Current drug metabolism最新文献

{"title":"Quality by Design Approach for the Development of Cariprazine Hydrochloride Loaded Lipid-Based Formulation for Brain Delivery via Intranasal Route.","authors":"Pallavi Chiprikar, Prakash Biradar, Vinayak Mastiholimath, Nisha Shirkoli","doi":"10.2174/0113892002327148240924071717","DOIUrl":"https://doi.org/10.2174/0113892002327148240924071717","url":null,"abstract":"<p><strong>Background: </strong>Cariprazine (CPZ) is a third-generation antipsychotic medication that has been approved for treating schizophrenia. This study aimed to develop a cariprazine-loaded nanostructured lipid carrier (CPZ-NLCs) to prevent first-pass metabolism and improve bioavailability and site-specific delivery from the nose to the brain.</p><p><strong>Method: </strong>The CPZ-NLCs were prepared using melt emulsification. The formulation was optimized using the Box-Behnken design (BBD); where the influence of independent variables on critical quality attributes, such as particle size and entrapment efficiency, was studied.</p><p><strong>Result: </strong>The optimized batch (F6) had a particle size of 173.3 ± 0.6 nm and an entrapment efficiency of 96.1 ± 0.57%, respectively. The in vitro release showed >96% release of CPZ from NLC within 30 min. The optimized formulation's ex vivo studies revealed significantly increased CPZ permeability (>75%) in sheep nasal mucosa compared to the CPZ suspension (~26%). The ciliotoxicity study of the nasal mucosa revealed that the CPZ-NLC formulation did not affect the nasal epithelium. The intranasal administration of the formulation achieved 76.14±6.23 μg/ml concentration in the brain which was significantly higher than the oral CPZ suspension administration (30.46±7.24 μg/ml). The developed formulation was stable for 3 months.</p><p><strong>Conclusion: </strong>The study concluded that the developed CPZ-NLC could significantly improve the bioavailability with quick delivery to the brain.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142371198","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":"https://doi.org/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":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2024-09-27","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":"Development of Hot Melt Extruded Co-Formulated Artesunate and AmodiaquineSoluplus® Solid Dispersion System in Fixed-Dose Form: Amorphous State Characterization and Pharmacokinetic Evaluation.","authors":"Md Ali Mujtaba, Ritesh Fule, Purnima Amin, Gamal Osman Elhassan, Meshal Meteab Majed Almoutairi, Mohammed Kaleem, Musarrat Husain Warsi","doi":"10.2174/0113892002330772240912055518","DOIUrl":"https://doi.org/10.2174/0113892002330772240912055518","url":null,"abstract":"<p><strong>Introduction: </strong>This study aims to develop co-amorphous Solid Dispersion (SD) system containing antimalarials Artesunate (ARS) and Amodiaquine (AMQ) to improve its oral bioavailability employing the Hot Melt Extrusion (HME) technique. Soluplus® was selected as a polymeric excipient, whereas Lutrol F127, Lutrol F68, TPGS, and PEG400 as surfactants were incorporated along with Soluplus® to enhance extrudability, improve hydrophilicity, and improve the blend viscosity during HME. Soluplus® with surfactant combination successfully stabilizes both drugs during extrusion by generating SD because of its lower glass transition temperature (Tg) and viscoelastic behavior.</p><p><strong>Methods: </strong>Physicochemical characterizations were performed using FTIR, DSC, TGA, and XRD, which confirmed the amorphousization of drugs in the SD system. The molecular level morphology of the optimized formulation was quantified using high-resolution techniques such as Atomic-Force Microscopy (AFM), Raman spectral, and mapping analysis. The transition of the crystalline drugs into a stable amorphous form has been demonstrated by 1H-NMR and 2D-NMR studies. The in vivo pharmacokinetics study in rats showed that the SD-containing drug-Soluplus-TPGS (FDC10) formulation has 36.63-56.13 (ARS-AMQ) folds increase in the Cmax and 41.87-54.34 (ARS-AMQ) folds increase AUC(0-72) as compared to pure drugs.</p><p><strong>Results: </strong>Pharmacokinetic analysis shows that a fixed-dose combination of 50:135 mg of both APIs (ARSAMQ) significantly increased oral bioavailability by elevating Cmax and AUC, in comparison to pure APIs and also better than the marketed product Coarsucam®.</p><p><strong>Conclusion: </strong>Therefore, the developed melt extruded co-amorphous formulation has enhanced bioavailability and has more effectiveness than the marketed product Coarsucam®<p> .</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142343118","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":null,"pages":null},"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":"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":"https://doi.org/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":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2024-09-05","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":"Biomimetic Nanoscale Systems for Targeted Delivery in Cancer: Current Advances and Future Prospects.","authors":"Dilpreet Singh, Neelam Poonia","doi":"10.2174/0113892002323535240830093452","DOIUrl":"https://doi.org/10.2174/0113892002323535240830093452","url":null,"abstract":"<p><p>The field of cancer therapy has witnessed a transformative shift with the emergence of biomimetic nanoscale drug delivery systems. These innovative platforms draw inspiration from nature's intricate designs and have the potential to revolutionize cancer treatment by precisely targeting tumor cells while sparing healthy tissues. In this critical appraisal, we explore the current advances in biomimetic nanosystems, examining their principles, diverse natural inspirations, benefits, and challenges. Biomimetic nanoscale systems, including liposomes, exosome-based carriers, virus-mimetic nanoparticles, and cell-membrane-coated nanoparticles, have demonstrated the ability to overcome the complexities of the tumor microenvironment. They offer enhanced target specificity, improved cellular uptake, and prolonged circulation, addressing limitations associated with conventional chemotherapy. We assess recent breakthroughs and discuss the potential impact of biomimetic nanosystems on oncology, emphasizing their versatility in encapsulating various therapeutic payloads, from small molecules to nucleic acids and immunotherapeutics. While these systems hold great promise, we also scrutinize safety concerns, scalability issues, and the necessity for rigorous clinical validation. In conclusion, biomimetic nanoscale drug delivery systems represent a promising avenue in the quest for more effective and targeted cancer therapies. This appraisal provides a comprehensive overview of the current state of the field, highlighting its potential to shape the future of cancer treatment and underscoring the importance of continued research and development efforts in this dynamic and transformative domain.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139558","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":null,"pages":null},"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":"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":"https://doi.org/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 (AUC0-16), 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 AUC0-16 lung/AUC0-16 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":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2024-08-21","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":"A Cross-sectional Comparative Analysis of Eleven Population Pharmacokinetic Models for Docetaxel in Chinese Breast Cancer Patients.","authors":"Genzhu Wang, Qiang Sun, Xiaojing Li, Shenghui Mei, Shihui Li, Zhongdong Li","doi":"10.2174/0113892002322494240816032948","DOIUrl":"https://doi.org/10.2174/0113892002322494240816032948","url":null,"abstract":"<p><strong>Objective: </strong>Various population pharmacokinetic (PPK) models have been established to help determine the appropriate dosage of docetaxel, however, no clear consensus on optimal dosing has been achieved. The purpose of this study is to perform an external evaluation of published models in order to test their predictive performance, and to find an appropriate PPK model for Chinese breast cancer patients.</p><p><strong>Methods: </strong>A systematic literature search of docetaxel PPK models was performed using PubMed, Web of Science, China National Knowledge Infrastructure, and WanFang databases. The predictive performance of eleven identified models was evaluated using prediction-based and simulation-based diagnostics on an independent dataset (112 docetaxel concentrations from 56 breast cancer patients). The -2×log (likelihood) and Akaike information criterion were also calculated to evaluate model fit.</p><p><strong>Results: </strong>The median prediction error of eight of the eleven models was less than 10%. The model fitting results showed that the three-compartment model of Bruno et al. had the best prediction performance and that the three compartment model of Wang et al. had the best simulation effect. Furthermore, although the covariates that significantly affect PK parameters were different between them, seven models demonstrated that docetaxel PK parameters were influenced by liver function.</p><p><strong>Conclusions: </strong>Three compartment PPK models may be predictive of optimal docetaxel dosage for Chinese breast cancer patients. However, for patients with impaired liver function, the choice of which model to use to predict the blood concentration of docetaxel still requires great care.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","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, Xin'an Wu","doi":"10.2174/0113892002289027240809114634","DOIUrl":"https://doi.org/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 in vivo.</p>","PeriodicalId":10770,"journal":{"name":"Current drug metabolism","volume":null,"pages":null},"PeriodicalIF":2.1,"publicationDate":"2024-08-16","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}