Curr. Drug Metab. [JOURNAL]
Sun
200 papers
Application of UPLC-MS/MS to Study Cellular Pharmacokinetics of Seven Active Components of Extracts.
Bai Y, Ouyang H, Liu Y … +5 more , Zuo F, Li C, Zhou S, Chang Y, He J
Curr Drug Metab · 2025 · PMID 39558687 · Publisher ↗
BACKGROUND: Cnidii Fructus (CF) is a herbal medicine with pharmacological activities such as antitumor, antiviral, antiallergic, antipruritic effects, and so on. OBJECTIVE: In this study, an ultra-high performance liquid...
BACKGROUND: Cnidii Fructus (CF) is a herbal medicine with pharmacological activities such as antitumor, antiviral, antiallergic, antipruritic effects, and so on. OBJECTIVE: In this study, an ultra-high performance liquid chromatography/tandem mass spectrometry (UPLC- MS/MS) method was prepared and verified to measure the concentrations of seven analytes (bergapten, xanthotoxol, xanthotoxin, imperatorin, osthole, isopimpinellin, isoimperatorin) in HepG2 cells. METHODS: The separation of seven analytes was performed on an ACQUITY UPLC® BEH C18 column (2.1×100 mm, 1.7 μm) with a gradient mobile phase system of 0.1% formic acid/water and acetonitrile. RESULTS: The CV of analytes was within 7.77%, and the bias was in the range of -5.43%-3.84%. The matrix effects of analytes ranged from 92.95% to 104.58%, and the extraction recoveries ranged from 76.45% to 104.69%. The relative standard deviation of stability results was less than 8.21%, indicating that seven analytes were stable. CONCLUSION: The method was successfully applied to the determination of the content of seven analytes of CF extracts by UPLC-MS/MS, and the results will provide a reference for the cellular pharmacokinetics of CF.
Unveiling the Interplay: Antioxidant Enzyme Polymorphisms and Oxidative Stress in Preterm Neonatal Renal and Hepatic Functions.
Sridharan K, Al Jufairi M
Curr Drug Metab · 2025 · PMID 39377382 · Publisher ↗
AIMS: To explore the relationship between oxidative stress biomarkers and the occurrence of acute kidney injury (AKI) alongside notable liver function disturbances in preterm neonates. BACKGROUND: Given the immaturity of...
AIMS: To explore the relationship between oxidative stress biomarkers and the occurrence of acute kidney injury (AKI) alongside notable liver function disturbances in preterm neonates. BACKGROUND: Given the immaturity of kidneys and incomplete liver development in preterm neonates, oxidative stress poses a considerable threat to their renal and hepatic health. OBJECTIVE: To find out the association between various oxidative stress biomarkers and polymorphisms of antioxidant enzymes with renal and live functions. METHODS: In this cross-sectional study, we gathered umbilical cord blood and peripheral blood samples for assessing oxidative stress biomarkers and identifying single nucleotide polymorphisms (SNPs) in antioxidant enzymes. Utilizing enzyme-linked immunosorbent assay kits, we quantified these oxidative stress biomarkers. Receiver-operating characteristics curve analysis was employed to ascertain the predictive capacity of these biomarkers, denoted by the area-under-the-curve (AUC). RESULTS: Our findings revealed that umbilical cord heat-shock proteins emerged as robust predictors of neonatal AKI (AUC: 0.92; 95% CI: 0.8-1) with a defined cut-off concentration of 1.8 ng/mL. Likewise, umbilical cord 8-hydroxy-2-deoxy guanosine demonstrated significant predictability for liver function alterations (AUC: 0.7; 95% CI: 0.6-0.9) at a cut-off concentration of 2487.6 pg/mL. CONCLUSIONS: We observed significant associations between SNPs in endothelial nitric oxide synthase and catalase with both AKI and impaired liver functions. Prospective studies are warranted to validate these findings, with a particular focus on exploring potential antioxidant interventions aimed at mitigating AKI and liver function abnormalities.
Drug Metabolizing Enzymes: An Exclusive Guide into Latest Research in Pharmaco-genetic Dynamics in Arab Countries.
Eitan LA, Khair IY, Alahmad S
Curr Drug Metab · 2024 · PMID 39377381 · Publisher ↗
Drug metabolizing enzymes play a crucial role in the pharmacokinetics and pharmacodynamics of therapeutic drugs, influencing their efficacy and safety. This review explores the impact of genetic polymorphisms in drug-met...
Drug metabolizing enzymes play a crucial role in the pharmacokinetics and pharmacodynamics of therapeutic drugs, influencing their efficacy and safety. This review explores the impact of genetic polymorphisms in drug-metabolizing genes on drug response within Arab populations. We examine the genetic diversity specific to Arab countries, focusing on the variations in key drug-metabolizing enzymes such as CYP450, GST, and UGT families. The review highlights recent research on polymorphisms in these genes and their implications for drug metabolism, including variations in allele frequencies and their effects on therapeutic outcomes. Additionally, the paper discusses how these genetic variations contribute to the variability in drug response and adverse drug reactions among individuals in Arab populations. By synthesizing current findings, this review aims to provide a comprehensive understanding of the pharmacogenetic landscape in Arab countries and offer insights into personalized medicine approaches tailored to genetic profiles. The findings underscore the importance of incorporating pharmacogenetic data into clinical practice to enhance drug efficacy and minimize adverse effects, ultimately paving the way for more effective and individualized treatment strategies in the region.
Quality by Design Approach for the Development of Cariprazine Hydrochloride Loaded Lipid-Based Formulation for Brain Delivery Intranasal Route.
Chiprikar P, Mastiholimath V, Biradar P … +1 more , Shirkoli N
Curr Drug Metab · 2024 · PMID 39364867 · Publisher ↗
BACKGROUND: 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...
BACKGROUND: 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 nose to the brain. METHODS: 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. RESULTS: 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. CONCLUSION: The study concluded that the developed CPZ-NLC could significantly improve the bioavailability with quick delivery to the brain.
Ceftobiprole and Cefiderocol for Patients on Extracorporeal Membrane Oxygenation: The Role of Therapeutic Drug Monitoring.
Castro DM, Granton J, Fan E
Curr Drug Metab · 2024 · PMID 39350410 · Publisher ↗
INTRODUCTION: 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 o...
INTRODUCTION: 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). CASE REPRESENTATION: 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. CONCLUSION: 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.
Development of Hot Melt Extruded Co-Formulated Artesunate and Amodiaquine- Soluplus Solid Dispersion System in Fixed-Dose Form: Amorphous State Characterization and Pharmacokinetic Evaluation.
Mujtaba MA, Fule R, Amin P … +4 more , Elhassan GO, Almoutairi MMM, Kaleem M, Warsi MH
Curr Drug Metab · 2024 · PMID 39323345 · Publisher ↗
INTRODUCTION: 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...
INTRODUCTION: 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. METHODS: 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 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. RESULTS: 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. CONCLUSION: Therefore, the developed melt extruded co-amorphous formulation has enhanced bioavailability and has more effectiveness than the marketed product Coarsucam. .
Quality by Design-Steered Development of Stealth Liposomal Formulation of Everolimus: A Systematic Optimization and Evaluation.
Kaur S, Singh R, Singh D
Curr Drug Metab · 2024 · PMID 39253920 · Publisher ↗
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 bioa...
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. cytotoxicity study suggested that the presence of vitamin E TPGS lowers the IC 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.
Metabolic Stability and Metabolite Identification of CYP450 Probe Substrates in Ferret Hepatocytes.
Pu J, Feng W
Curr Drug Metab · 2025 · PMID 39252619 · Publisher ↗
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. Howeve...
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: testosterone > phenacetin > bupropion > omeprazole > midazolam > dextromethorphan > chlorzoxazone > taxol > diclofenac. 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 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 the CYP2D6 enzyme. 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-.-testosterone as probed with the CYP3A4 enzyme. Six metabolites were identified from taxol. Hydrolysis and mono-oxygenation were the top two metabolic pathways. No metabolite was matched with 6-.-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. CONCLUSION: Nine human CYP probe substrates were clearly metabolized in ferret hepatocytes, demonstrating substrate-dependent metabolic rates in ferret hepatocytes and species-dependent metabolic rates in mouse, rat, dog, monkey, and human hepatocytes. Except for 6-a-5-OH-omeprazole, 6-.-OH-taxol, and hydroxy-bupropion, specific metabolites of other six probe substrates in ferret hepatocytes were detected and identified as probed with six human CYP enzymes, respectively.
Metabolic Pathway of Osilodrostat in Equine Urine Established through High-resolution Mass Spectrometric Characterization for Doping Control.
Ishii H, Shigematsu R, Takemoto S … +11 more , Ishikawa Y, Mizobe F, Nomura M, Arima D, Kunii H, Yuasa R, Yamanaka T, Tanabe S, Nagata SI, Yamada M, Leung GN
Curr Drug Metab · 2024 · PMID 39238378 · Publisher ↗
OBJECTIVE: 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...
OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
Biomimetic Nanoscale Systems for Targeted Delivery in Cancer: Current Advances and Future Prospects.
Singh D, Poonia N
Curr Drug Metab · 2024 · PMID 39238377 · Publisher ↗
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...
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.
Effect of Salbutamol on the Disposition Kinetics of Levofloxacin in the Plasma and Lung of Rats.
Cicekler MA, Oguz H, Corum O
Curr Drug Metab · 2024 · PMID 39171585 · Publisher ↗
BACKGROUND: 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. Ho...
BACKGROUND: 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. OBJECTIVE: The purpose of this study was to investigate the influence of SLB on the plasma and lung pharmacokinetics of LVX in rats. METHODS: 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. RESULTS: The area under the curve from 0 to 16 h (AUC), terminal elimination half-life, volume of distribution, total body clearance, and peak concentration of LVX in the plasma were 42.57 h*μg/mL, 2.32 h, 3.91 L/kg, 1.17 L/h/kg, and 23.96 μg/mL, respectively. There were no alterations observed in the plasma and lung pharmacokinetic parameters of LVX when co-administered with SLB. The AUC lung/AUC ratios of LVX were 1.60 and 1.39 after administration alone and co-administration with SLB, respectively. CONCLUSION: 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.
A Cross-sectional Comparative Analysis of Eleven Population Pharmacokinetic Models for Docetaxel in Chinese Breast Cancer Patients.
Wang G, Sun Q, Li X … +3 more , Mei S, Li S, Li Z
Curr Drug Metab · 2024 · PMID 39161139 · Full text
OBJECTIVE: 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...
OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Hepatic Metabolic Enzyme Activity with Endogenous Substances-Current Status, Challenges and Limitations.
Kou W, Wu X
Curr Drug Metab · 2024 · PMID 39161138 · Publisher ↗
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...
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 .
Hydrogen Peroxide Induces Ethanol-inducible CYP2E1 the NF-kB-classical Pathway: CYP2E1 mRNA Levels are not High in Alcoholic Hepatitis.
Tamura A, Siswanto FM, Yoshimura T … +2 more , Oguro A, Imaoka S
Curr Drug Metab · 2024 · PMID 39129159 · Publisher ↗
AIMS: The aim of the present study is to elucidate the mechanism of CYP2E1 induction as a causative factor of Alcoholic Hepatitis (AH) and its relationship with inflammation. BACKGROUND: Chronic alcohol consumption induc...
AIMS: The aim of the present study is to elucidate the mechanism of CYP2E1 induction as a causative factor of Alcoholic Hepatitis (AH) and its relationship with inflammation. BACKGROUND: Chronic alcohol consumption induces CYP2E1, which is involved in the development of Alcoholic Hepatitis (AH). However, the mechanisms underlying the induction of CYP2E1 by alcohol remain unclear. Therefore, we herein investigated the induction of drug-metabolizing enzymes, particularly CYP2E1, by hydrogen peroxide (HO), the concentration of which is elevated under inflammatory conditions. OBJECTIVE: The mechanisms underlying the induction of CYP2E1 by HO were examined with a focus on Keap1, a target factor of HO. METHODS: We assessed changes in the expression of drug-metabolizing enzymes in the human hepatoma cell line, Hep3B, following treatment with HO, and evaluated changes in the expression of the NF-kB-related factor RelA(p65) after the knockdown of Keap1, a regulator of Nrf2 expression by reactive oxygen species. We also performed a promoter analysis using the upstream region of the CYP2E1 gene. We herein used the GSE89632 series for non-alcoholic hepatitis (NASH) and the GSE28619 series for AH. RESULTS: The induction of CYP2E1 by HO was significantly stronger than that of other drugmetabolizing enzymes. On the other hand, the knockdown of Keap1, a target of HO, markedly increased RelA(p65), an NFkB factor. Furthermore, the overexpression of RelA(p65) strongly induced the expression of CYP2E1. Four candidate p65-binding sequences were identified upstream of the CYP2E1 gene, and promoter activity assays showed that the third sequence was responsive to the overexpression of RelA(p65). We used the GSE89632 series for NASH and the GSE28619 series for AH in the present study. The expression of CYP2E1 mRNA in the liver was significantly lower in AH patients than in HC patients, but was similar in HC patients and NASH patients. CONCLUSION: We herein demonstrated that the expression of CYP2E1 was induced by HO. The overexpression of RelA(p65) also induced CYP2E1 mRNA expression, whereas HO did not after the knockdown of RelA. These results suggest that HO acts on Keap1 to upregulate RelA (p65) in the NFkB system. One of the mechanisms underlying the induction of CYP2E1 was dependent on the HO-Keap1-RelA axis. The results of the database analysis revealed that the expression of CYP2E1 in the liver was significantly lower in AH patients than in NASH patients, suggesting that CYP2E1 is not the main cause of AH; however, CYP2E1 may exacerbate the pathogenesis of AH.
Innovative Nanoscale Drug Delivery Strategies for Breast Carcinoma: A Comprehensive Exploration.
Jaishree S, Kousalya S, Prakash S … +1 more , Vineesh D
Curr Drug Metab · 2024 · PMID 39108118 · Publisher ↗
Breast cancer (BC) is one of the major causes of poor health in women and the most devastating disease after lung cancer. The term "cancer" refers to a collection of problems resulting from abnormal cell proliferation, p...
Breast cancer (BC) is one of the major causes of poor health in women and the most devastating disease after lung cancer. The term "cancer" refers to a collection of problems resulting from abnormal cell proliferation, particularly cells that can spread to other parts of the body. Surgery, followed by chemotherapy or radiotherapy, is now accepted for BC-related cancers. However, chemotherapy and radiotherapy are rarely effective in the treatment of BC due to the adverse effects of these treatments on healthy tissues and organs. Consequently, the use of NPs in targeted Drug Delivery Systems (DDSs) has emerged as a promising strategy for BC treatment. This review provides a summary of recent clinical investigations of nanoparticle-mediated DDS that offer a novel therapeutic strategy commonly used for the treatment of breast cancer.
Carboxylesterase 1-Based Drug-Drug Interaction Potential of Remimazolam: Studies and Literature Review.
Petersen KU, Schmalix W, Pesic M … +1 more , Stohr T
Curr Drug Metab · 2024 · PMID 39108117 · Publisher ↗
BACKGROUND: The ultra-short-acting benzodiazepine remimazolam, approved for procedural sedation and general anesthesia, is inactivated by carboxylesterase 1 (CES1). OBJECTIVE: Remimazolam´s involvement in CES1-mediated d...
BACKGROUND: The ultra-short-acting benzodiazepine remimazolam, approved for procedural sedation and general anesthesia, is inactivated by carboxylesterase 1 (CES1). OBJECTIVE: Remimazolam´s involvement in CES1-mediated drug-drug interactions (DDIs) was investigated. METHODS: 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 inhibition using pharmacokinetic and Ki or IC values. Compounds with only one published inhibitory concentration and CES1 substrates lacking inhibition data were assigned conservative Ki values. RESULTS: 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, IC 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 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 inhibitors of remimazolam metabolism. CONCLUSION: 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.
Effects of High-altitude Hypoxia on Drug Metabolism and Pharmacokinetics of Sedative-hypnotic Drugs and Regulatory Mechanism.
Tian L, Liu G, Han J … +1 more , Li X
Curr Drug Metab · 2024 · PMID 39108116 · Publisher ↗
Sedative hypnotics effectively improve sleep quality under high-altitude hypoxia by reducing central nervous system excitability. High-altitude hypoxia causes sleep disorders and modifies the metabolism and mechanisms of...
Sedative hypnotics effectively improve sleep quality under high-altitude hypoxia by reducing central nervous system excitability. High-altitude hypoxia causes sleep disorders and modifies the metabolism and mechanisms of drug action, impacting medication therapy's effectiveness. This review aims to provide a theoretical basis for the treatment of central nervous system diseases in high-altitude areas by summarizing the progress and mechanism of sedative-hypnotics in hypoxic environments, as well as the impact of high-altitude hypoxia on sleep.
Prediction of Protein-Drug Interactions, Pharmacophore Modeling, and Toxicokinetics of Novel Leads for Type 2 Diabetes Treatment.
Mehra A, Mittal A, Vishwakarma PK
Curr Drug Metab · 2024 · PMID 39108115 · Publisher ↗
BACKGROUND: Small heterocyclic compounds have been crucial in pioneering advances in type 2 diabetes treatment. There has been a dramatic increase in the pharmacological development of novel heterocyclic derivatives aime...
BACKGROUND: Small heterocyclic compounds have been crucial in pioneering advances in type 2 diabetes treatment. There has been a dramatic increase in the pharmacological development of novel heterocyclic derivatives aimed at stimulating the activation of Glucokinase (GK). A pharmaceutical intervention for diabetes is increasingly targeting GK as a legitimate target. Diabetes type 2 compromises Glucokinase's function, an enzyme vital for maintaining the balance of blood glucose levels. Medicinal substances strategically positioned to improve type 2 diabetes management are used to stimulate the GK enzyme using heterocyclic derivatives. OBJECTIVE: The research endeavor aimed to craft novel compounds, drawing inspiration from the inherent coumarin nucleus found in nature. The goal was to evoke the activity of the glucokinase enzyme, offering a tailored approach to mitigate the undesired side effects typically associated with conventional therapies employed in the treatment of type 2 diabetes. METHODS: Coumarin, sourced from nature's embrace, unfolds as a potent and naturally derived ally in the quest for innovative antidiabetic interventions. Coumarin was extracted from a variety of botanical origins, including Artemisia keiskeana, Mallotus resinosus, Jatropha integerrima, Ferula tingitana, Zanthoxylum schinifolium, Phebalium clavatum, and Mammea siamensis. This inclusive evaluation was conducted on Muybridge's digital database containing 53,000 hit compounds. The presence of the coumarin nucleus was found in 100 compounds, that were selected from this extensive repository. Utilizing Auto Dock Vina 1.5.6 and ChemBioDraw Ultra, structures generated through this process underwent docking analysis. Furthermore, these compounds were accurately predicted online log P using the Swiss ADME algorithm. A predictive analysis was conducted using PKCSM software on the primary compounds to assess potential toxicity. RESULTS: Using Auto Dock Vina 1.5.6, 100 coumarin derivatives were assessed for docking. Glucokinase (GK) binding was significantly enhanced by most of these compounds. Based on superior binding characteristics compared with Dorzagliatin (standard GKA) and MRK (co-crystallized ligand), the top eight molecules were identified. After further evaluation through ADMET analysis of these eight promising candidates, it was confirmed that they met the Lipinski rule of five and their pharmacokinetic profile was enhanced. The highest binding affinity was demonstrated by APV16 at -10.6 kcal/mol. A comparison between the APV16, Dorzagliatin and MRK in terms of toxicity predictions using PKCSM indicated that the former exhibited less skin sensitization, AMES toxicity, and hepatotoxicity. CONCLUSION: Glucokinase is most potently activated by 100 of the compound leads in the database of 53,000 compounds that contain the coumarin nucleus. APV12, with its high binding affinity, favorable ADMET (adjusted drug metabolic equivalents), minimal toxicity, and favorable pharmacokinetic profile warrants consideration for progress to in vitro testing. Nevertheless, to uncover potential therapeutic implications, particularly in the context of type 2 diabetes, thorough investigations and in-vivo evaluations are necessary for benchmarking before therapeutic use, especially experiments involving the STZ diabetic rat model.
Role of P-glycoprotein in Regulating the Efficacy, Toxicity and Pharmacokinetics of Yunaconitine.
Li X, Liang Q, Wang C … +6 more , Qiu H, Lin T, Li W, Zhang R, Liu Z, Zhu L
Curr Drug Metab · 2024 · PMID 39108114 · Publisher ↗
BACKGROUND: Yunaconitine (YAC) is a hidden toxin that greatly threatens the life safety of patients who are prescribed herbal medicines containing species; however, its underlying mechanism remains unclear. OBJECTIVE: T...
BACKGROUND: Yunaconitine (YAC) is a hidden toxin that greatly threatens the life safety of patients who are prescribed herbal medicines containing species; however, its underlying mechanism remains unclear. OBJECTIVE: The objective of this study is to elucidate the functions of P-glycoprotein (P-gp) in regulating the efficacy, toxicity, and pharmacokinetics of YAC. METHODS: The efflux function of P-gp on YAC was explored by using Caco-2 monolayers in combination with the P-gp inhibitor verapamil. The impact of P-gp on regulating the analgesic and anti-inflammatory effects, acute toxicity, tissue distribution, and pharmacokinetics of YAC was determined male Mdr1a gene knocked-out mice and wild-type FVB mice. RESULTS: The presence of verapamil significantly decreased the efflux ratio of YAC from 20.41 to 1.07 in Caco- 2 monolayers (P < 0.05). Moreover, oral administration of 0.07 and 0.14 mg/kg YAC resulted in a notable decrease in writhing times in Mdr1a mice by 23.53% and 49.27%, respectively, compared to wild-type FVB mice (P < 0.05). Additionally, the deficiency of P-gp remarkably decreased the half-lethal dose (LD) of YAC from 2.13 to 0.24 mg/kg (P < 0.05). Moreover, the concentrations of YAC in the tissues of Mdr1a mice were statistically higher than those in wild-type FVB mice (P < 0.05). Particularly, the brain accumulation of YAC in Mdr1a mice significantly increased by 12- and 19-fold, respectively, after oral administration for 30 and 120 min, when compared to wild-type FVB mice (P < 0.05). There were no significant differences in the pharmacokinetic characteristics of YAC between Mdr1a and wild-type FVB mice. CONCLUSION: YAC is a sensitive substrate of P-gp. The absence of P-gp enhances the analgesic effect and toxicity of YAC by upregulating its brain accumulation. Co-administration with a P-gp inhibitor may lead to severe YAC poisoning.
An Efficient Integrated Strategy for Comprehensive Metabolite Profiling of Sakurasosaponin from Aegiceras corniculatum in Rats.
Wang X, Yang X, Hao E … +5 more , Xie J, Du Z, Deng J, Hou X, Wei W
Curr Drug Metab · 2024 · PMID 39108113 · Full text
OBJECTIVE: Sakurasosaponin, a primary bioactive saponin from Aegiceras corniculatum, shows potential as an anti-cancer agent. However, there is a lack of information on its in vivo metabolism. This study aims to profile...
OBJECTIVE: Sakurasosaponin, a primary bioactive saponin from Aegiceras corniculatum, shows potential as an anti-cancer agent. However, there is a lack of information on its in vivo metabolism. This study aims to profile the in vivo metabolites of sakurasosaponin in rat feces, urine, and plasma after oral administration. An efficient strategy using ultra-high-performance liquid chromatography/quadrupole time-of-flight mass spectrometry was developed, which combined metabolic prediction, multiple mass defects filtering, and highresolution extracted ion chromatograms for rapid and systematic analysis. METHODS: Firstly, a theoretical list of metabolites for sakurasosaponin was developed. This was done by considering the metabolic pathways of saponins. Next, the multiple mass defects filtering method was employed to identify potential metabolites in feces and urine, using the unique metabolites of sakurasosaponin as multiple mass defects filtering templates. Subsequently, a high-resolution extracted ion chromatogram was used to quickly determine the metabolites in rat plasma post-identification in feces and urine. Lastly, the analysis of accurate mass, typical neutral loss, and diagnostic ion of the candidate metabolites was carried out to confirm their structural elucidation, and metabolic pathways of sakurasosaponin in vivo were also proposed. RESULTS: In total, 30 metabolites were provisionally identified in feces, urine, and plasma. Analysis of metabolic pathways revealed isomerization, deglycosylation, oxidation, hydroxylation, sulfate conjugation, glucuronide conjugation, and other related reactions as the primary biotransformation reactions of sakurasosaponin in vivo. CONCLUSION: The findings demonstrate that the designed research strategy effectively minimizes matrix interference, prevents the omission of low-concentration metabolites, and serves as a foundation for the discovery of active metabolites of sakurasosaponin.
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