout and, consequently, the clinical phenotype. Here, we synthesize rare CYP-related diseases within a pathway-resolved framework and propose that they are best interpreted not as isolated syndromes, but as tightly coupled metabolic systems linking gene defects, enzymatic block, metabolite signature, and disease expression. Steroidogenic CYP disorders provide the clearest example of biomarker-guided disease architecture, as defects in CYP11A1, CYP21A2, CYP11B1, CYP11B2, CYP17A1, and CYP19A1 generate characteristic steroid profiles with direct endocrine correlates. Vitamin D-related disorders involving CYP2R1, CYP27B1, CYP24A1, and gain-of-function CYP3A4 variants illustrate how altered activation, catabolism, or alternative inactivation produces diagnostically and therapeutically informative metabolite patterns. Bile acid and oxysterol disorders caused by CYP27A1, CYP7B1, and CYP7A1 defects show that the most informative analyte may be cholestanol, oxysterols, or bile acid intermediates, whereas tissue vulnerability shapes neurologic, hepatobiliary, or metabolic presentation. By contrast, organ-specific CYP disorders involving CYP4V2, CYP1B1, CYP4F22, and CYP26B1 are typically phenotype-led, with diagnosis driven by imaging, examination, or tissue pathology rather than circulating biomarkers. Across categories, mechanistic resolution depends on aligning pathway architecture with the appropriate biochemical readout and locus-aware molecular interrogation.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":" ","pages":"1-25"},"PeriodicalIF":4.7,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149166408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Physical Organic Chemistry in Biochemical Toxicology and the Career of Robert P. \"Bob\" Hanzlik.","authors":"John R Cashman","doi":"10.1080/03602532.2026.2745032","DOIUrl":"10.1080/03602532.2026.2745032","url":null,"abstract":"<p><p>The career of Robert Hanzlik had a dramatic impact on the application of physical organic chemistry to the field of biochemical toxicology. Publications that came out of the Hanzlik laboratory helped to establish and broaden the exploration of physical organic chemistry in biochemical toxicology. Bob expertly employed model compounds and systems to probe and explore various facets of the chemistries resulting in toxic insults. His lab examined mechanisms of formation of reactive metabolites in detail. Bob engaged a range of approaches in support of these studies including synthetic chemistry, radiolabeled tracers, analytical chemistry, biochemistry and spectroscopy (including high field NMR and mass spectrometry). Bob applied these approaches to <i>in vitro</i> and <i>in vivo</i> studies of importance to model toxins. In the latter part of his career, he published extensively on characterization of protein adducts of reactive metabolites. This led him to work in bioinformatics of metabolic activation studies and filling and mining reactive metabolite target protein databases. Bob entered new areas of research with gusto. It was a hallmark of his career and that of his students. His work had broad applications to chemicals and drugs. He laid the groundwork for many future studies. Below, I trace his research areas over the years and the involvement of physical organic chemistry therein.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":" ","pages":"1-21"},"PeriodicalIF":4.7,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149135582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reprogramming of hepatic drug metabolism following early-life xenobiotic exposure: insights from nuclear receptor pathways.","authors":"Yanjiao Qiu, Xiaoyang Hou, Jing Guo, Qiangyu Zhang, Yali Nie, Shengna Han, Lirong Zhang, Pei Wang","doi":"10.1080/03602532.2026.2730198","DOIUrl":"10.1080/03602532.2026.2730198","url":null,"abstract":"<p><p>Substantial interindividual variability in the expression and activity of drug-metabolizing enzymes (DMEs) contributes to variability in drug disposition and response. Early-life, encompassing the fetal and neonatal periods, is a critical developmental window for the establishment and functional programming of the hepatic DME system. Exposure to xenobiotics such as pharmaceuticals, environmental pollutants, inflammatory mediators, and nutritional interventions during this vulnerable period can exert long-term programming effects on hepatic drug metabolism. These effects are mediated primarily through the disruption of nuclear receptor signaling networks, ultimately altering hepatic drug-metabolizing capacity and potentially influencing susceptibility to altered drug responses in later life. This review systematically examines the pivotal roles of the constitutive androstane receptor, pregnane X receptor, and glucocorticoid receptor in mediating the reprogramming of DME expression following early-life xenobiotic exposure. Furthermore, it delineates how epigenetic reprogramming, with a particular focus on histone modifications, converts nuclear receptor-derived signals into persistent transcriptional memories, thereby consolidating the long-term phenotypic effects of early-life events. Additionally, the review integrates evidence on how endogenous factors, including inflammation and nutritional status, modulate drug metabolic programming by regulating nuclear receptor networks. Framed within the Developmental Origins of Health and Disease paradigm, this review elucidates the mechanistic foundations of interindividual differences in drug responses. The insights provided herein aim to provide a critical scientific basis for understanding the long-term consequences of early-life exposure and informing future research on risk assessment and translational evaluation.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":" ","pages":"1-18"},"PeriodicalIF":4.7,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148900223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic pharmacology of anthelmintic drugs targeting mitochondrial fumarate reductase in neurocysticercosis.","authors":"Marina Clare Vinaud, José Clecildo Barreto Bezerra","doi":"10.1080/03602532.2026.2724981","DOIUrl":"10.1080/03602532.2026.2724981","url":null,"abstract":"<p><p>Neurocysticercosis (NCC), caused by <i>Taenia solium</i> larvae in the central nervous system, is a significant cause of acquired epilepsy. The cysts' resistance to standard treatments highlights the need for new metabolic targets, particularly the anaerobic respiratory pathways in helminth mitochondria. Cestodes exhibit metabolic flexibility, utilizing the fumarate reductase (FRD) complex to thrive in low-oxygen environments, using rhodoquinone (RQ) for electron transfer. This unique system enables them to convert fumarate to succinate, essential for energy generation. The effectiveness of benzimidazole-based chemotherapy relies on factors like metabolism and tissue distribution, with the RQ-dependent system absent in humans, making it a selective chemotherapy target. Benzimidazoles like albendazole inhibit the FRD complex in parasites by binding to a unique quinone-binding pocket. This action halts the anaerobic electron transport chain, causing energy depletion and mitochondrial damage. The result is osmotic imbalance, tegumental rupture, and release of antigens that heighten the host immune response. Additionally, FRD inhibition leads to significant bioenergetic changes, including disrupted succinate levels, increased glycolysis, and a breakdown of mitochondrial adaptability, ultimately removing the metabolic safety net necessary for parasite survival in low-oxygen environments, which aids in host clearance of the parasite. This review critically examines the metabolic pharmacology of FRD-targeting anthelmintics, synthesizes current evidence on their mechanisms of action and metabolic consequences, and highlights emerging metabolomics-based opportunities for improving therapeutic strategies against neurocysticercosis.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":" ","pages":"1-15"},"PeriodicalIF":4.7,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148817854","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolism-driven hepatotoxicity of 5-fluorouracil: molecular mechanisms and future therapeutic directions.","authors":"Muthusethupathi Sharmila, Devaraj Ezhilarasan","doi":"10.1080/03602532.2026.2724971","DOIUrl":"10.1080/03602532.2026.2724971","url":null,"abstract":"<p><p>5-Fluorouracil (5-FU) is a widely used chemotherapeutic agent for the treatment of various solid malignancies; however, its clinical application is also associated with hepatotoxicity. As the liver is the primary site of 5-FU metabolism, excessive accumulation of the drug and its metabolites can lead to hepatic injury through multiple interconnected mechanisms. This review summarizes the current understanding of the 5-FU metabolism and molecular pathways involved in 5-FU-induced liver damage. Evidence indicates that 5-FU induces oxidative stress,which is a key event in its hepatotoxicity, characterized by excessive generation of ROS, depletion of antioxidant defenses, and oxidative damage to cellular macromolecules. Increased oxidative stress promotes lipid peroxidation, DNA damage, and mitochondrial dysfunction, ultimately leading to hepatocyte death. 5-FU-induced apoptosis is mediated by the activation of p53 signaling, disruption of the Bcl-2-associated X protein (Bax)/B-cell lymphoma 2 (Bcl-2) balance, subsequent cytochrome c release, caspase activation, and DNA fragmentation. 5-FU induces Inflammatory responses by activation of nuclear factor kappa B signaling and transcription of pro-inflammatory cytokines, further aggravating hepatic injury. Emerging studies also suggest that necroptosis and activation of the NOD-like receptor pyrin domain-containing protein 3 inflammasome contribute to the progression of 5-FU-induced liver injury. Additionally, impairment of mitochondrial fatty acid β-oxidation contributes to lipid accumulation and hepatic steatosis. Despite significant advances in understanding the pathogenesis of 5-FU-induced hepatotoxicity, several molecular pathways remain insufficiently explored. A comprehensive understanding of these mechanisms may facilitate the development of effective hepatoprotective interventions and improve the safety of 5-FU-based chemotherapy.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":" ","pages":"1-18"},"PeriodicalIF":4.7,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148817869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SAR and mechanistic pathways of oxadiazole derivatives: targeting enzymes for antidiabetic therapy.","authors":"Anuradha Mehra, Amit Mittal","doi":"10.1080/03602532.2026.2721999","DOIUrl":"https://doi.org/10.1080/03602532.2026.2721999","url":null,"abstract":"<p><p>The global prevalence of diabetes mellitus continues to rise sharply, creating an urgent need for effective strategies to manage postprandial hyperglycemia. Inhibition of the carbohydrate-hydrolysing enzymes α-glucosidase and α-amylase is a well-established approach for reducing glucose absorption and improving glycaemic control. Among the heterocyclic scaffolds investigated for antidiabetic drug discovery, oxadiazoles have attracted particular attention because of their structural versatility, balanced electronic properties, and capacity to engage enzyme active sites through hydrogen bonding, π-π stacking, hydrophobic contacts, and van der Waals interactions. Several oxadiazole derivatives also show favorable predicted pharmacokinetic profiles, supporting their potential as orally active antidiabetic agents, although systematic pharmacokinetic evaluation across the class remains limited. This review summarizes recent advances in oxadiazole derivatives as α-glucosidase and α-amylase inhibitors, with emphasis on structure activity relationships (SAR), molecular interactions, and mechanisms of enzyme inhibition. Relevant studies published between 2016 and 2024 were identified through a systematic search of PubMed, Scopus, Web of Science, ScienceDirect, and Google Scholar. The reviewed derivatives showed IC₅₀ values ranging from 0.07 to 215 μM against α-glucosidase and from 10.60 to 92.16 μM against α-amylase, with several compounds substantially more potent than their corresponding reference inhibitors. Collectively, these findings position the oxadiazole scaffold as a promising framework for the rational design and optimization of next-generation antidiabetic agents.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":" ","pages":"1-39"},"PeriodicalIF":4.7,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148808454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the clinical pharmacokinetics and pharmacodynamics of SGLT2 inhibitor, empagliflozin: a systematic review.","authors":"Tahir Saleem, Muhammad Fawad Rasool, Hamid Saeed, Faleh Alqahtani","doi":"10.1080/03602532.2026.2668704","DOIUrl":"10.1080/03602532.2026.2668704","url":null,"abstract":"<p><p>Empagliflozin is a potent, highly selective antihyperglycemic agent indicated for the treatment of adults with type 2 diabetes mellitus. This review aims to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of empagliflozin in healthy and diseased subjects. Google Scholar, PubMed, and Cochrane Library databases were systematically searched for PK and PD studies on empagliflozin. Of the 1,340 articles identified, 28 studies met the eligibility criteria and were involved in this systematic review. PK analysis showed dose-proportional increases in area under the curve for empagliflozin from 0 to infinity (AUC_0-∞), similar bioavailability across formulations, and reduced absorption under fed conditions. In healthy subjects, urinary glucose excretion (UGE) after an evening dose of empagliflozin was approximately 1.7-fold higher compared with morning administration. The AUC_0-∞ for empagliflozin in patients with severe renal impairment was significantly higher than in subjects with normal renal function, i.e. 7485.1 ng.hr/mL vs. 4779.646 ng.hr/mL. The maximum plasma concentration (C_max) of empagliflozin was 1.4-fold greater in patients with severe liver impairment. The AUC_0-∞ in the fasting condition was significantly greater than that of the fed state. Furthermore, empagliflozin exhibited a C_max that was 1.1-fold greater when administered alone but decreased in the presence of linagliptin. This systematic review consolidates all available PK and PD parameters of empagliflozin from accessible studies to assist clinicians in dose adjustment for patients with renal or hepatic impairment and type 2 diabetes, as well as in minimizing the risk of adverse reactions and drug-drug interactions.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":" ","pages":"455-466"},"PeriodicalIF":4.7,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147834989","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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 arachidonic acid metabolites as emerging therapeutic targets in menopause-associated cardiac hypertrophy.","authors":"Mostafa K Abd El-Aziz, Ali H Shalaby, Sara R El-Mahrouk, Ayman O S El-Kadi","doi":"10.1080/03602532.2026.2667929","DOIUrl":"10.1080/03602532.2026.2667929","url":null,"abstract":"<p><p>Menopause is associated with a marked increase in cardiac hypertrophy and progression to heart failure with preserved ejection fraction (HFpEF), a condition that disproportionately affects women and lacks effective targeted therapies. Although estrogen deficiency has long been implicated in postmenopausal cardiac remodeling, emerging evidence highlights a critical role for cytochrome P450 (CYP)-derived arachidonic acid metabolites as central regulators of myocardial structure and function. In a healthy premenopausal heart, a balance between cardioprotective epoxyeicosatrienoic acids (EETs), produced by the CYP2J2 and CYP2C enzymes, and the pro-hypertrophic metabolite 20-hydroxyeicosatetraenoic acid (20-HETE), produced by the CYP4A and CYP4F isoforms, supports adaptive remodeling and diastolic function. Menopause disrupts this equilibrium by estrogen-mediated reprogramming of CYP expression and activity, leading to diminished EET bioavailability, heightened 20-HETE signaling, and accelerated EETs breakdown by soluble epoxide hydrolase (sEH). This metabolic shift induces oxidative stress, calcium imbalance, fibroblast activation, extracellular matrix buildup, and cardiomyocyte enlargement, which together lead to ventricular stiffness and diastolic failure. This review aims to consolidate contemporary experimental and translational evidence linking CYP-derived eicosanoids to menopause-related cardiac hypertrophy and to assess novel non-hormonal therapeutic approaches, including sEH inhibitors, stable EET analogs, and CYP4A/20-HETE inhibitors, that target these molecular pathways. Targeting CYP-derived metabolites represents a promising mechanism-based approach to prevent or reverse postmenopausal cardiac hypertrophy and to modify the natural history of HFpEF. Importantly, these non-hormonal strategies may offer a safer therapeutic alternative to hormone replacement therapy by avoiding the systemic risks associated with exogenous estrogen exposure while directly targeting disease-specific molecular pathways.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":" ","pages":"437-454"},"PeriodicalIF":4.7,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147765603","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug transporters in drug disposition - highlights from the year 2025.","authors":"Philip Sandoval, Pallabi Mitra, Masanori Nakakariya, Diane Ramsden, Charles J Rotter, Ning Ding, Paresh P Chothe","doi":"10.1080/03602532.2026.2690529","DOIUrl":"10.1080/03602532.2026.2690529","url":null,"abstract":"<p><p>On behalf of my co-authors, I am pleased to present our sixth annual review highlighting articles that have been deemed as impactful in the field of drug transporter sciences. Drug transporters influence the absorption, distribution, and elimination of prescribed drugs and, as a result, it is necessary to understand their impact on new drug development programs. The articles highlighted in this review were selected based on their scientific impact, novelty, and relevance to advancing key areas of transporter research, including mechanistic understanding, translational application, and implications for drug development and regulatory science.Similar to our previous reviews, each co-author has selected peer-reviewed articles and provided a brief synopsis of the article and commentary on the article's significance (Chothe et al. 2021,2022,2023,2024; Sandoval et al. 2025). The review is divided into the following sections: (1) transporter function and DDI evaluation, (2) novel <i>in vivo</i> models, (3) endogenous biomarkers, and (4) drug transporter structure and regulation. The following synopses and commentaries are meant to provide high-level highlights of the articles and readers are encouraged to review these articles for further details. While individual studies are discussed within these categories, a key objective of this review is to place these findings within broader emerging trends in transporter sciences. The synopsis and commentaries are therefore intended not only to highlight individual studies but also to provide perspective on how these advances collectively shape the field.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":" ","pages":"395-422"},"PeriodicalIF":4.7,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148301292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biotransformation research advances-2025 year in review.","authors":"Lionel Cheruzel, Upendra A Argikar, Pietro Brunetti, Maria Chatzopoulou, Luying Chen, Sungjoon Cho, Deepika Dhaware, Carley J S Heck, Chandrashekhar Honrao, S Cyrus Khojasteh, Jed N Lampe, Jakob Lang, Bin Ma, Shuguang Ma, Karoline Rehm, Jessica A Rowley, Herana Kamal Seneviratne, Hyeonglim Seo, Lloyd Wei Tat Tang, Yue-Ting Wang, Caroline Wei","doi":"10.1080/03602532.2026.2666155","DOIUrl":"10.1080/03602532.2026.2666155","url":null,"abstract":"","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":" ","pages":"306-354"},"PeriodicalIF":4.7,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147765576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}