Current drug metabolism最新文献

{"title":"Effects of Clarithromycin and Ketoconazole on FK506 Metabolism in Different CYP3A4 Genotype Recombinant Metabolic Enzyme Systems.","authors":"Jinhua Wen, Yuwei Xiao, Menghua Zhao, Chen Yang, Weiqiang Hu","doi":"10.2174/0113892002286019240315052145","DOIUrl":"10.2174/0113892002286019240315052145","url":null,"abstract":"<p><strong>Objective: </strong>This study aimed to investigate the effects of clarithromycin and ketoconazole on the pharmacokinetic properties of tacrolimus in different CYP3A4 genotype recombinant metabolic enzyme systems, so as to understand the drug interactions and their mechanisms further.</p><p><strong>Method: </strong>The experiment was divided into three groups: a blank control group, CYP3A4*1 group and CYP3A4*18 recombinant enzyme group. Each group was added with tacrolimus (FK506) of a series of concentrations. Then 1 umol/L clarithromycin or ketoconazole was added to the recombinant enzyme group and incubated in the NADPH system for 30 minutes to examine the effects of clarithromycin and ketoconazole on the metabolizing enzymes' activity of different genotypes. The remaining concentration of FK506 in the reaction system was determined using UPLC-MS/MS, and the enzyme kinetic parameters were calculated using the software.</p><p><strong>Results: </strong>The metabolism of CYP3A4*18 to FK506 was greater than that of CyP3А4*1B. Compared with the CYP3A4*1 group, the metabolic rate and clearance of FK506 in the CYP3A4*18 group significantly increased, with Km decreasing. Clarithromycin and ketoconazole inhibit the metabolism of FK506 by affecting the enzyme activity of CYP3A4*1B and CYP3A4*18B. After adding clarithromycin or ketoconazole, the metabolic rate of FK506 significantly decreased in CYP3A4*1 and CYP3A4*18, with Km increasing, Vmax and Clint decreasing.</p><p><strong>Conclusion: </strong>Compared with CYP3A4*1, CYP3A4*18 has a greater metabolism of FK506, clarithromycin and ketoconazole can inhibit both the enzymatic activities of CYP3A4*1 and CYP3A4*18, consequently affecting the metabolism of FK506 and the inhibitory on CYP3A4*1 is stronger.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"174-177"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140206417","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":"Hepatic Metabolic Enzyme Activity with Endogenous Substances-Current Status, Challenges and Limitations.","authors":"Wen Kou, Xinan Wu","doi":"10.2174/0113892002289027240809114634","DOIUrl":"10.2174/0113892002289027240809114634","url":null,"abstract":"<p><p>Precision dosing is essential in improving drug efficacy and minimizing adverse reactions, especially in liver impaired patients. However, there is no objective index to directly evaluate the body's ability to metabolize specific drugs. Many factors affect the activity of enzymes, and alter the systemic exposure of substrate drugs, like genetic polymorphism, drug-drug interactions and physiological/pathological state. So, quantifying the activities of enzymes dynamically would be helpful to make precision dosing. Recently, some endogenous substrates of enzymes, such as 6β-hydroxycortisol (6β-OH-cortisol)/cortisol and 6β-hydroxycortisone, have been identified to investigate variations in drug enzymes in humans. Clinical data obtained support their performance as surrogate probes in terms of reflecting the activities of corresponding enzyme. Therefore, a group of Monitored endogenous biomarkers in multiple points can address the uncertainty in drug metabolization in the preclinical phase and have the potential to fulfill precision dosing. This review focuses on recent progress in the contribution of endogenous substances to drug precision dosing, factors that influence enzyme activities, and drug exposure <i>in vivo</i>.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"381-390"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003806","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":"Reassessment of Radiation Exposure From Bone Scintigraphy","authors":"Handan Tanyildizi-Kökkülünk, Ahmet Murat Şenişik, Mahmut Yüksel","doi":"10.2174/0113892002274982231211102127","DOIUrl":"https://doi.org/10.2174/0113892002274982231211102127","url":null,"abstract":"Aim: This study was aimed to re-determine the radiation dose rate emitted from the patients who underwent bone scintigraphy Material and Methods: A mean of 20.87±2.54 mCi 99mTc-MDP was injected into patients. A GM counter was used to measure dose rates in 3 different periods, at intervals of 25, 50, 100, 150, and 200 cm from the patient's anterior for head, thorax, abdomen, and pelvis levels. Measurements were used to determine patient-induced environmental doses and radiation doses to personnel/patient relatives. Results and Discussion: There were strong correlations between mean dose rate (mRh-1mCi-1) and time at all regions and distances. The received dose for staff was calculated between a range of 0.01-0.02 mSv/mCi per patient. The total dose to be received by the companion was estimated to be between 0.019-0.039 and 0.011-0.022 mSv for public and personal vehicle transportation, respectively. The radiation dose exposed by nurses (4th, 6th, and 8th hours after injection) was found to be 0.012-0.064, 0.006-0.038, and 0.002-0.018 mSv/patient, respectively. Conclusion: The fact that the doses of personnel and patient relatives in the study were below the legal limits shows that the study was carried out within a safe range. However, in terms of radiation protection, it is necessary to limit the time spent with the patient as much as possible and increase the distance. Since the dangers of low radiation dosages are unknown, there is a need to inform the patient's relatives and staff about the potential risks.","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":"6 1","pages":""},"PeriodicalIF":2.3,"publicationDate":"2023-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139031796","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":"The Impacts and Changes Related to the Cancer Drug Resistance Mechanism","authors":"Prachi varshney, Vishal Sharma, Devdhar Yadav, Yogesh Kumar, Amit Singh, Naga Rani Kagithala, Pramod Kumar Sharma, Omji Porwal, Neeraj Kumar Fuloria, Pradeep Kumar Sharma, Ashok Kumar Gupta, Koteswara Rao GSN","doi":"10.2174/0113892002266408231207150547","DOIUrl":"https://doi.org/10.2174/0113892002266408231207150547","url":null,"abstract":"Background: Cancer drug resistance remains a difficult barrier to effective treatment, necessitating a thorough understanding of its multi-layered mechanism. Objective: This study aims to comprehensively explore the diverse mechanisms of cancer drug resistance, assess the evolution of resistance detection methods, and identify strategies for overcoming this challenge. The evolution of resistance detection methods and identification strategies for overcoming the challenge. Methods: A comprehensive literature review was conducted to analyze intrinsic and acquired drug resistance mechanisms, including altered drug efflux, reduced uptake, inactivation, target mutations, signaling pathway changes, apoptotic defects, and cellular plasticity. The evolution of mutation detection techniques, encompassing clinical predictions, experimental approaches, and computational methods, was investigated. Strategies to enhance drug efficacy, modify pharmacokinetics, optimizoptimizee binding modes, and explore alternate protein folding states were examined. Results: The study comprehensively overviews the intricate mechanisms contributing to cancer drug resistance. It outlines the progression of mutation detection methods and underscores the importance of interdisciplinary approaches. Strategies to overcome drug resistance challenges, such as modulating ATP-binding cassette transporters and developing multidrug resistance inhibitors, are discussed. The study underscores the critical need for continued research to enhance cancer treatment efficacy. Conclusion: This study provides valuable insights into the complexity of cancer drug resistance mechanisms, highlights evolving detection methods, and offers potential strategies to enhance treatment outcomes.","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":"65 1","pages":""},"PeriodicalIF":2.3,"publicationDate":"2023-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139028841","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 Pharmacokinetics of İntravenous Enrofloxacin in One- Six- And Twelve-Month-Old Sheep","authors":"Devran Coskun, Orhan Corum, Duygu Durna Corum, Kamil Uney","doi":"10.2174/0113892002278220231208072351","DOIUrl":"https://doi.org/10.2174/0113892002278220231208072351","url":null,"abstract":"Background: Enrofloxacin (ENR) is a fluoroquinolone antibiotic approved for use in sheep of all ages. The body composition and metabolic capability change with age. These changes may alter the pharmacokinetics of drugs and thus their effect. Therefore, the pharmacokinetics of drugs need to be established in target-age animals Objective: To determine the pharmacokinetics of ENR and its active metabolite, ciprofloxacin (CIP), following a single intravenous administration of ENR at a dose of 10 mg/kg in different ages of sheep. Methods: The study was carried out in the one-, six- and twelve-month age period of the sheep. A single dose of 10 mg/kg ENR was administered intravenously through the jugular vein to sheep in all age periods. ENR and CIP plasma concentrations were determined using HPLC–UV and analyzed using a non-compartmental method. Results: ENR was detected in the plasma until 36 h in one-month-old and up to 24 h in other ages. CIP was detected in the plasma up to 24 h in all age groups. The t1/2ʎz and Vdss were significantly higher in one-month-old sheep than in six and twelve-months old sheep. There was no difference in ClT and AUC values in different age groups. AUC0-∞CIP/AUC0-∞ENR ratios were higher in one-month-old than in six- and twelve-months sheep. Conclusion: The most important pharmacokinetic changes associated with aging in sheep are decreased Vdss and t1/2ʎz of ENR and the low ratio metabolizing of ENR to CIP. Pharmacokinetic/pharmacodynamic data showed that ENR after IV administration of 10 mg/kg dose provided the optimal AUC0–24/MIC90 ratios for E. coli, P. multocida and Mycoplasma spp. (&gt;125) with MIC of 0.37 µg/mL and for S. aureus (&gt;30) with MIC of 0.5 µg/mL in all ages of sheep.","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":"60 1","pages":""},"PeriodicalIF":2.3,"publicationDate":"2023-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139028919","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":"Theoretical Evaluation of Oleocanthal Reactive Centers","authors":"Mohammad Hossein Asgarshamsi, Mehrdad Mohammadpour Dehkordi, Seyed Mohamad Reza Nazifi, Krzysztof K. Zborowski","doi":"10.2174/0113892002276499231201094142","DOIUrl":"https://doi.org/10.2174/0113892002276499231201094142","url":null,"abstract":"Background:: Decarboxymethyl ligstroside aglycone (oleocanthal) is an essential component of olive oil. It is therefore interesting to study its metabolism in the human body. In order to find the best possible starting point for this metabolism, a theoretical study was carried out using DFT calculations and docking studies. Methods:: The DFT, B3LYP/6-311++G** and the PCM solvation model calculations were used to study the initial process of oleocanthal metabolism by the CYP1A2 enzyme. Structures of radicals formed by homolytic dissociation of hydrogen atoms from the oleocanthal structure were obtained and their properties were studied. Several parameters such as HOMO and LUMO energy gaps, Bond Dissociation Energy (BDE), hardness, and spin density of possible oleocanthal radicals were taken into account. Docking of oleocanthal into an enzyme binding pocket was also performed to locate the most probably metabolic site. Detailed analysis of the theoretical results allows the determination of the most likely reaction sites in oleocanthal. The mode of binding of oleocanthal to the CYP1A2 enzyme was also predicted. Results:: The results of the molecular docking studies are in agreement with the calculated quantum parameters. The theoretical predictions were compared with experimental data available in the scientific literature. A high correlation between theoretical calculations and experimental data was observed. The most likely site of oleocanthal metabolism was identified. Conclusion:: The results of our research support the usefulness of theoretical calculations in predicting metabolic pathways.","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":"152 1","pages":""},"PeriodicalIF":2.3,"publicationDate":"2023-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138692643","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":"Pharmacokinetics, Mass Balance, Tissue Distribution and Metabolism of [14C]101BHG-D01, a Novel Muscarinic Receptor Antagonist, in Rats","authors":"Huaye Gao, Cheng Yang, Wenhui Hu, Juefang Ding, Xingxing Diao, Yuandong Zheng, Chang Shu, Li Ding","doi":"10.2174/0113892002275839231205111422","DOIUrl":"https://doi.org/10.2174/0113892002275839231205111422","url":null,"abstract":"Background:: 101BHG-D01, a novel long-acting and selective muscarinic receptor antagonist for the treatment of chronic obstructive pulmonary disease (COPD), is undergoing Phase Ib clinical trial in patients and has shown its potential efficacy. Its preparation method and medical use thereof have been patented in the United States (Patent No.US9751875B2). Objective:: In this study, the pharmacokinetics, mass balance, tissue distribution and metabolism of radioactive 101BHG-D01 were investigated in rats after an intravenous dose of 1 mg/kg [14C]101BHG-D01 (100 μCi/kg). objective: In this study, the pharmacokinetics, mass balance, tissue distribution and metabolism of radioactive 101BHG-D01 were investigated in rats after an intravenous dose of 1 mg/kg [14C]101BHG-D01 (100 µCi/kg). Methods:: Radioactivity in rat plasma, urine, feces, and tissues was measured by liquid scintillation counting (LSC), and metabolite profiling and identification were conducted by UHPLC-β-RAM and UHPLC-Q-Exactive Plus MS. Results:: The total radioactivity of the study drug in rat plasma rapidly declined with an average terminal elimination half-life of 0.35 h. The radioactivity in most tissues reached the maximum concentration at 0.25 h post-- dosing. The radioactivity is mainly concentrated in the kidney and pancreas. The drug-related substances tended to be distributed into the blood cells in the circulation. At 168 h post dosing, the mean recovery of the total radioactivity in urine and feces was 78.82%. Fecal excretion was the major excretion route, accounting for approximately 61% of the radioactive dose. The study drug was metabolized extensively, and a total of 17 metabolites were identified in rat plasma, urine, and feces. The major metabolic pathways involved oxidation, oxidation and dehydrogenation, and O-dephenylation. result: The total radioactivity of the study drug in rat plasma rapidly declined with an average terminal elimination half-life of 0.19 h. The radioactivity in most tissues reached the maximum concentration at 0.25 h post dosing. The radioactivity mainly concentrated in the kidney and pancreas. The drug-related substances tended to be distributed into the blood cells in the circulation. At 168 h post dosing, the mean recovery of the total radioactivity in urine and feces was 78.82%. Fecal excretion was the major excretion route, accounting for approximately 61% of the radioactive dose. The study drug was metabolized extensively and a total of 17 metabolites were identified in rat plasma, urine, and feces. The major metabolic pathways involved oxidation, oxidation and dehydrogenation, and O-dephenylation. There was no significant sex difference in the distribution, metabolism and excretion of [14C]101BHG-D01. Conclusion:: In conclusion, the study results are useful for better understanding the pharmacokinetic profiles of 101BHG-D01 and provide a robust foundation for subsequent clinical studies.","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":"5 1","pages":""},"PeriodicalIF":2.3,"publicationDate":"2023-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138576480","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":"Meet the Editorial Board Member","authors":"Ramesh Jayaraman","doi":"10.2174/138920022404230714101907","DOIUrl":"https://doi.org/10.2174/138920022404230714101907","url":null,"abstract":"","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":"72 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136119852","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":"Meet the Associate Editor","authors":"Hiroshi Yamazaki","doi":"10.2174/138920022408230928105612","DOIUrl":"https://doi.org/10.2174/138920022408230928105612","url":null,"abstract":"","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":"15 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135053971","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":"Meet the Editorial Board Member","authors":"Mohammad A. Kamal","doi":"10.2174/138920022407230928095028","DOIUrl":"https://doi.org/10.2174/138920022407230928095028","url":null,"abstract":"","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":"19 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135855890","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}