Current drug metabolism最新文献

{"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":"Fluoropyrimidine Toxicity: the Hidden Secrets of DPYD.","authors":"Vangelis G Manolopoulos, Georgia Ragia","doi":"10.2174/0113892002296707240311105527","DOIUrl":"10.2174/0113892002296707240311105527","url":null,"abstract":"<p><strong>Background: </strong>Fluoropyrimidine-induced toxicity is a main limitation of therapy. Currently, polymorphisms in the DPYD gene, which encodes the 5-FU activation enzyme dihydropyrimidine dehydrogenase (DPD), are used to adjust the dosage and prevent toxicity. Despite the predictive value of DPYD genotyping, a great proportion of fluoropyrimidine toxicity cannot be solely explained by DPYD variations.</p><p><strong>Objective: </strong>We herein summarize additional sources of DPD enzyme activity variability, spanning from epigenetic regulation of DPYD expression, factors potentially inducing protein modifications, as well as drug-enzyme interactions that contribute to fluoropyrimidine toxicity.</p><p><strong>Results: </strong>While seminal <i>in vitro</i> studies provided evidence that DPYD promoter methylation downregulates DPD expression, the association of DPYD methylation with fluoropyrimidine toxicity was not replicated in clinical studies. Different non-coding RNA molecules, such as microRNA, piwi-RNAs, circular-RNAs and long non-coding RNAs, are involved in post-transcriptional DPYD regulation. DPD protein modifications and environmental factors affecting enzyme activity may also add a proportion to the pooled variability of DPD enzyme activity. Lastly, DPD-drug interactions are common in therapeutics, with the most well-characterized paradigm the withdrawal of sorivudine due to fluoropyrimidine toxicity deaths in 5-FU treated cancer patients; a mechanism involving DPD severe inhibition.</p><p><strong>Conclusions: </strong>DPYD polymorphisms are the main source of DPD variability. A study on DPYD epigenetics (both transcriptionally and post-transcriptionally) holds promise to provide insights into molecular pathways of fluoropyrimidine toxicity. Additional post-translational DPD modifications, as well as DPD inhibition by other drugs, may explain a proportion of enzyme activity variability. Therefore, there is still a lot we can learn about the DPYD/DPD fluoropyrimidine-induced toxicity machinery.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"91-95"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140174063","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":"Isopsoralen Improves Glucocorticoid-induced Osteoporosis by Regulating Purine Metabolism and Promoting cGMP/PKG Pathway-mediated Osteoblast Differentiation.","authors":"Defeng Liu, Lingyun Ma, Jihui Zheng, Zhenqun Zhang, Nana Zhang, Zhongqian Han, Xuejie Wang, Jianyong Zhao, Shuquan Lv, Huantian Cui","doi":"10.2174/0113892002308141240628071541","DOIUrl":"10.2174/0113892002308141240628071541","url":null,"abstract":"<p><strong>Background: </strong>The effects of Isopsoralen (ISO) in promoting osteoblast differentiation and inhibiting osteoclast formation are well-established, but the mechanism underlying ISO's improvement of Glucocorticoid- Induced Osteoporosis (GIOP) by regulating metabolism remains unclear.</p><p><strong>Methods: </strong>This study aims to elucidate the mechanism of ISO treatment for GIOP through non-targeted metabolomics based on ISO's efficacy in GIOP. Initially, we established a GIOP female mouse model and assessed ISO's therapeutic effects using micro-CT detection, biomechanical testing, serum calcium (Ca), and phosphorus (P) level detection, along with histological analyses using hematoxylin and eosin (HE), Masson, and tartrate-resistant acidic phosphatase (TRAP) staining. Subsequently, non-targeted metabolomics was employed to investigate ISO's impact on serum metabolites in GIOP mice. RT-qPCR and Western blot analyses were conducted to measure the levels of enzymes associated with these metabolites. Building on the metabolomic results, we explored the effects of ISO on the cyclic Guanosine Monophosphate (cGMP)/Protein Kinase G (PKG) pathway and its role in mediating osteoblast differentiation.</p><p><strong>Results: </strong>Our findings demonstrate that ISO intervention effectively enhances the bone microarchitecture and strength of GIOP mice. It mitigates pathological damage, such as structural damage in bone trabeculae, reduced collagen fibers, and increased osteoclasts, while improving serum Ca and P levels in GIOP mice. Non-- targeted metabolomics revealed purine metabolism as a common pathway between the Control and GIOP groups, as well as between the ISO high-dose (ISOH) group and the GIOP group. ISO intervention upregulated inosine and adenosine levels, downregulated guanosine monophosphate levels, increased Adenosine Deaminase (ADA) expression, and decreased cGMP-specific 3',5'-cyclic phosphodiesterase (PDE5) expression. Additionally, ISO intervention elevated serum cGMP levels, upregulated PKGI and PKGII expression in bone tissues, as well as the expression of Runt-related transcription factor 2 (Runx2) and Osterix, and increased serum Alkaline Phosphatase (ALP) activity.</p><p><strong>Conclusion: </strong>In summary, ISO was able to enhance the bone microstructure and bone strength of GIOP mice and improve their Ca, P, and ALP levels, which may be related to ISO's regulation of purine metabolism and promotion of osteoblast differentiation mediated by the cGMP/PKG pathway. This suggests that ISO is a potential drug for treating GIOP. However, further research is still needed to explore the specific targets and clinical applications of ISO.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"288-297"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141616055","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}

{"title":"Innovative Nanoscale Drug Delivery Strategies for Breast Carcinoma: A Comprehensive Exploration.","authors":"S Jaishree, Selvaraj Kousalya, S Prakash, D Vineesh","doi":"10.2174/0113892002298034240802110752","DOIUrl":"10.2174/0113892002298034240802110752","url":null,"abstract":"<p><p>Breast cancer (BC) is one of the major causes of poor health in women and the most devastating disease after lung cancer. The term \"cancer\" refers to a collection of problems resulting from abnormal cell proliferation, particularly cells that can spread to other parts of the body. Surgery, followed by chemotherapy or radiotherapy, is now accepted for BC-related cancers. However, chemotherapy and radiotherapy are rarely effective in the treatment of BC due to the adverse effects of these treatments on healthy tissues and organs. Consequently, the use of NPs in targeted Drug Delivery Systems (DDSs) has emerged as a promising strategy for BC treatment. This review provides a summary of recent clinical investigations of nanoparticle-mediated DDS that offer a novel therapeutic strategy commonly used for the treatment of breast cancer.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"391-402"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141897015","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":"Drug Metabolizing Enzymes: An Exclusive Guide into Latest Research in Pharmaco-genetic Dynamics in Arab Countries.","authors":"Laith Al Eitan, Iliya Yacoub Khair, Saif Alahmad","doi":"10.2174/0113892002323910240924145310","DOIUrl":"10.2174/0113892002323910240924145310","url":null,"abstract":"<p><p>Drug metabolizing enzymes play a crucial role in the pharmacokinetics and pharmacodynamics of therapeutic drugs, influencing their efficacy and safety. This review explores the impact of genetic polymorphisms in drug-metabolizing genes on drug response within Arab populations. We examine the genetic diversity specific to Arab countries, focusing on the variations in key drug-metabolizing enzymes such as CYP450, GST, and UGT families. The review highlights recent research on polymorphisms in these genes and their implications for drug metabolism, including variations in allele frequencies and their effects on therapeutic outcomes. Additionally, the paper discusses how these genetic variations contribute to the variability in drug response and adverse drug reactions among individuals in Arab populations. By synthesizing current findings, this review aims to provide a comprehensive understanding of the pharmacogenetic landscape in Arab countries and offer insights into personalized medicine approaches tailored to genetic profiles. The findings underscore the importance of incorporating pharmacogenetic data into clinical practice to enhance drug efficacy and minimize adverse effects, ultimately paving the way for more effective and individualized treatment strategies in the region.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"465-478"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142388731","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":"Comparative Analysis of Machine Learning Algorithms Evaluating the Single Nucleotide Polymorphisms of Metabolizing Enzymes with Clinical Outcomes Following Intravenous Paracetamol in Preterm Neonates with Patent Ductus Arteriosus.","authors":"Kannan Sridharan, George Priya Doss C, Hephzibah Cathryn R, Thirumal Kumar D, Muna Al Jufairi","doi":"10.2174/0113892002289238240222072027","DOIUrl":"10.2174/0113892002289238240222072027","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Aims: &lt;/strong&gt;Pharmacogenomics has been identified to play a crucial role in determining drug response. The present study aimed to identify significant genetic predictor variables influencing the therapeutic effect of paracetamol for new indications in preterm neonates.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Paracetamol has recently been preferred as a first-line drug for managing Patent Ductus Arteriosus (PDA) in preterm neonates. Single Nucleotide Polymorphisms (SNPs) in CYP1A2, CYP2A6, CYP2D6, CYP2E1, and CYP3A4 have been observed to influence the therapeutic concentrations of paracetamol.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Objectives: &lt;/strong&gt;The purpose of this study was to evaluate various Machine Learning Algorithms (MLAs) and bioinformatics tools for identifying the key genotype predictor of therapeutic outcomes following paracetamol administration in neonates with PDA.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Preterm neonates with hemodynamically significant PDA were recruited in this prospective, observational study. The following SNPs were evaluated: CYP2E1*5B, CYP2E1*2, CYP3A4*1B, CYP3A4*2, CYP3A4*3, CYP3A5*3, CYP3A5*7, CYP3A5*11, CYP1A2*1C, CYP1A2*1K, CYP1A2*3, CYP1A2*4, CYP1A2*6, and CYP2D6*10. Amongst the MLAs, Artificial Neural Network (ANN), C5.0 algorithm, Classification and Regression Tree analysis (CART), discriminant analysis, and logistic regression were evaluated for successful closure of PDA. Generalized linear regression, ANN, CART, and linear regression were used to evaluate maximum serum acetaminophen concentrations. A two-step cluster analysis was carried out for both outcomes. Area Under the Curve (AUC) and Relative Error (RE) were used as the accuracy estimates. Stability analysis was carried out using &lt;i&gt;in silico&lt;/i&gt; tools, and Molecular Docking and Dynamics Studies were carried out for the above-mentioned enzymes.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Two-step cluster analyses have revealed CYP2D6*10 and CYP1A2*1C to be the key predictors of the successful closure of PDA and the maximum serum paracetamol concentrations in neonates. The ANN was observed with the maximum accuracy (AUC = 0.53) for predicting the successful closure of PDA with CYP2D6*10 as the most important predictor. Similarly, ANN was observed with the least RE (1.08) in predicting maximum serum paracetamol concentrations, with CYP2D6*10 as the most important predictor. Further MDS confirmed the conformational changes for P34A and P34S compared to the wildtype structure of CYP2D6 protein for stability, flexibility, compactness, hydrogen bond analysis, and the binding affinity when interacting with paracetamol, respectively. The alterations in enzyme activity of the mutant CYP2D6 were computed from the molecular simulation results.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;We have identified CYP2D6*10 and CYP1A2*1C polymorphisms to significantly predict the therapeutic outcomes following the administration of paracetamol in preterm neonates with PDA. Prospective studies are required","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"128-139"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140038850","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}