Drug Metabolism Reviews最新文献

In-Depth Understanding of the Structure-Based Reactive Metabolite Formation of Organic Functional Groups.

IF 3.4 2区医学

Drug Metabolism Reviews Pub Date : 2025-02-26 DOI: 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":"https://doi.org/10.1080/03602532.2025.2472076","url":null,"abstract":"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 aids 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.","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":" ","pages":"1-47"},"PeriodicalIF":3.4,"publicationDate":"2025-02-26","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}

引用次数: 0

Scaling factors to inform in vitro-in vivo extrapolation from preclinical and livestock animals: state of the field and recommendations for development of missing data.

IF 3.4 2区医学

Drug Metabolism Reviews Pub Date : 2025-02-24 DOI: 10.1080/03602532.2025.2462527

Austin A Zimmer, Abby C Collier

{"title":"Scaling factors to inform in vitro-in vivo extrapolation from preclinical and livestock animals: state of the field and recommendations for development of missing data.","authors":"Austin A Zimmer, Abby C Collier","doi":"10.1080/03602532.2025.2462527","DOIUrl":"10.1080/03602532.2025.2462527","url":null,"abstract":"The use of in-vitro-in-vivo physiologically based pharmacokinetic (IVIVE-PBPK) modeling approaches assists for prediction of first-in animal or human trials. These approaches are underpinned by the scaling factors: microsomal protein per gram (MPPG) and cytosolic protein per gram (CPPG). In addition, IVIVE-PBPK has significant application in the reduction and refinement of live animal models in research. While human scaling factors are well-defined, many preclinical and livestock species remain poorly elucidated or uncharacterized. The MPPG parameter for liver (MPPGL) is the best characterized across all species and is well-defined for mouse, rat, and dog models. The MPPG parameters for Kidney (MPPGK) and intestine (MPPGI), are however; relatively indefinite for most species. Similarly, CPPG scaling factors for liver, kidney, and intestine (CPPGL/CPPGK/CPPGI) are generally sparse in all species. In addition to generation of mathematical values for scaling factors, methodological and animal-specific considerations, such as age, sex, and strain differences, have not yet been comprehensively described. Here, we review the current state-of-the-field for microsomal and cytosolic scaling factors, including highlighting areas that may need further description and development, with the intention of drawing attention to key knowledge gaps. The intention is to promote improved accuracy and precision in IVIVE-PBPK, concordance between laboratories, and stimulate work in underserved, but increasingly vital areas.","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":" ","pages":"1-24"},"PeriodicalIF":3.4,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078744","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}

引用次数: 0

Metabolism of m-CPP, trazodone, nefazodone, and etoperidone: clinical and forensic aspects.

IF 3.4 2区医学

Drug Metabolism Reviews Pub Date : 2025-02-20 DOI: 10.1080/03602532.2025.2465482

Mariana Duarte Costa Alegre, Daniel José Barbosa, Ricardo Jorge Dinis-Oliveira

{"title":"Metabolism of m-CPP, trazodone, nefazodone, and etoperidone: clinical and forensic aspects.","authors":"Mariana Duarte Costa Alegre, Daniel José Barbosa, Ricardo Jorge Dinis-Oliveira","doi":"10.1080/03602532.2025.2465482","DOIUrl":"10.1080/03602532.2025.2465482","url":null,"abstract":"Trazodone, nefazodone, and etoperidone are classified as atypical antidepressants belonging to the phenylpiperazine class. These antidepressants are primarily metabolized by CYP3A4 into m-chlorophenylpiperazine (mCPP), which was initially employed in veterinary medicine but has gained widespread use as a recreational drug globally despite legal restrictions in numerous countries. The active metabolite, mCPP, exerts various neuropsychiatric effects by interacting with serotonin receptors. It primarily exhibits nonselective agonistic properties with some antagonistic effects and influences temperature, behavior, and hormone release via central 5-HT receptors. The surge in mCPP popularity can be attributed to its MDMA-like effects, and its initial misidentification as an MDMA substitute facilitated its unregulated distribution worldwide. This review aims to comprehensively explore the pharmacokinetics and pharmacodynamics of these compounds, with a specific focus on the forensic challenges posed by mCPP as a metabolite of antidepressants. The primary objective is to delineate the consumption patterns of these compounds in laboratory settings, making this review crucial for understanding the intricate nuances of these drugs in forensic contexts.","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":" ","pages":"1-32"},"PeriodicalIF":3.4,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143406249","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}

引用次数: 0

Herb-drug interaction potential of Astragali Radix: a metabolic perspective. 黄芪的药物相互作用潜力：代谢的观点。

IF 3.4 2区医学

Drug Metabolism Reviews Pub Date : 2025-02-01 Epub Date: 2024-12-18 DOI: 10.1080/03602532.2024.2441235

Tianwang Wang, Xiaofei Chen, Qing Gao, Chonggang Huang, Kai Wang, Feng Qiu

{"title":"Herb-drug interaction potential of Astragali Radix: 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":"Astragali Radix (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.","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":" ","pages":"9-25"},"PeriodicalIF":3.4,"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}

引用次数: 0

In silico ADME and target prediction studies of Alogliptin as drug molecule. 阿格列汀作为药物分子的ADME及靶标预测研究。

IF 3.4 2区医学

Drug Metabolism Reviews Pub Date : 2025-02-01 Epub Date: 2024-12-13 DOI: 10.1080/03602532.2024.2439102

Vaishnavi Sanjay Patil, Bhavika Kapil Seth, Hemchandra K Chaudhari

{"title":"In silico 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":"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.","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":" ","pages":"1-8"},"PeriodicalIF":3.4,"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}

引用次数: 0

Cytochrome P450-mediated carbon-carbon bond formation in drug metabolism.

IF 3.4 2区医学

Drug Metabolism Reviews Pub Date : 2025-02-01 Epub Date: 2025-02-05 DOI: 10.1080/03602532.2025.2451847

Joyce Liu, Donglu Zhang

引用次数: 0

Promising role of peroxisome proliferator-activated receptors in respiratory disorders, a review. 过氧化物酶体增殖物激活受体在呼吸系统疾病中的重要作用

IF 3.4 2区医学

Drug Metabolism Reviews Pub Date : 2025-02-01 Epub Date: 2024-12-26 DOI: 10.1080/03602532.2024.2442012

Sima Beigoli, Sahar Kiani, Fereshteh Asgharzadeh, Arghavan Memarzia, Mohammad Hossein Boskabady

{"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":"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.","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":" ","pages":"26-50"},"PeriodicalIF":3.4,"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}

引用次数: 0

Molecular docking to investigate HLA-associated idiosyncratic drug reactions. 分子对接研究 HLA 相关的特异性药物反应。

IF 3.4 2区医学

Drug Metabolism Reviews Pub Date : 2025-02-01 Epub Date: 2025-01-20 DOI: 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":"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 HLA-B*57:01, HLA-B*15:02, and HLA-B*58:01, 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.","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":" ","pages":"67-90"},"PeriodicalIF":3.4,"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}

引用次数: 0

Drug metabolism and transport mediated the hepatotoxicity of Pleuropterus multiflorus root: a review. 药物代谢和转运介导的多花蛇床子根肝毒性：综述。

IF 3.4 2区医学

Drug Metabolism Reviews Pub Date : 2024-11-01 Epub Date: 2024-10-01 DOI: 10.1080/03602532.2024.2405163

Zhaoquan Wu, Dangang Shangguan, Qi Huang, Yi-Kun Wang

引用次数: 0

Metabolism and detection of designer benzodiazepines: a systematic review. 特制苯并二氮杂卓的代谢和检测；系统综述。

IF 3.4 2区医学

Drug Metabolism Reviews Pub Date : 2024-11-01 Epub Date: 2024-10-14 DOI: 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":"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®, ScopusTM, Web of ScienceTM, and Cochrane databases was conducted independently by two coauthors adhering to PRISMA guidelines. Data from 30 in vitro and in vivo models of designer benzodiazepines metabolism from January 2007 to February 2023 were included. 1,4-benzodiazepines (n = 10), 2,3-benzodiazepines (n = 1), triazolo-benzodiazepines (n = 9), and thieno-triazolo-benzodiazepines (n = 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. N-Glucuronidation of parent azole-fused benzodiazepines, and nitro-reduced and N-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.","PeriodicalId":11307,"journal":{"name":"Drug Metabolism Reviews","volume":" ","pages":"359-384"},"PeriodicalIF":3.4,"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}

引用次数: 0