Current drug metabolism最新文献

{"title":"Drug-Protein Interactions Prediction Models Using Feature Selection and Classification Techniques","authors":"T. Idhaya, A. Suruliandi, S. P. Raja","doi":"10.2174/0113892002268739231211063718","DOIUrl":"https://doi.org/10.2174/0113892002268739231211063718","url":null,"abstract":"Background: Drug-Protein Interaction (DPI) identification is crucial in drug discovery. The high dimensionality of drug and protein features poses challenges for accurate interaction prediction, necessitating the use of computational techniques. Docking-based methods rely on 3D structures, while ligand-based methods have limitations such as reliance on known ligands and neglecting protein structure. Therefore, the preferred approach is the chemogenomics-based approach using machine learning, which considers both drug and protein characteristics for DPI prediction. Methods: In machine learning, feature selection plays a vital role in improving model performance, reducing overfitting, enhancing interpretability, and making the learning process more efficient. It helps extract meaningful patterns from drug and protein data while eliminating irrelevant or redundant information, resulting in more effective machine-learning models. On the other hand, classification is of great importance as it enables pattern recognition, decision-making, predictive modeling, anomaly detection, data exploration, and automation. It empowers machines to make accurate predictions and facilitates efficient decision-making in DPI prediction. For this research work, protein data was sourced from the KEGG database, while drug data was obtained from the DrugBank data machine-learning base. Results: To address the issue of imbalanced Drug Protein Pairs (DPP), different balancing techniques like Random Over Sampling (ROS), Synthetic Minority Over-sampling Technique (SMOTE), and Adaptive SMOTE were employed. Given the large number of features associated with drugs and proteins, feature selection becomes necessary. Various feature selection methods were evaluated: Correlation, Information Gain (IG), Chi-Square (CS), and Relief. Multiple classification methods, including Support Vector Machines (SVM), Random Forest (RF), Adaboost, and Logistic Regression (LR), were used to predict DPI. Finally, this research identifies the best balancing, feature selection, and classification methods for accurate DPI prediction. Conclusion: This comprehensive approach aims to overcome the limitations of existing methods and provide more reliable and efficient predictions in drug-protein interaction studies.","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":"79 1","pages":""},"PeriodicalIF":2.3,"publicationDate":"2024-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139398687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Altitude effect on Propofol Pharmacokinetics in Rats.","authors":"Lijun Li, Xuejun Wang, Sheng Wang, Li Wen, Haopeng Zhang","doi":"10.2174/0113892002285571240220131547","DOIUrl":"10.2174/0113892002285571240220131547","url":null,"abstract":"<p><strong>Background: </strong>Propofol is an intravenous agent for clinical anesthesia. As the influence of the hypobaric-hypoxic environment (Qinghai-Tibetan region, altitude: 2800-4300 m, PaO2: 15.1-12.4 kPa) on the metabolism of Propofol is complex, the research results on the metabolic characteristics of Propofol in high-altitude areas remain unclear. This study aimed to investigate the pharmacokinetic characteristics of Propofol in a high-altitude hypoxic environment using animal experiments.</p><p><strong>Methods: </strong>Rats were randomly divided into three groups: high-altitude, medium-altitude, and plain groups. The time of disappearance and recovery of the rat righting reflex was recorded as the time of anesthesia induction and awakening, respectively. The plasma concentration of Propofol was determined by gas chromatography-mass spectrometry. A pharmacokinetic analysis software was used to analyze the blood-drug concentrations and obtain the pharmacokinetic parameters.</p><p><strong>Results: </strong>We observed that when Propofol anesthetizes rats, the anesthesia induction time was shortened, and\u0000the recovery time was prolonged with increased altitude. Compared with the plain group, the clearance of\u0000Propofol decreased, whereas the half-life, area under the concentration-time curve, peak plasma concentration,\u0000and average residence time extension increased.</p><p><strong>Conclusion: </strong>The pharmacokinetic characteristics of Propofol are significantly altered in high-altitude hypoxic environments.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"81-90"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11327735/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140101201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Carboxylesterase 1-Based Drug-Drug Interaction Potential of Remimazolam: <i>In-Vitro</i> Studies and Literature Review.","authors":"Karl-Uwe Petersen, Wolfgang Schmalix, Marija Pesic, Thomas Stohr","doi":"10.2174/0113892002308233240801104910","DOIUrl":"10.2174/0113892002308233240801104910","url":null,"abstract":"<p><strong>Background: </strong>The ultra-short-acting benzodiazepine remimazolam, approved for procedural sedation and general anesthesia, is inactivated by carboxylesterase 1 (CES1).</p><p><strong>Objective: </strong>Remimazolam´s involvement in CES1-mediated drug-drug interactions (DDIs) was investigated.</p><p><strong>Methods: </strong>Possible interactions of remimazolam were studied in co-exposure experiments with eleven different drugs. Further, substrates and inhibitors of CES1, identified in the literature, were evaluated for possible <i>in-vivo</i> inhibition using pharmacokinetic and Ki or IC₅₀ values. Compounds with only one published inhibitory concentration and CES1 substrates lacking inhibition data were assigned conservative Ki values.</p><p><strong>Results: </strong>In human liver homogenates and/or blood cells, remimazolam showed no significant inhibition of esmolol and landiolol metabolism, which, in turn, at up to 98 and 169 μM, respectively, did not inhibit remimazolam hydrolysis by human liver homogenates. In human liver S9 fractions, IC₅₀ values ranged from 0.69 μM (simvastatin) and 57 μM (diltiazem) to > 100 μM (atorvastatin) and, for the remaining test items (bupropion, carvedilol, nelfinavir, nitrendipine, and telmisartan), they ranged from 126 to 658 μM. Remifentanil was ineffective even at 1250 μM. Guidance-conforming evaluation revealed no relevant drug-drug interactions with remimazolam <i>via</i> CES1. The algorithm-based predictions were consistent with human study data. Among CES1 inhibitors and substrates identified in the literature, only dapsone and rufinamide were found to be possible <i>in-vivo</i> inhibitors of remimazolam metabolism.</p><p><strong>Conclusion: </strong>Data and analyses suggest a very low potential of remimazolam for pharmacokinetic DDIs mediated by CES1. The theoretical approach and compiled data are not specific to remimazolam and, hence, applicable in the evaluation of other CES1 substrates.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"431-445"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141897013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hallmarks of Quercetin Benefits as a Functional Supplementary in the Management of Diabetes Mellitus-Related Maladies: From Basic to Clinical Applications.","authors":"Faegheh Farhadi, Fariba Sharififar, Mandana Jafari, Vafa Baradaran Rahimi, Nafiseh Askari, Vahid Reza Askari","doi":"10.2174/0113892002339410250108031621","DOIUrl":"10.2174/0113892002339410250108031621","url":null,"abstract":"<p><p>Quercetin (QE), a particular flavonoid, is well known for its medicinal effects, including anti-oxidant, hypoglycemic, and anti-inflammatory effects. In this review, the findings of QE effects on diabetes STZinduced, alloxan-induced, and its complications have been summarized with a particular focus on in vitro, in vivo, and clinical trials. Consequently, QE mediates several mechanisms, including ameliorating tumor necrosis factor (TNF)-α, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), interleukin (IL)-1β, IL-8, and IL-10 expression, increasing insulin glucose uptake to inhibit insulin resistance. Moreover, QE stimulates insulin secretion and attenuates insulin resistance through various pathways, namely transient KATP channel, motivating peroxisome proliferator-activated receptor expression, increasing glucose transporter-4, and decreasing inducible nitric oxide synthase in skeletal muscle. QE has protective effects on the complications caused by diabetes, such as polycystic ovary syndrome, high-fat diet-induced obesity, diabetic-induced hepatic damage, vascular inflammation, nephropathy, and neuropathy.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"653-669"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143058263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Cross-sectional Comparative Analysis of Eleven Population Pharmacokinetic Models for Docetaxel in Chinese Breast Cancer Patients.","authors":"Genzhu Wang, Qiang Sun, Xiaojing Li, Shenghui Mei, Shihui Li, Zhongdong Li","doi":"10.2174/0113892002322494240816032948","DOIUrl":"10.2174/0113892002322494240816032948","url":null,"abstract":"<p><strong>Objective: </strong>Various population pharmacokinetic (PPK) models have been established to help determine the appropriate dosage of docetaxel, however, no clear consensus on optimal dosing has been achieved. The purpose of this study is to perform an external evaluation of published models in order to test their predictive performance, and to find an appropriate PPK model for Chinese breast cancer patients.</p><p><strong>Methods: </strong>A systematic literature search of docetaxel PPK models was performed using PubMed, Web of Science, China National Knowledge Infrastructure, and WanFang databases. The predictive performance of eleven identified models was evaluated using prediction-based and simulation-based diagnostics on an independent dataset (112 docetaxel concentrations from 56 breast cancer patients). The -2×log (likelihood) and Akaike information criterion were also calculated to evaluate model fit.</p><p><strong>Results: </strong>The median prediction error of eight of the eleven models was less than 10%. The model fitting results showed that the three-compartment model of Bruno et al. had the best prediction performance and that the three compartment model of Wang et al. had the best simulation effect. Furthermore, although the covariates that significantly affect PK parameters were different between them, seven models demonstrated that docetaxel PK parameters were influenced by liver function.</p><p><strong>Conclusions: </strong>Three compartment PPK models may be predictive of optimal docetaxel dosage for Chinese breast cancer patients. However, for patients with impaired liver function, the choice of which model to use to predict the blood concentration of docetaxel still requires great care.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"479-488"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11826906/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety Issues of Herb-Warfarin Interactions.","authors":"Subhajit Hazra, Preet Amol Singh, Neha Bajwa","doi":"10.2174/0113892002290846240228061506","DOIUrl":"10.2174/0113892002290846240228061506","url":null,"abstract":"<p><p>Warfarin is a popular anticoagulant with high global demand. However, studies have underlined serious safety issues when warfarin is consumed concomitantly with herbs or its formulations. This review aimed to highlight the mechanisms behind herb-warfarin interactions while laying special emphasis on its PKPD interactions and evidence on Herb-Warfarin Interaction (HWI) with regards to three different scenarios, such as when warfarin is consumed with herbs, taken as foods or prescribed as medicine, or when used in special situations. A targeted literature methodology involving different scientific databases was adopted for acquiring information on the subject of HWIs. Results of the present study revealed some of the fatal consequences of HWI, including post-operative bleeding, thrombosis, subarachnoid hemorrhage, and subdural hematomas occurring as a result of interactions between warfarin and herbs or commonly associated food products from <i>Hypericum perforatum, Zingiber officinale, Vaccinium oxycoccos, Citrus paradisi</i>, and <i>Punica granatum</i>. In terms of PK-PD parameters, herbs, such as <i>Coptis chinensis</i> Franch. and <i>Phellodendron amurense</i> Rupr., were found to compete with warfarin for binding with plasma proteins, leading to an increase in free warfarin levels in the bloodstream, resulting in its augmented antithrombic effect. Besides, HWIs were also found to decrease International Normalised Ratio (INR) levels following the consumption of Persea americana or avocado. Therefore, there is an urgent need for an up-to-date interaction database to educate patients and healthcare providers on these interactions, besides promoting the adoption of novel technologies, such as natural language processing, by healthcare professionals to guide them in making informed decisions to avoid HWIs.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"13-27"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140093542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of P-glycoprotein in Regulating the Efficacy, Toxicity and Pharmacokinetics of Yunaconitine.","authors":"Xiaocui Li, Qi Liang, Caiyan Wang, Huawei Qiu, Tingting Lin, Wentao Li, Rong Zhang, Zhongqiu Liu, Lijun Zhu","doi":"10.2174/0113892002302427240801072910","DOIUrl":"10.2174/0113892002302427240801072910","url":null,"abstract":"<p><strong>Background: </strong>Yunaconitine (YAC) is a hidden toxin that greatly threatens the life safety of patients who are prescribed herbal medicines containing <i>Aconitum</i> species; however, its underlying mechanism remains unclear.</p><p><strong>Objective: </strong>The objective of this study is to elucidate the functions of P-glycoprotein (P-gp) in regulating the efficacy, toxicity, and pharmacokinetics of YAC.</p><p><strong>Methods: </strong>The efflux function of P-gp on YAC was explored by using Caco-2 monolayers in combination with the P-gp inhibitor verapamil. The impact of P-gp on regulating the analgesic and anti-inflammatory effects, acute toxicity, tissue distribution, and pharmacokinetics of YAC was determined <i>via</i> male Mdr1a gene knocked-out mice and wild-type FVB mice.</p><p><strong>Results: </strong>The presence of verapamil significantly decreased the efflux ratio of YAC from 20.41 to 1.07 in Caco- 2 monolayers (P < 0.05). Moreover, oral administration of 0.07 and 0.14 mg/kg YAC resulted in a notable decrease in writhing times in Mdr1a^-/- mice by 23.53% and 49.27%, respectively, compared to wild-type FVB mice (P < 0.05). Additionally, the deficiency of P-gp remarkably decreased the half-lethal dose (LD₅₀) of YAC from 2.13 to 0.24 mg/kg (P < 0.05). Moreover, the concentrations of YAC in the tissues of Mdr1a^-/- mice were statistically higher than those in wild-type FVB mice (P < 0.05). Particularly, the brain accumulation of YAC in Mdr1a^-/- mice significantly increased by 12- and 19-fold, respectively, after oral administration for 30 and 120 min, when compared to wild-type FVB mice (P < 0.05). There were no significant differences in the pharmacokinetic characteristics of YAC between Mdr1a^-/- and wild-type FVB mice.</p><p><strong>Conclusion: </strong>YAC is a sensitive substrate of P-gp. The absence of P-gp enhances the analgesic effect and toxicity of YAC by upregulating its brain accumulation. Co-administration with a P-gp inhibitor may lead to severe YAC poisoning.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"317-329"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141897017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of Salbutamol on the Disposition Kinetics of Levofloxacin in the Plasma and Lung of Rats.","authors":"Murat Ali Cicekler, Halis Oguz, Orhan Corum","doi":"10.2174/0113892002314136240816094609","DOIUrl":"10.2174/0113892002314136240816094609","url":null,"abstract":"<p><strong>Background: </strong>Antibiotics and bronchodilator drugs can be used together in respiratory distress caused by bacterial infections. Levofloxacin (LVX) and Salbutamol (SLB) can be used simultaneously in respiratory distress. However, there have been no investigations on how the concurrent use of SLB can affect the pharmacokinetics of LVX in rats.</p><p><strong>Objective: </strong>The purpose of this study was to investigate the influence of SLB on the plasma and lung pharmacokinetics of LVX in rats.</p><p><strong>Methods: </strong>A total of 132 rats were randomly assigned to two groups: LVX (n=66) and LVX+SLB (n=66). LVX (intraperitoneal) and SLB (oral) were administered to rats at doses of 50 and 3 mg/kg, respectively. The concentrations of LVX in the plasma and lungs were determined through the utilization of high-performance liquid chromatography along with UV. Pharmacokinetic parameters were assessed by non-compartmental analysis.</p><p><strong>Results: </strong>The area under the curve from 0 to 16 h (AUC_0-16), terminal elimination half-life, volume of distribution, total body clearance, and peak concentration of LVX in the plasma were 42.57 h*μg/mL, 2.32 h, 3.91 L/kg, 1.17 L/h/kg, and 23.96 μg/mL, respectively. There were no alterations observed in the plasma and lung pharmacokinetic parameters of LVX when co-administered with SLB. The AUC_0-16 lung/AUC_{0-16 plasma} ratios of LVX were 1.60 and 1.39 after administration alone and co-administration with SLB, respectively.</p><p><strong>Conclusion: </strong>The concentration of LVX in lung tissue was higher than that in plasma. SLB administration to rats did not affect the plasma and lung pharmacokinetics and lung penetration ratio of LVX. There is a need to reveal the change in the pharmacokinetics of LVX after multiple administration of both drugs and after administration of SLB by different routes.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"425-430"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142016605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ceftobiprole and Cefiderocol for Patients on Extracorporeal Membrane Oxygenation: The Role of Therapeutic Drug Monitoring.","authors":"Diana Morales Castro, John Granton, Eddy Fan","doi":"10.2174/0113892002331260240919055056","DOIUrl":"10.2174/0113892002331260240919055056","url":null,"abstract":"<p><strong>Introduction: </strong>Limited data exist on therapeutic ranges for newer antimicrobials in the critically ill, with few pharmacokinetic studies including patients undergoing renal replacement therapy or extracorporeal membrane oxygenation (ECMO).</p><p><strong>Case representation: </strong>These interventions can potentially alter the pharmacokinetic profile of antibiotics, resulting in therapeutic failures, antimicrobial resistance, or increased toxicity. In this report, we present two ECMO patients treated with cefiderocol and ceftobiprole, where therapeutic drug monitoring (TDM) aided in the successful treatment of severe infections. Antibiotic trough concentrations in both cases were consistent with previously reported therapeutic levels in critically ill and ECMO patients, meeting minimal inhibitory concentrations recommended by the European Committee on Antimicrobial Susceptibility Testing for the respective pathogens.</p><p><strong>Conclusion: </strong>Treatment might be suboptimal if doses are not adjusted based on physicochemical properties and extracorporeal support. In an era marked by highly resistant pathogens, these cases highlight the importance of timely access to real-time TDM for optimizing and individualizing antimicrobial treatment.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"542-546"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142343117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metabolic Pathway of Osilodrostat in Equine Urine Established through High-resolution Mass Spectrometric Characterization for Doping Control.","authors":"Hideaki Ishii, Ryo Shigematsu, Shunsuke Takemoto, Yuhiro Ishikawa, Fumiaki Mizobe, Motoi Nomura, Daisuke Arima, Hirokazu Kunii, Reiko Yuasa, Takashi Yamanaka, Sohei Tanabe, Shun-Ichi Nagata, Masayuki Yamada, Gary Ngai-Wa Leung","doi":"10.2174/0113892002325954240903062440","DOIUrl":"10.2174/0113892002325954240903062440","url":null,"abstract":"<p><strong>Objective: </strong>Osilodrostat, used to treat Cushing's disease, exhibits an anabolic effect, leading to its classification as a prohibited substance in horseracing and equestrian sports. This study reports the characterization of osilodrostat metabolites in horse urine and elucidates its metabolic pathways for the first time for doping control purposes.</p><p><strong>Methods: </strong>Osilodrostat was administered nasoesophageally to four thoroughbreds (one gelding and three mares) at a dose of 50 mg each. Potential metabolites were extensively screened via our developed generic approach employing differential analysis to identify metabolites. Specifically, high-resolution mass spectral data were compared between pre- and post-administration samples on the basis of criteria of fold-changes of peak areas and their P values. Potential metabolite candidates were further identified through mass spectral interpretations using product ion scan data.</p><p><strong>Results: </strong>A total of 37 metabolites were identified after comprehensive analysis. Osilodrostat was predominantly metabolized into a mono-hydroxylated form M1c (~40%) alongside osilodrostat glucuronide M2 (~17%). Given their longest detection time (2 weeks after administration) and the identification of several conjugates of osilodrostat and M1c, including a novel conjugate of riburonic acid, we recommend monitoring both osilodrostat and M1c after hydrolysis during the screening stage. However, only osilodrostat can be used for confirmation because of the availability of a reference material.</p><p><strong>Conclusion: </strong>It is advisable to screen for both osilodrostat and its mono-hydroxylated metabolite M1c to effectively monitor horse urine for the potential misuse or abuse of osilodrostat. For suspicious samples, confirmation of osilodrostat using its reference material is required.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"489-504"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}