Drug Metabolism ReviewsPub Date : 2025-05-01Epub Date: 2025-03-05DOI: 10.1080/03602532.2025.2472076
Chunyong He, Yuchang Mao, Hong Wan
{"title":"In-depth understanding of the structure-based reactive metabolite formation of organic functional groups.","authors":"Chunyong He, Yuchang Mao, Hong Wan","doi":"10.1080/03602532.2025.2472076","DOIUrl":"10.1080/03602532.2025.2472076","url":null,"abstract":"<p><p>Idiosyncratic drug-induced liver injury (DILI) is a leading cause of drug attrition and/or withdrawal. The formation of reactive metabolites is widely accepted as a key factor contributing to idiosyncratic DILI. Therefore, identifying reactive metabolites has become a critical focus during lead optimization, and a combination of GSH-/cyano-trapping and cytochrome P450 inactivation studies is recommended to identify compounds with the potential to generate reactive metabolites. Daily dose, clinical indication, detoxication pathways, administration route, and treatment duration are the most considerations when deprioritizing candidates that generate reactive metabolites. Removing the structural alerts is considered a pragmatic strategy for mitigating the risk associated with reactive metabolites, although this approach may sometimes exclude otherwise potent molecules. In this context, an in-depth insight into the structure-based reactive metabolite formation of organic functional groups can significantly aid in the rational design of drug candidates with improved safety profiles. The primary goal of this review is to delve into an analysis of the bioactivation mechanisms of organic functional groups and their potential detrimental effects with recent examples to assist medicinal chemists and metabolism scientists in designing safer drug candidates with a higher likelihood of success.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":" ","pages":"147-189"},"PeriodicalIF":3.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143499708","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":"Genetic determinants of paclitaxel-induced peripheral neuropathy: a review of current literature.","authors":"Swathi Krishna Sivadas, Aiswarya Das, Nandana Vijayakumar, Nandana Shaji, Sabitha Mangalath, Keechilat Pavithran, Lalitha Biswas","doi":"10.1080/03602532.2025.2485055","DOIUrl":"10.1080/03602532.2025.2485055","url":null,"abstract":"<p><p>Paclitaxel is a widely used chemotherapeutic agent recognized for its efficacy against various malignancies. However, its clinical utility is often limited by paclitaxel-induced peripheral neuropathy (PIPN), a dose-dependent and debilitating side effect that significantly impacts patient quality of life. Genetic predisposition plays a critical role in individual susceptibility to PIPN, influencing both drug metabolism and neuropathic responses. This review examines the genetic basis of PIPN, focusing on polymorphisms in key genes associated with paclitaxel metabolism, transport, neuroinflammation, and neuronal signaling. Variants in <i>CYP2C8</i>, <i>CYP3A4</i>, and <i>CYP2C9</i> affect drug metabolism, while polymorphisms in <i>ABCB1</i> and <i>SLCO1B1</i> influence drug transport. Genes involved in neuroinflammatory pathways (<i>TNF-α</i>, <i>IL-6</i>, <i>IL-1β</i>), peripheral nerve integrity (<i>MAPT</i>, <i>TUBB2</i>), and neuronal signaling (<i>SCN9A</i>) have also been implicated in PIPN susceptibility. Understanding genetic contributions to PIPN is essential for unraveling its pathophysiology and developing targeted interventions. Integrating genetic markers into clinical practice can facilitate personalized treatment strategies, minimizing PIPN risk and enhancing therapeutic outcomes. Further studies are needed to validate these findings across diverse populations and uncover novel genetic determinants.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":" ","pages":"190-207"},"PeriodicalIF":3.8,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143751324","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}
Drug Metabolism ReviewsPub Date : 2025-02-01Epub Date: 2024-12-13DOI: 10.1080/03602532.2024.2439102
Vaishnavi Sanjay Patil, Bhavika Kapil Seth, Hemchandra K Chaudhari
{"title":"<i>In silico</i> ADME and target prediction studies of Alogliptin as drug molecule.","authors":"Vaishnavi Sanjay Patil, Bhavika Kapil Seth, Hemchandra K Chaudhari","doi":"10.1080/03602532.2024.2439102","DOIUrl":"10.1080/03602532.2024.2439102","url":null,"abstract":"<p><p>Alogliptin is an oral hypoglycemic agent selective inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme. Inhibition of DPP-4 increases the levels of the incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) by preventing their degradation. The main goal is to study the predicted and experimental properties of absorption, distribution, metabolism, and elimination (ADME), compare them, examine predicted targets, and understand the use of SwissADME in designing other drug molecules. SwissADME, an online tool for ADME prediction, was used together with Swiss Target Prediction to understand drug targets. In addition, we obtained experimental data from the available scientific literature. Molecular docking studies against human DPP-4 were also conducted. We found similarities between the predicted and experimental data; however, some errors depended on the test conditions. The results are interpreted in the first half of the article. We describe the predicted ADME properties of Alogliptin, and based on the results, we can conclude that these tools can be used to predict other drug molecules similarly. It can also reconfigure and manufacture several different formulations of the drug based on predictive data.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":" ","pages":"1-8"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142784480","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":"Herb-drug interaction potential of <i>Astragali Radix</i>: a metabolic perspective.","authors":"Tianwang Wang, Xiaofei Chen, Qing Gao, Chonggang Huang, Kai Wang, Feng Qiu","doi":"10.1080/03602532.2024.2441235","DOIUrl":"10.1080/03602532.2024.2441235","url":null,"abstract":"<p><p><i>Astragali Radix</i> (AR) is one of the most widely used herbs in Asia and has a wide range of biological activities. These activities are attributed to its various compounds like flavonoids, saponins, and polysaccharides. AR and its major components are often used in combination with other drugs for the treatment of diseases such as cancer and cerebral ischemia. With the expanding range of AR combinations, the potential for herb-drug interaction (HDI) has been raised. Key targets in HDI studies include drug-metabolizing enzymes (DMEs) and transporters. Existing studies have shown that AR and its major components have various regulatory effects on these targets, notably CYP2C9, CYP3A4, UGT1A6, and P-gp. AR may contribute to HDI when it is taken with substrates of these biomolecules, such as tolbutamide, midazolam, and digoxin. However, there are also different views in the current study, such as the effect of AR on CYP3A4. To better understand the interactions of AR with drugs, we review the metabolic pathways and pharmacokinetic parameters of the main components of AR. Meanwhile, the regulatory effects and mechanisms of AR on DMEs and transporters are summarized to provide a theoretical and technical basis for the rational use of AR in clinical practice.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":" ","pages":"9-25"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142846149","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}
Drug Metabolism ReviewsPub Date : 2025-02-01Epub Date: 2025-02-05DOI: 10.1080/03602532.2025.2451847
Joyce Liu, Donglu Zhang
{"title":"Cytochrome P450-mediated carbon-carbon bond formation in drug metabolism.","authors":"Joyce Liu, Donglu Zhang","doi":"10.1080/03602532.2025.2451847","DOIUrl":"10.1080/03602532.2025.2451847","url":null,"abstract":"<p><p>Cytochrome P450 (CYPs) enzymes are essential for the metabolism of numerous drug compounds and are capable of catalyzing many types of biotransformation reactions. One of the more unusual reactions catalyzed by CYPs is carbon-carbon (C-C) bond formation, which is critical in organic synthesis but found less commonly in nature. This review focuses on examples of C-C bond formation that occur during drug metabolism and highlights the mechanism for the formation of novel drug metabolites that result from these reactions. The different roles that mammalian CYPs can play in C-C bond formations are also discussed in detail. Ultimately, an understanding of the range of xenobiotics that undergo C-C bond formation and the mechanisms by which they do so can further facilitate metabolite identification and drug design efforts.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":" ","pages":"51-66"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188488","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":"Promising role of peroxisome proliferator-activated receptors in respiratory disorders, a review.","authors":"Sima Beigoli, Sahar Kiani, Fereshteh Asgharzadeh, Arghavan Memarzia, Mohammad Hossein Boskabady","doi":"10.1080/03602532.2024.2442012","DOIUrl":"10.1080/03602532.2024.2442012","url":null,"abstract":"<p><p>Several studies indicate various pharmacological and therapeutic effects of peroxisome proliferator-activated receptors (PPARs) in different disorders. The current review describes the influences of PPARs on respiratory, allergic, and immunologic diseases. Various databases, including PubMed, Science Direct, and Scopus, were searched regarding the effect of PPARs on respiratory and allergic disorders from 1990 to 2024. The effects of PPARs stimulation on experimental animal models of respiratory diseases such as asthma, chronic obstructive pulmonary diseases (COPD), pulmonary fibrosis (PF), and lung infections were shown. Therapeutic potential mediated through PPARs has also been demonstrated in lung cancer, lung infections, and allergic and immunologic disorders. However, few clinical studies showed PPARs mediated therapeutic effects on asthma and COPD. The PPARs-mediated effects on various respiratory disorders were shown through antioxidant, immunomodulatory, anti-inflammatory, and other mechanisms. Therefore, this review indicated possible remedy effects mediated by these receptors in treating respiratory, allergic, and immunologic diseases. Moreover, this mechanistic review paves the way for researchers to consider further experimental and clinical studies.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":" ","pages":"26-50"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142892504","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}
Drug Metabolism ReviewsPub Date : 2025-02-01Epub Date: 2025-01-20DOI: 10.1080/03602532.2025.2453521
Kejun Li, Volker M Lauschke, Yitian Zhou
{"title":"Molecular docking to investigate HLA-associated idiosyncratic drug reactions.","authors":"Kejun Li, Volker M Lauschke, Yitian Zhou","doi":"10.1080/03602532.2025.2453521","DOIUrl":"10.1080/03602532.2025.2453521","url":null,"abstract":"<p><p>Idiosyncratic drug reactions (IDRs) pose severe threats to patient health. Unlike conventionally dose-dependent side effects, they are unpredictable and more frequently manifest as life-threatening conditions, such as severe cutaneous adverse reactions (SCARs) and drug-induced liver injury (DILI). Some HLA alleles, such as <i>HLA-B*57:01</i>, <i>HLA-B*15:02</i>, and <i>HLA-B*58:01</i>, are known risk factors for adverse reactions induced by multiple drugs. However, the structural basis underlying most HLA-associated adverse events remains poorly understood. This review summarizes the application of molecular docking to reveal the mechanisms of IDR-related HLA associations, covering studies using this technique to examine drug-HLA binding pockets and identify key binding residues. We provide a comprehensive overview of risk HLA alleles associated with IDRs, followed by a discussion of the utility and limitations of commonly used molecular docking tools in simulating complex molecular interactions within the HLA binding pocket. Through examples, including the binding of abacavir and flucloxacillin to HLA-B*57:01, carbamazepine to HLA-B*15:02, and allopurinol to HLA-B*58:01, we demonstrate how docking analyses can provide insights into the drug and HLA allele-specificity of adverse events. Furthermore, the use of molecular docking to screen drugs with unknown IDR liability is examined, targeting either multiple HLA variants or a single specific variant. Despite multiple challenges, molecular docking presents a promising toolkit for investigating drug-HLA interactions and understanding IDR mechanisms, with significant implications for preemptive HLA typing and safer drug development.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":" ","pages":"67-90"},"PeriodicalIF":3.8,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142983068","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}
Drug Metabolism ReviewsPub Date : 2024-11-01Epub Date: 2024-10-01DOI: 10.1080/03602532.2024.2405163
Zhaoquan Wu, Dangang Shangguan, Qi Huang, Yi-Kun Wang
{"title":"Drug metabolism and transport mediated the hepatotoxicity of <i>Pleuropterus multiflorus</i> root: a review.","authors":"Zhaoquan Wu, Dangang Shangguan, Qi Huang, Yi-Kun Wang","doi":"10.1080/03602532.2024.2405163","DOIUrl":"10.1080/03602532.2024.2405163","url":null,"abstract":"<p><p><i>Pleuropterus multiflorus</i> root (PMR, Polygoni Multiflori Radix) is an herbal medicine widely used in East Asia, particularly China. However, the potential hepatotoxicity has hindered its rational and safe application of PMR in clinical practice. Recently, the hepatotoxic study of PMR have made great progress, especially drug metabolism and transport-mediated liver injury. In this review, we summarized the advancement of drug metabolism and transport regluated hepatic injury of PMR, pointed out the key role of drug metabolizing enzymes and transporters in regulating hepatic injury of PMR, and emphasized the main hepatotoxic substances, toxicity promoter, and hepatic toxic substance-toxicity promoter interactions in PMR. On this basis, the clinical prospect of preventing and treating hepatic injury of PMR from the perspective of metabolism and transporter was discussed, to provide a useful reference and theoretical basis for the prevention and treatment of hepatic injury of PMR.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":" ","pages":"349-358"},"PeriodicalIF":3.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142343668","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}
Drug Metabolism ReviewsPub Date : 2024-11-01Epub Date: 2024-10-14DOI: 10.1080/03602532.2024.2410747
Prince S Gameli, Marilyn A Huestis, Aurora Balloni, Francesco P Busardò, Jeremy Carlier
{"title":"Metabolism and detection of designer benzodiazepines: a systematic review.","authors":"Prince S Gameli, Marilyn A Huestis, Aurora Balloni, Francesco P Busardò, Jeremy Carlier","doi":"10.1080/03602532.2024.2410747","DOIUrl":"10.1080/03602532.2024.2410747","url":null,"abstract":"<p><p>Synthesis and illicit use of designer benzodiazepines are growing concerns, with these new psychoactive substances (NPS) posing serious health consequences and new hurdles for toxicologists. Consumption marker identification and characterization is paramount in confirming their use. The benzodiazepine core structure is a fusion of benzene and a seven-membered heterocycle with two nitrogen atoms forming the diazepine ring. Minor variations on the core structure produce different classes of benzodiazepines with marked differences in physiological effects. The present review provides a comprehensive designer benzodiazepines metabolism overview and suggests suitable human consumption biomarkers for toxicology casework. A systematic literature search of PubMed<sup>®</sup>, Scopus<sup>TM</sup>, Web of Science<sup>TM</sup>, and Cochrane databases was conducted independently by two coauthors adhering to PRISMA guidelines. Data from 30 <i>in vitro</i> and <i>in vivo</i> models of designer benzodiazepines metabolism from January 2007 to February 2023 were included. 1,4-benzodiazepines (<i>n</i> = 10), 2,3-benzodiazepines (<i>n</i> = 1), triazolo-benzodiazepines (<i>n</i> = 9), and thieno-triazolo-benzodiazepines (<i>n</i> = 3) study design, sample pretreatment, analytical techniques, and major metabolites detected in various matrices are addressed. Metabolites following hydroxylation and phase II glucuronide conjugation were the most prevalent analytes. <i>N</i>-Glucuronidation of parent azole-fused benzodiazepines, and nitro-reduced and <i>N</i>-acetylated metabolites of nitro-containing designer benzodiazepines were also common. From these data, we propose a generic metabolic pathway for designer benzodiazepines. The sporadic illicit market presents challenges in toxicological casework and necessitates comprehensive biomarker investigations, especially in cases with legal implications. There are few metabolism data for many designer benzodiazepines, emphasizing the need for research focusing on closing these gaps.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":" ","pages":"359-384"},"PeriodicalIF":3.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142343669","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}
Drug Metabolism ReviewsPub Date : 2024-11-01Epub Date: 2024-09-11DOI: 10.1080/03602532.2024.2399523
Paresh P Chothe, Upendra A Argikar, Pallabi Mitra, Masanori Nakakariya, Diane Ramsden, Charles J Rotter, Philip Sandoval, Kimio Tohyama
{"title":"Drug transporters in drug disposition - highlights from the year 2023.","authors":"Paresh P Chothe, Upendra A Argikar, Pallabi Mitra, Masanori Nakakariya, Diane Ramsden, Charles J Rotter, Philip Sandoval, Kimio Tohyama","doi":"10.1080/03602532.2024.2399523","DOIUrl":"10.1080/03602532.2024.2399523","url":null,"abstract":"<p><p>Drug transporter field is rapidly evolving with significant progress in <i>in vitro</i> and <i>in vivo</i> tools and, computational models to assess transporter-mediated drug disposition and drug-drug interactions (DDIs) in humans. On behalf of all coauthors, I am pleased to share the fourth annual review highlighting articles published and deemed influential in the field of drug transporters in the year 2023. Each coauthor independently selected peer-reviewed articles published or available online in the year 2023 and summarized them as shown previously (Chothe et al. 2021; Chothe et al. 2022, 2023) with unbiased perspectives. Based on selected articles, this review was categorized into four sections: (1) transporter structure and <i>in vitro</i> evaluation, (2) novel <i>in vitro</i>/<i>ex vivo</i> models, (3) endogenous biomarkers, and (4) PBPK modeling for evaluating transporter DDIs (Table 1). As the scope of this review is not to comprehensively review each article, readers are encouraged to consult original paper for specific details. Finally, I appreciate all the authors for their time and continued support in writing this review.</p>","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":" ","pages":"318-348"},"PeriodicalIF":3.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142105410","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}