Pub Date : 2024-01-01DOI: 10.2174/0113892002282271231219044508
Teslime Erdogan, Halis Oguz, Orhan Corum
Background: The simultaneous use of NSAIDs and antibiotics is recommended for bacterial diseases in human and veterinary medicine. Moxifloxacin (MFX) and dexketoprofen (DEX) can be used simultaneously in bacterial infections. However, there are no studies on how the simultaneous use of DEX affects the pharmacokinetics of MFX in rats.
Objectives: The aim of this study was to determine the effect of DEX on plasma and lung pharmacokinetics of MFX in male and female rats.
Methods: A total of 132 rats were randomly divided into 2 groups: MFX (n=66, 33 males/33 females) and MFX+DEX (n=66, 33 females/33 males). MFX at a dose of 20 mg/kg and DEX at a dose of 25 mg/kg were administered intraperitoneally. Plasma and lung concentrations of MFX were determined using the highperformance liquid chromatography-UV and pharmacokinetic parameters were evaluated by noncompartmental analysis.
Results: Simultaneous administration of DEX increased the plasma and lung area under the curve from 0 to 8 h (AUC0-8) and peak concentration (Cmax) of MFX in rats, while it significantly decreased the total body clearance (CL/F). When female and male rats were compared, significant differences were detected in AUC0-8, Cmax, CL/F and volume of distribution. The AUC0-8lung/AUC0-8plasma ratios of MFX were calculated as 1.68 and 1.65 in female rats and 5.15 and 4.90 in male rats after single and combined use, respectively.
Conclusion: MFX was highly transferred to the lung tissue and this passage was remarkably higher in male rats. However, DEX administration increased the plasma concentration of MFX in both male and female rats but did not change its passage to the lung. However, there is a need for a more detailed investigation of the difference in the pharmacokinetics of MFX in male and female rats.
{"title":"Effect of Dexketoprofen on the Disposition Kinetics of Moxifloxacin in Plasma and Lung in Male and Female Rats.","authors":"Teslime Erdogan, Halis Oguz, Orhan Corum","doi":"10.2174/0113892002282271231219044508","DOIUrl":"10.2174/0113892002282271231219044508","url":null,"abstract":"<p><strong>Background: </strong>The simultaneous use of NSAIDs and antibiotics is recommended for bacterial diseases in human and veterinary medicine. Moxifloxacin (MFX) and dexketoprofen (DEX) can be used simultaneously in bacterial infections. However, there are no studies on how the simultaneous use of DEX affects the pharmacokinetics of MFX in rats.</p><p><strong>Objectives: </strong>The aim of this study was to determine the effect of DEX on plasma and lung pharmacokinetics of MFX in male and female rats.</p><p><strong>Methods: </strong>A total of 132 rats were randomly divided into 2 groups: MFX (n=66, 33 males/33 females) and MFX+DEX (n=66, 33 females/33 males). MFX at a dose of 20 mg/kg and DEX at a dose of 25 mg/kg were administered intraperitoneally. Plasma and lung concentrations of MFX were determined using the highperformance liquid chromatography-UV and pharmacokinetic parameters were evaluated by noncompartmental analysis.</p><p><strong>Results: </strong>Simultaneous administration of DEX increased the plasma and lung area under the curve from 0 to 8 h (AUC<sub>0-8</sub>) and peak concentration (C<sub>max</sub>) of MFX in rats, while it significantly decreased the total body clearance (CL/F). When female and male rats were compared, significant differences were detected in AUC<sub>0-8</sub>, C<sub>max</sub>, CL/F and volume of distribution. The AUC<sub>0-8lung</sub>/AUC<sub>0-8plasma</sub> ratios of MFX were calculated as 1.68 and 1.65 in female rats and 5.15 and 4.90 in male rats after single and combined use, respectively.</p><p><strong>Conclusion: </strong>MFX was highly transferred to the lung tissue and this passage was remarkably higher in male rats. However, DEX administration increased the plasma concentration of MFX in both male and female rats but did not change its passage to the lung. However, there is a need for a more detailed investigation of the difference in the pharmacokinetics of MFX in male and female rats.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"63-70"},"PeriodicalIF":2.1,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139520283","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}
Pub Date : 2024-01-01DOI: 10.2174/0113892002286019240315052145
Jinhua Wen, Yuwei Xiao, Menghua Zhao, Chen Yang, Weiqiang Hu
Objective: 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.
Method: 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.
Results: 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.
Conclusion: 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.
{"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}
Pub Date : 2024-01-01DOI: 10.2174/0113892002289027240809114634
Wen Kou, Xinan Wu
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 in vivo.
{"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}
Pub Date : 2023-12-23DOI: 10.2174/0113892002274982231211102127
Handan Tanyildizi-Kökkülünk, Ahmet Murat Şenişik, Mahmut Yüksel
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.
{"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}
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.
背景：癌症耐药性仍然是有效治疗的一个难以逾越的障碍，因此有必要深入了解其多层次的机制。研究目的本研究旨在全面探讨癌症耐药性的多种机制，评估耐药性检测方法的演变，并确定克服这一挑战的策略。耐药性检测方法的演变，并确定克服这一挑战的策略。方法：通过全面的文献综述，分析内在和获得性耐药机制，包括药物外流改变、摄取减少、失活、靶点突变、信号通路变化、凋亡缺陷和细胞可塑性。研究还探讨了突变检测技术的演变，包括临床预测、实验方法和计算方法。研究还探讨了提高药物疗效、改变药代动力学、优化结合模式和探索替代蛋白质折叠状态的策略。研究结果该研究全面概述了导致癌症耐药性的复杂机制。它概述了突变检测方法的进展，并强调了跨学科方法的重要性。研究还讨论了克服耐药性挑战的策略，如调节 ATP 结合盒转运体和开发多药耐药性抑制剂。该研究强调了继续开展研究以提高癌症治疗效果的迫切需要。结论：本研究为了解癌症耐药机制的复杂性提供了宝贵的见解，强调了不断发展的检测方法，并提供了提高治疗效果的潜在策略。
{"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}
Pub Date : 2023-12-23DOI: 10.2174/0113892002278220231208072351
Devran Coskun, Orhan Corum, Duygu Durna Corum, Kamil Uney
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. (>125) with MIC of 0.37 µg/mL and for S. aureus (>30) with MIC of 0.5 µg/mL in all ages of sheep.
{"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. (>125) with MIC of 0.37 µg/mL and for S. aureus (>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}
Pub Date : 2023-12-15DOI: 10.2174/0113892002276499231201094142
Mohammad Hossein Asgarshamsi, Mehrdad Mohammadpour Dehkordi, Seyed Mohamad Reza Nazifi, Krzysztof K. Zborowski
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.
{"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}
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.
{"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}
Pub Date : 2023-08-04DOI: 10.2174/138920022404230714101907
Ramesh Jayaraman
{"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}
Pub Date : 2023-08-01DOI: 10.2174/138920022408230928105612
Hiroshi Yamazaki
{"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}
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