Current drug metabolism最新文献

{"title":"Characterizing Pharmacokinetic Variability of Topiroxostat in Chinese Population: Insights from a Phase I Randomized Clinical Trial.","authors":"Tianqi Zhong, Kaizong Huang, LuYao Han, Wenbo Pang, Yan Xia, Shengjun Qu, Guo Yu, Yangsheng Chen, Hongwei Fan","doi":"10.2174/0113892002348045241210071452","DOIUrl":"10.2174/0113892002348045241210071452","url":null,"abstract":"<p><strong>Objective: </strong>This Phase I clinical trial aimed to address the knowledge gap regarding topiroxostat's use outside Japan by characterizing its pharmacokinetic profile, safety, and efficacy in healthy Chinese subjects.</p><p><strong>Methods: </strong>The trial followed a randomized, open-label, three-dose group design, enrolling 12 healthy participants and administering topiroxostat at three different dose levels. The study utilized NONMEM software for pharmacokinetic analysis, evaluating the impact of demographic and biochemical covariates on drug disposition.</p><p><strong>Results: </strong>Pharmacokinetic analysis shows the peak drug concentration (Cmax) under a single oral administration of 20, 40, and 80 mg of Topiroxostat, which was found in healthy subjects to be 215.46 ± 94.04 ng/mL, 473.74 ± 319.83 ng/mL and 1009.63 ± 585.98 ng/mL, respectively. The time to peak drug concentration (Tmax) was longer in females (0.79-0.98 h) than in males (0.53-0.93 h). Activated partial thromboplastin time (APTT) and triglycerides (TG) were included as covariates for the typical value of the absorption rate constant (TVKA) in our pharmacokinetic model. The dose (DOSE) was considered a covariate for the typical value of bioavailability (TVF1), and sex (SEX) was considered a covariate for the typical value of clearance (TVCL). The typical population values for topiroxostat included Q/F at 4.91 L/h, KA at 0.657 h-¹, Vc/F at 32.5 L, Vp/F at 30 L, and CL/F at 124 L/h.</p><p><strong>Conclusion: </strong>The trial successfully established the pharmacokinetic parameters of topiroxostat in a Chinese population, confirming its safety and efficacy. The results support the need for individualized dosing strategies and optimize therapeutic outcomes.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":"622-635"},"PeriodicalIF":2.1,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142834556","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 Stability and Metabolite Identification of CYP450 Probe Substrates in Ferret Hepatocytes","authors":"Jiang Pu, Wanyong Feng","doi":"10.2174/0113892002302675240903075500","DOIUrl":"https://doi.org/10.2174/0113892002302675240903075500","url":null,"abstract":"Background: Ferrets exhibit similar lung physiology to humans and display similar clinical signs following influenza infection, making them a valuable model for studying high susceptibility and infection patterns. However, the metabolic fate of several common human CYP450 probe substrates in ferrets is still unknown and has not been studied. Objective: The purpose of this study was to investigate the metabolism of nine human CYP450 probe substrates in ferret hepatocytes and explore their metabolic rate differences between ferrets and other species. Method: Nine substrates were individually incubated in ferret hepatocytes for up to 120 min. At each time point, 30 μL mixtures were extracted for stability analysis using LC-MS/MS methods. After a 120-minute incubation period, 400 μL of the mixtures were extracted for metabolite identification using UHPLC-QExactive Plus. Results: The metabolic clearance was determined as follows: diclofenac &gt; taxol &gt; chlorzoxazone &gt; dextromethorphan &gt; midazolam &gt; omeprazole &gt; bupropion &gt; phenacetin &gt; testosterone. Seven metabolites were identified from phenacetin. Deethylation was found to be the major pathway, and the major metabolite was matched with acetaminophen as probed with the CYP1A2 enzyme. Six metabolites were identified from diclofenac. Glucuronidation was the primary pathway, and a metabolite was found to match 4-OH-diclofenac as probed with the CYP2C9 enzyme. Twenty-two metabolites were identified from omeprazole. The major metabolic pathways included mono-oxygenation and sulfoxide to thioether conversion. No metabolite was found to match with the 5-OH-omeprazole as probed with the CYP2C19 enzyme. Twenty-two metabolites were identified from dextromethorphan. Demethylation was found to be the major metabolic pathway, and one demethylation metabolite was matched with dextrorphan as probed with CYP2D6. Fourteen metabolites were identified from midazolam. Mono-oxygenation was found to be the primary metabolic pathway, and one of the mono-oxygenation metabolites was matched with 1-OH-midazolam as probed with the CYP3A4 enzyme. Eight metabolites were identified from testosterone. Mono-oxygenation and glucuronidation were identified as the major metabolic pathways. One mono-oxygenation was matched with 6-β-testosterone as probed with CYP3A4 enzyme. Six metabolites were identified from taxol. Hydrolysis and mono-oxygenation were the top two metabolic pathways. No metabolite was matched with 6-α-OH-taxol as probed with the CYP2C8 enzyme. Ten metabolites were identified from bupropion. Mono-oxygenation and hydrogenation were identified as the top two metabolic pathways. No mono-oxygenation metabolite was matched with hydroxy-bupropion as probed with the CYP2B6 enzyme. Nine metabolites were identified from chlorzoxazone. Monooxygenation and sulfation were the top two metabolic pathways. One mono-oxygenation metabolite was matched with 6-OH-chlorzoxazone as probed with the CYP2E1 enzyme. Concl","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":"13 1","pages":""},"PeriodicalIF":2.3,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142217722","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":"Quality by Design-Steered Development of Stealth Liposomal Formulation of Everolimus: A Systematic Optimization and Evaluation","authors":"Simranjeet Kaur, Rajveer Sidhu, Dilpreet Singh","doi":"10.2174/0113892002322171240821104152","DOIUrl":"https://doi.org/10.2174/0113892002322171240821104152","url":null,"abstract":"Background: Everolimus is a drug approved for the treatment of breast cancer with HR+ and advanced breast cancer reoccurring in postmenopausal women. The oral administration of EVE has been observed to have low oral bioavailability and severe epithelial cutaneous events that include rashes and lip ulceration followed by mouth ulceration after oral administration. Aim: The present research aimed to enhance the bioavailability by loading the EVE into a stealth liposomal formulation (S-EVE-LIPO) intended for intravenous administration. Methods: The surface of the liposomes was modified with vitamin E TPGS, which prolongs the systemic circulation of the drug and provides additional benefits like inhibition of the P-gp efflux pump and acting synergistically with EVE. Results: The formulation was prepared using the thin film hydration method and optimized using a D-optimal mixture design. ANOVA suggested the significance of the proposed mathematic model, and the optimized formulation was generated by design expert software. The optimized formulation (S-EVE-LIPO) was observed with nanometric size (99.5 ± 3.70 nm) with higher encapsulation efficacy (81.5 ± 2.86 %). The S-EVELIPO formulation indicated a sustained release profile as 90.22% drug release was observed in 48 h, whereas the formulation without vitamin E TPGS (EVE-LIPO) released only 74.15 drugs in 24 hours. In vitro cytotoxicity study suggested that the presence of vitamin E TPGS lowers the IC50 value (54.2 ± 1.69), increases the cellular uptake of the formulation, also increases the generation of ROS, and shows better hemocompatibility. result: The formulation was prepared by thin film hydration method and optimized by D-optimal mixture design. ANOVA suggested significancy of the proposed mathematic model and optimized formulation was generated by design expert software The optimized formulation (S-EVE-LIPO) has observed with nanometric size (99.5 ± 3.70 nm) with higher encapsulation efficacy (81.5 ± 2.86 %). The S-EVE-LIPO formulation indicated with a sustained release profile as 90.22% drug release was observed in 48 h, whereas the formulation without vitamin E TPGS (EVE-LIPO) releases only 74.15 drug in 24 hours. In vitro cytotoxicity study suggested that the presence of vitamin E TPGS lowers the IC50 value (54.2 ± 1.69), increases the cellular uptake of the formulation, also increases the generation of ROS and shows better hemocompatibility. Conclusion: Vitamin E TPGS could be set as a vital additive to improve therapeutic efficacy and reduce offsite toxicity and dosing frequency.","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":"37 1","pages":""},"PeriodicalIF":2.3,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142217745","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":"WITHDRAWN: Pharmacokinetic Drug Interactions of Piperine: A Review of Pre-clinical and Clinical Studies","authors":"Imtiyaz Ahmed Najar, Sagar Pamu, Anushka Paul, Poonam Arora, Gaganjit Kaur, Manish Kumar","doi":"10.2174/0113892002302273240607055945","DOIUrl":"10.2174/0113892002302273240607055945","url":null,"abstract":"<p><p>The article has been withdrawn at the request of the author and the editor of the journal Current Drug Metabolism.</p><p><p>Bentham Science apologizes to the readers of the journal for any inconvenience this may have caused.</p><p><p>The Bentham editorial policy on article withdrawal can be found at https://benthamscience.com/editorial-policiesmain.php</p><p><strong>Bentham science disclaimer: </strong>It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously\u0000submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere\u0000must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submitting\u0000the article for publication, the authors agree that the publishers have the legal right to take appropriate action against the\u0000authors if plagiarism or fabricated information is discovered. By submitting a manuscript, the authors agree that the copyright\u0000of their article is transferred to the publishers if and when the article is accepted for publication.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":" ","pages":""},"PeriodicalIF":2.1,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141442216","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 the Gelsemium Alkaloids Metabolism in Human, Pig, Goat, and Rat Liver Microsomes","authors":"Yi-Rong Wang, Meng-Ting Zuo, Wen-Bo Xu, Zhao-Ying Liu","doi":"10.2174/0113892002298633240322071126","DOIUrl":"https://doi.org/10.2174/0113892002298633240322071126","url":null,"abstract":"Aim: The aim of this study was to investigate the metabolism of Gelsemium elegans in human, pig, goat and rat liver microsomes and to elucidate the metabolic pathways and cleavage patterns of the Gelsemium alkaloids among different species. Methods: A human, goat, pig and rat liver microparticles were incubated in vitro. After incubating at 37°C for 1 hour and centrifuging, the processed samples were detected by HPLC/Qq-TOFMS was used to detect alcohol extract of Gelsemium elegans and its metabolites. Results: Forty-six natural products were characterized from alcohol extract of Gelsemium elegans and 13 metabolites were identified. These 13 metabolites belong to the gelsemine, koumine, gelsedine, humantenine, yohimbane, and sarpagine classes of alkaloids. The metabolic pathways included oxidation, demethylation and dehydrogenation. After preliminary identification, the metabolites detected in the four species were different. All 13 metabolites were detected in pig and rat microsomes, but no oxidative metabolites of Gelsedine-type alkaloids were detected in goat and human microsomes. Conclusion: In this study, Gelsemium elegans metabolic patterns in different species are clarified and the in vitro metabolism of Gelsemium elegans is investigated. It is of great significance for its clinical development and rational application. result: 46 natural products were characterized from alcohol extract of Gelsemium elegan and 13 metabolites were identified. The metabolic pathways included oxidation， demethylation and dehydrogenation. After preliminary identification, the metabolites detected in the four species were different. all 13 metabolites were detected in pig and rat, but no oxidative metabolites of Gelsedine-type alkaloids were detected in goat and human.","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":"107 1","pages":""},"PeriodicalIF":2.3,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140571310","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":"Regulation of Gut Microbiota by Herbal Medicines","authors":"Yogita Shinde, Gitanjali Deokar","doi":"10.2174/0113892002287336240328083220","DOIUrl":"https://doi.org/10.2174/0113892002287336240328083220","url":null,"abstract":": Preserving host health and homeostasis is largely dependent on the human gut microbiome, a varied and ever-changing population of bacteria living in the gastrointestinal tract. This article aims to explore the multifaceted functions of the gut microbiome and shed light on the evolving field of research investigating the impact of herbal medicines on both the composition and functionality of the gut microbiome. Through a comprehensive overview, we aim to provide insights into the intricate relationship between herbal remedies and the gut microbiome, fostering a better understanding of their potential implications for human health.The gut microbiota is composed of trillions of microorganisms, predominantly bacteria, but also viruses, fungi, and archaea. It functions as a complex ecosystem that interacts with the host in various ways. It aids in nutrient metabolism, modulates the immune system, provides protection against pathogens, and influences host physiology. Moreover, it has been linked to a range of health outcomes, including digestion, metabolic health, and even mental well-being. Recent research has shed light on the potential of herbal medicines to modulate the gut microbiome. Herbal medicines, derived from plants and often used in traditional medicine systems, contain a diverse array of phytochemicals, which can directly or indirectly impact gut microbial composition. These phytochemicals can either act as prebiotics, promoting the growth of beneficial bacteria, or possess antimicrobial properties, targeting harmful pathogens. Several studies have demonstrated the effects of specific herbal medicines on the gut microbiome. For example, extracts from herbs have been shown to enhance the abundance of beneficial bacteria, such as Bifidobacterium and Lactobacillus, while reducing potentially harmful microbes. Moreover, herbal medicines have exhibited promising antimicrobial effects against certain pathogenic bacteria. The modulation of the gut microbiome by herbal medicines has potential therapeutic implications. Research suggests herbal interventions could be harnessed to alleviate gastrointestinal disorders, support immune function, and even impact metabolic health. However, it is important to note that individual responses to herbal treatments can vary due to genetics, diet, and baseline microbiome composition.","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":"30 1","pages":""},"PeriodicalIF":2.3,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140570995","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":"Inhibitory Effects of Tricyclic Antidepressants on Human Liver Microsomal Morphine Glucuronidation: Application of IVIVE to Predict Potential Drug-Drug Interactions in Humans","authors":"Verawan Uchaipichat","doi":"10.2174/0113892002270594231212090958","DOIUrl":"https://doi.org/10.2174/0113892002270594231212090958","url":null,"abstract":" Background: Tricyclic antidepressants (TCAs) are commonly co-administered with morphine as an adjuvant analgesic. Nevertheless, there remains a lack of information concerning metabolic drug-drug interactions (DDIs) resulting from TCA inhibition on morphine glucuronidation Objective: This study aimed to (i) examine the inhibitory effects of TCAs (viz., amitriptyline, clomipramine, imipramine, and nortriptyline) on human liver microsomal morphine 3- and 6-glucuronidation and (ii) evaluate the potential of DDI in humans by employing in vitro-in vivo extrapolation (IVIVE) approaches. Method: The inhibition parameters for TCA inhibition on morphine glucuronidation were derived from the in vitro system containing 2% BSA. The Ki values were employed to predict the DDI magnitude in vivo by using static and dynamic mechanistic PBPK approaches Results: TCAs moderately inhibited human liver microsomal morphine glucuronidation, with clomipramine exhibiting the most potent inhibition potency. Amitriptyline, clomipramine, imipramine, and nortriptyline competitively inhibited morphine 3- and 6-glucuronide formation with the respective Ki values of 91 ± 7.5 and 82 ± 11 μM, 23 ± 1.3 and 14 ± 0.7 μM, 103 ± 5 and 90 ± 7 μM, and 115 ± 5 and 110 ± 3 μM. Employing the static mechanistic IVIVE, a prediction showed an estimated 20% elevation in the morphine AUC when co-administered with either clomipramine or imipramine, whereas the predicted increase was ","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":"111 1","pages":""},"PeriodicalIF":2.3,"publicationDate":"2024-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139396630","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-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}