Expert opinion on drug metabolism & toxicology最新文献_第7页

Evaluating the drug-drug interactions of SHR4640 on repaglinide and midazolam in healthy subjects. 评估 SHR4640 对健康受试者中瑞格列奈和咪达唑仑的药物相互作用。

Expert opinion on drug metabolism & toxicology Pub Date : 2025-01-01 Epub Date: 2024-11-14 DOI: 10.1080/17425255.2024.2428367

Yuanzhi Cheng, Xiaotong Hu, Zejun Pei, Zhe Zhang, Hongda Lin, Sheng Feng, Zhenyan Gao, Yanlin Ma, Zhihai Cao, Qian Zhang, Liang Zheng, Wei Zhang, Kai Shen, Wei Hu

{"title":"Evaluating the drug-drug interactions of SHR4640 on repaglinide and midazolam in healthy subjects.","authors":"Yuanzhi Cheng, Xiaotong Hu, Zejun Pei, Zhe Zhang, Hongda Lin, Sheng Feng, Zhenyan Gao, Yanlin Ma, Zhihai Cao, Qian Zhang, Liang Zheng, Wei Zhang, Kai Shen, Wei Hu","doi":"10.1080/17425255.2024.2428367","DOIUrl":"10.1080/17425255.2024.2428367","url":null,"abstract":"Background: SHR4640, a highly selective URAT1 inhibitor, was evaluated to investigate its inhibitory effects on CYP2C8 and CYP3A4 in vivo clinical trial. This study assessed the pharmacokinetic (PK) impact of SHR4640 when co-administered with the CYP2C8 probe substrate repaglinide and the CYP3A4 probe substrate midazolam.Research design and methods: In this single-center, randomized, double-blind, placebo-controlled study, participants were randomly allocated in a 1:1:1 ratio to SHR4640 Group A, SHR4640 Group B, and placebo group and received oral repaglinide, midazolam, SHR4640 or placebo at specific times. The primary endpoints included the main PK parameters of repaglinide and midazolam, both alone and in combination with SHR4640 (AUC0-inf, AUC0-t, and Cmax).Results: The increase in the area under the concentration-time curve (AUC) for repaglinide, when co-administered with SHR4640, was less than 1.25-fold, while the AUC for midazolam exhibited a slight increase of 46%.Conclusions: SHR4640 exerts a weak inhibitory effect on the AUC of CYP enzyme probe substrates and has minimal potential for drug-drug interactions and presents a favorable safety profile.Clinical trial registration: www.clinicaltrials.gov identifier is NCT06196580 (Name: PK Effects of SHR4640 on Repaglinide and Midazolam, and the Impact of SHR4640 on QT Interval).","PeriodicalId":94005,"journal":{"name":"Expert opinion on drug metabolism & toxicology","volume":" ","pages":"217-224"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142635043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Safety of potassium-competitive acid blockers in the treatment of gastroesophageal reflux disease. 钾竞争性胃酸阻滞剂治疗胃食管反流病的安全性。

Expert opinion on drug metabolism & toxicology Pub Date : 2025-01-01 Epub Date: 2024-09-24 DOI: 10.1080/17425255.2024.2397433

Angela Tietto, Sofia Faggin, Carmelo Scarpignato, Edoardo Vincenzo Savarino, Maria Cecilia Giron

{"title":"Safety of potassium-competitive acid blockers in the treatment of gastroesophageal reflux disease.","authors":"Angela Tietto, Sofia Faggin, Carmelo Scarpignato, Edoardo Vincenzo Savarino, Maria Cecilia Giron","doi":"10.1080/17425255.2024.2397433","DOIUrl":"10.1080/17425255.2024.2397433","url":null,"abstract":"Introduction: Proton pump inhibitors (PPIs) are the first-line treatment for gastroesophageal reflux disease (GERD). However, due to their intrinsic limitations, there are still unmet clinical needs that have fostered the development of potassium-competitive acid blockers (P-CABs). Currently, four different drugs (vonoprazan, tegoprazan, fexuprazan, and keverprazan) are marketed in some Asian countries, whereas only vonoprazan and tegoprazan are available in Western countries (USA and Brazil or Mexico, respectively).Areas covered: This review summarizes the current knowledge on P-CABs acute and long-term safety in GERD treatment compared to that of PPIs. Full-text articles and abstracts were searched in PubMed.Expert opinion: P-CABs proved to address some of the unmet clinical needs in GERD, with a favorable risk-benefit ratio compared to conventional PPIs. Preclinical and clinical findings have highlighted P-CAB safety to be superimposable, to that of PPIs, in short-term treatments, although further studies are warranted to monitor their effects in long-term therapy. From an epidemiological point of view, the paucity of rigorous data for many variables (e.g. age, ethnicity, drug interactions, comorbidities, genetic polymorphisms, interindividual susceptibility, and gut dysbiosis) deserves a worldwide framework of continuous pre/post-marketing pharmacovigilance programs to reduce potential confounding factors and accurately link acute and chronic P-CAB therapy to adverse outcomes.","PeriodicalId":94005,"journal":{"name":"Expert opinion on drug metabolism & toxicology","volume":" ","pages":"53-68"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142074784","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Drug dosing optimization in critically ill children under continuous renal replacement therapy: from basic concepts to the bedside model informed precision dosing. 对接受持续肾脏替代治疗的重症儿童进行药物剂量优化：从基本概念到床边精准用药模型。

Expert opinion on drug metabolism & toxicology Pub Date : 2025-01-01 Epub Date: 2024-11-04 DOI: 10.1080/17425255.2024.2422875

Mehdi Oualha, Michael Thy, Naïm Bouazza, Sihem Benaboud, Agathe Béranger

{"title":"Drug dosing optimization in critically ill children under continuous renal replacement therapy: from basic concepts to the bedside model informed precision dosing.","authors":"Mehdi Oualha, Michael Thy, Naïm Bouazza, Sihem Benaboud, Agathe Béranger","doi":"10.1080/17425255.2024.2422875","DOIUrl":"10.1080/17425255.2024.2422875","url":null,"abstract":"Introduction: Optimizing drug dosage in critically ill children undergoing Continuous Renal Replacement Therapy (CRRT) is mandatory and challenging, given the many factors impacting pharmacokinetics and pharmacodynamics coupled with the vulnerability of this population.Areas covered: A good understanding of the mechanisms that determine drug elimination via the CRRT technique is useful to avoid prescription pitfalls, however limited by the high between and within subject variability. The developments of population pharmacokinetic and physiologically based pharmacokinetic models derived from in-vivo and in-vitro studies, are challenging, but remain the most appropriate tool to suggest adjusted dosage regimens for every patient, throughout treatment. We searched PubMed using the search string: 'pediatrics OR children' AN 'continuous renal replacement therapy' AND 'pharmacokinetics' AND 'model informed precision dosing' AND, 'physiologically based pharmacokinetics,' AND 'therapeutic drug monitoring' until January 2024, regardless of language or publication status.Expert opinion: Familiarizing the pediatric intensivists with the therapeutic drug monitoring and providing clinicians the individualized prescribing software such as Model Informed Precision Dosing would be a significant step forward. The clinical benefit for patients remains to be demonstrated.","PeriodicalId":94005,"journal":{"name":"Expert opinion on drug metabolism & toxicology","volume":" ","pages":"173-190"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142523929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Association of GST polymorphism with adverse drug reactions: an analysis across multiple drug categories. GST 多态性与药物不良反应的关系：对多种药物类别的分析。

Expert opinion on drug metabolism & toxicology Pub Date : 2025-01-01 Epub Date: 2024-11-06 DOI: 10.1080/17425255.2024.2426616

Soukaina Ettoury, Sara Louati, Ibtissam Saad, Kaoutar Bentayebi, Oumaima Zarrik, Jamal Eddine Bourkadi, Lahcen Belyamani, Youssef Daali, Rachid Eljaoudi

{"title":"Association of GST polymorphism with adverse drug reactions: an analysis across multiple drug categories.","authors":"Soukaina Ettoury, Sara Louati, Ibtissam Saad, Kaoutar Bentayebi, Oumaima Zarrik, Jamal Eddine Bourkadi, Lahcen Belyamani, Youssef Daali, Rachid Eljaoudi","doi":"10.1080/17425255.2024.2426616","DOIUrl":"10.1080/17425255.2024.2426616","url":null,"abstract":"Introduction: Adverse drug reactions (ADRs) pose a significant challenge in clinical practice, impacting patient safety and treatment outcomes. Genetic variations in drug-metabolizing enzymes, particularly glutathione S-transferases (GSTs), have been implicated in modulating individual susceptibility to ADRs.Areas covered: This overview aims to explore the association between GSTs genetic polymorphisms and ADRs across diverse drug categories documented in current literature. Here we cover antiepileptic, immunosuppressive, chemotherapeutic agents, analgesics, antivirals, and antibiotics.Expert opinion: According to the existing literature, the association between genetic polymorphisms in GST theta (GSTT1), GST mu (GSTM1), and GST pi (GSTP1) and adverse drug reaction occurrence has been frequently reported. However, the strength of these associations varies considerably among studies, with some showing inconsistent or contradictory results, underscoring the need for further investigations.","PeriodicalId":94005,"journal":{"name":"Expert opinion on drug metabolism & toxicology","volume":" ","pages":"191-201"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142585315","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Pharmacokinetic evaluation of efanesoctocog alfa: breakthrough factor VIII therapy for hemophilia A. efanesoctocog alfa 的药代动力学评估：A 型血友病的突破性 VIII 因子疗法。

Expert opinion on drug metabolism & toxicology Pub Date : 2025-01-01 Epub Date: 2024-10-04 DOI: 10.1080/17425255.2024.2409931

Koji Yada, Keiji Nogami

{"title":"Pharmacokinetic evaluation of efanesoctocog alfa: breakthrough factor VIII therapy for hemophilia A.","authors":"Koji Yada, Keiji Nogami","doi":"10.1080/17425255.2024.2409931","DOIUrl":"10.1080/17425255.2024.2409931","url":null,"abstract":"Introduction: Blood coagulation factor (F)VIII functions as a cofactor in the tenase complex responsible for phospholipid-dependent FIXa-mediated activation of FX in plasma. Congenital defect of FVIII causes severe bleeding disorder, hemophilia (H) A. Intravenous FVIII replacement therapy is the gold standard therapy in patients with HA (PwHA) but requirement for frequent dosing of FVIII owing to pharmacokinetics burdens PwHA a lot. Efanesoctocog alfa is a new class of recombinant FVIII and has the ability to overcome conceivable unmet needs in treatment for PwHA.Areas covered: Efanesoctocog alfa is a B domain-deleted single-chain fusion FVIII connected to the Fc-region of human immunoglobulin G1, D'D3-fragment of von Willebrand factor (VWF), and unstructured hydrophilic recombinant polypeptides (XTEN). Owing to its novel design, it can function independently of endogenous VWF and elicits 2 to 4 times longer half-life compared to other existing FVIII products. The prolonged half-life contributes to maintain high level of FVIII activity for most of the week and has led to excellent hemostatic effect by once-weekly administration in phase 3 clinical trials.Expert opinion: Efanesoctocog alfa with outstanding pharmacological properties, well tolerated in the clinical trials, is a promising FVIII therapy for PwHA. Future studies should include long-term safety, especially in previously untreated patients.","PeriodicalId":94005,"journal":{"name":"Expert opinion on drug metabolism & toxicology","volume":" ","pages":"5-14"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142335161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","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 prediction of drug-induced nephrotoxicity: current progress and pitfalls. 药物诱发肾毒性的硅学预测：当前进展与陷阱。

Expert opinion on drug metabolism & toxicology Pub Date : 2025-01-01 Epub Date: 2024-10-09 DOI: 10.1080/17425255.2024.2412629

Na Li, Juan Shi, Zhaoyang Chen, Zhonghua Dong, Shiyu Ma, Yan Li, Xin Huang, Xiao Li

{"title":"In silico prediction of drug-induced nephrotoxicity: current progress and pitfalls.","authors":"Na Li, Juan Shi, Zhaoyang Chen, Zhonghua Dong, Shiyu Ma, Yan Li, Xin Huang, Xiao Li","doi":"10.1080/17425255.2024.2412629","DOIUrl":"10.1080/17425255.2024.2412629","url":null,"abstract":"Introduction: Due to its role in absorption and metabolism, the kidney is an important target for drug toxicity. Drug-induced nephrotoxicity (DIN) presents a significant challenge in clinical practice and drug development. Conventional methods for assessing nephrotoxicity have limitations, highlighting the need for innovative approaches. In recent years, in silico methods have emerged as promising tools for predicting DIN.Areas covered: A literature search was performed using PubMed and Web of Science, from 2013 to February 2023 for this review. This review provides an overview of the current progress and pitfalls in the in silico prediction of DIN, which discusses the principles and methodologies of computational models.Expert opinion: Despite significant advancements, this review identified issues accentuates the pivotal imperatives of data fidelity, model optimization, interdisciplinary collaboration, and mechanistic comprehension in sculpting the vista of DIN prediction. Integration of multiple data sources and collaboration between disciplines are essential for improving predictive models. Ultimately, a holistic approach combining computational, experimental, and clinical methods will enhance our understanding and management of DIN.","PeriodicalId":94005,"journal":{"name":"Expert opinion on drug metabolism & toxicology","volume":" ","pages":"203-215"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142368019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Optimizing drug therapy during pregnancy: a spotlight on population pharmacokinetic modeling. 优化孕期药物治疗：聚焦群体药代动力学模型。

Expert opinion on drug metabolism & toxicology Pub Date : 2025-01-01 Epub Date: 2024-11-18 DOI: 10.1080/17425255.2024.2420195

Prerna Dodeja, Nupur Chaphekar, Steve N Caritis, Raman Venkataramanan

{"title":"Optimizing drug therapy during pregnancy: a spotlight on population pharmacokinetic modeling.","authors":"Prerna Dodeja, Nupur Chaphekar, Steve N Caritis, Raman Venkataramanan","doi":"10.1080/17425255.2024.2420195","DOIUrl":"10.1080/17425255.2024.2420195","url":null,"abstract":"Introduction: Optimizing drug therapy during pregnancy is crucial for ensuring the safety of mothers and babiesPhysiological changes that occur during pregnancy can significantly alter the pharmacokinetics of medications. Population pharmacokinetic (PopPK) modeling is a valuable tool to guide drug dosing regimens in pregnant women.Areas covered: This narrative review summarizes the current literature on the application of PopPK modeling to optimize drug therapy during human pregnancy. It provides an overview of the physiological changes affecting drug disposition in pregnancy and the basic concepts of PopPK modeling including structural, stochastic, and covariate models. We have conducted an exhaustive literature search (PubMed, Web of Science) spanning May 2014-May 2024 to identify PopPK models in the pregnant population. We have highlighted strategies for model building, evaluation, and interpretation with a focus on identifying clinically relevant covariates that inform dose individualization. Case studies illustrating the utility of PopPK models in guiding dosing recommendations for specific drugs are discussed.Expert opinion: Covariate identification can lead to improved mechanistic understanding of drug disposition and establishment of improved dosing regimens during pregnancy. Insufficient data across trimesters may limit the ability of PopPK models to capture time-varying gestational effects.","PeriodicalId":94005,"journal":{"name":"Expert opinion on drug metabolism & toxicology","volume":" ","pages":"143-160"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142650367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Rezafungin acetate for the treatment of candidemia and invasive candidiasis: a pharmacokinetic evaluation. 用于治疗念珠菌血症和侵袭性念珠菌病的醋酸雷沙芬净：药代动力学评估。

Expert opinion on drug metabolism & toxicology Pub Date : 2025-01-01 Epub Date: 2024-11-18 DOI: 10.1080/17425255.2024.2424899

Matteo Bassetti, Adam Stewart, Claudia Bartalucci, Antonio Vena, Daniele Roberto Giacobbe, Jason Roberts

{"title":"Rezafungin acetate for the treatment of candidemia and invasive candidiasis: a pharmacokinetic evaluation.","authors":"Matteo Bassetti, Adam Stewart, Claudia Bartalucci, Antonio Vena, Daniele Roberto Giacobbe, Jason Roberts","doi":"10.1080/17425255.2024.2424899","DOIUrl":"10.1080/17425255.2024.2424899","url":null,"abstract":"Introduction: Rezafungin, formerly SP3025 and CD101, is a next-generation echinocandin, chemically related to anidulafungin, with differentiated pharmacokinetic characteristics, including a prolonged half-life allowing extended-interval dosing.Areas covered: Herein, we discuss the role of rezafungin in the treatment of candidemia and invasive candidiasis, with a specific focus on pharmacokinetics considerations.Expert opinion: Rezafungin exhibits potent in vitro activity against most wild-type and azole-resistant Candida species, including Candida auris. The differentiated PK characteristics of rezafungin which enables once weekly dosing could reduce catheter overuse and provide a rapid transition to outpatient treatment for Candida infections in which azoles cannot be used, due to resistance or drug-drug interactions. Besides weekly dosing, other potential pharmacokinetic/pharmacodynamic advantages of rezafungin are its good penetration into anatomically challenging sites and a potentially reduced probability of local resistance promotion, making it an attractive option also for deep-seated infections that could warrant dedicated clinical investigation.","PeriodicalId":94005,"journal":{"name":"Expert opinion on drug metabolism & toxicology","volume":" ","pages":"125-132"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142650382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cefepime/Enmetazobactam: a microbiological, pharmacokinetic, pharmacodynamic, and clinical evaluation. 头孢吡肟/恩美唑巴坦：微生物学、药代动力学、药效学和临床评估。

Expert opinion on drug metabolism & toxicology Pub Date : 2025-01-01 Epub Date: 2024-11-10 DOI: 10.1080/17425255.2024.2427310

Christopher A Darlow, William Hope, Vineet Dubey

{"title":"Cefepime/Enmetazobactam: a microbiological, pharmacokinetic, pharmacodynamic, and clinical evaluation.","authors":"Christopher A Darlow, William Hope, Vineet Dubey","doi":"10.1080/17425255.2024.2427310","DOIUrl":"10.1080/17425255.2024.2427310","url":null,"abstract":"Introduction: Cefepime/enmetazobactam is a novel β-lactam/β-lactamase inhibitor (BL-BLI) combination with broad Gram-positive and -negative activity. Cefepime is relatively resistant to hydrolysis by AmpC, and enmetazobactam inhibits all Ambler Class A extended spectrum β-lactamases (ESBLs). Hence, the combination is resistant to hydrolysis by many ESBLs. Important spectrum gaps are MRSA, enterococci, Acinetobacter spp. and anaerobes. There is no completely reliable activity against carbapenem-resistant organisms.Areas covered: We describe the chemistry, pharmacodynamics, pharmacokinetics, toxicities, drug-drug interactions, clinical efficacy, and current regulatory position of cefepime/enmetazobactam, following a review of available published literature relating to cefepime/enmetazobactam.Expert opinion: The main potential role for cefepime/enmetazobactam is as a carbapenem-sparing agent for the treatment of infections caused by ESBL-producing Enterobacterales to prevent the use of carbapenems and to avoid the toxicities of non-β-lactam alternatives.There may be potential uses for cefepime/enmetazobactam for the treatment of reproductive tract infections, abdominal infections and neonatal sepsis, given the spectrum of activity and pharmacokinetic properties. However, additional non-clinical and clinical studies are required before use in these settings.","PeriodicalId":94005,"journal":{"name":"Expert opinion on drug metabolism & toxicology","volume":" ","pages":"115-123"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A high-throughput liquid chromatography-tandem mass spectrometry assay for the simultaneous quantification of p-cresol sulfate, p-cresol glucuronide, indoxyl sulfate, and indoxyl glucuronide in HepaRG culture medium and the demonstration of mefenamic acid as a potent and selective detoxifying agent. 一种高通量液相色谱-串联质谱测定法，用于同时定量测定 HepaRG 培养基中对甲酚硫酸盐、对甲酚葡萄糖醛酸苷、吲哚硫酸盐和吲哚葡萄糖醛酸苷，并证明甲灭酸是一种有效的选择性解毒剂。

Expert opinion on drug metabolism & toxicology Pub Date : 2025-01-01 Epub Date: 2024-09-29 DOI: 10.1080/17425255.2024.2409257

Ala'a R Al-Dajani, Tony K L Kiang

{"title":"A high-throughput liquid chromatography-tandem mass spectrometry assay for the simultaneous quantification of p-cresol sulfate, p-cresol glucuronide, indoxyl sulfate, and indoxyl glucuronide in HepaRG culture medium and the demonstration of mefenamic acid as a potent and selective detoxifying agent.","authors":"Ala'a R Al-Dajani, Tony K L Kiang","doi":"10.1080/17425255.2024.2409257","DOIUrl":"10.1080/17425255.2024.2409257","url":null,"abstract":"Background: p-cresol and indole are uremic compounds which undergo sulfonation to generate the highly toxic p-cresol sulfate (pCS) and indoxyl sulfate (IxS). They are also subjected to glucuronidation to produce the less toxic p-cresol glucuronide (pCG) and indoxyl glucuronide (IG). We developed and validated an assay to quantify these metabolites in HepaRG cells. We also tested the effects of mefenamic acid on their in-situ formations in relation to the development of cellular necrosis.Research design and methods: HepaRG cells were exposed to p-cresol or indole (0-1 mM) with mefenamic acid (0-3000 nM) for 24 hours to generate uremic metabolites. Cells were also exposed to 0.5 mM p-cresol or indole with/without 30 nM mefenamic acid to characterize lactate dehydrogenase (LDH) release.Results: The assay exhibited high sensitivity and wide calibration ranges covering human concentrations. HepaRG cells also generated physiologically-relevant concentrations of each metabolite. Mefenamic acid inhibited pCS formation in a concentration-dependent manner without affecting pCG, IxS, or IG. Mefenamic acid also reduced LDH release from p-cresol (by 50.12±5.86%) or indole (56.26±3.58%).Conclusions: This novel assay is capable of quantifying these metabolites in HepaRG cells. Our novel findings suggest that mefenamic acid can be potentially utilized therapeutically to attenuate pCS-associated toxicities.","PeriodicalId":94005,"journal":{"name":"Expert opinion on drug metabolism & toxicology","volume":" ","pages":"81-93"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142335160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0