Curr. Drug Metab. [JOURNAL]
Sun
200 papers
Mass Balance and Metabolic Profiling of Avacopan, a Selective C5a Receptor 1 Antagonist, in Healthy Humans.
Song Y, Miao S, Zhao R … +9 more , Liu X, Tai E, Krasinski A, Zeng Y, Zhang P, Wills S, Pennell A, Bekker P, Oberoi RK
Curr Drug Metab · 2025 · PMID 41088978 · Publisher ↗
INTRODUCTION: Avacopan (Tavneos) is approved as an oral adjunctive treatment at a dose of 30 mg twice daily with food for adult patients with severe active granulomatosis with polyangiitis (GPA) and microscopic polyangii...
INTRODUCTION: Avacopan (Tavneos) is approved as an oral adjunctive treatment at a dose of 30 mg twice daily with food for adult patients with severe active granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) in combination with standard therapy including glucocorticoids. METHODS: In this pharmacokinetic (PK) study, the absorption, metabolism, and excretion of avacopan were evaluated following a single 100 mg/400 μCi oral 14C-avacopan dose solution in six healthy male participants. The mass balance recovery, plasma concentrations, and metabolite profile in plasma, urine, and feces were determined. RESULTS: Fecal and renal excretion accounted for 77.2% and 9.5%, respectively, of the total administered radioactivity, with none of the mono- or bis-oxidation metabolites present at greater than 7% of the total radioactive dose. In urine, intact avacopan was present at <1% of the radioactive dose. In feces, intact avacopan was present at 8.7%, which represented 6.7% of the total radioactive dose, suggesting at least 93.3% of the radioactive dose was absorbed. The predominant component in plasma was avacopan, which accounted for 18.0% of the dose. The major circulating metabolite, M1, a monohydroxylation metabolite with similar potency in C5a receptor inhibition as avacopan, accounted for 11.9% of the total radioactivity. DISCUSSION: The primary route of elimination of avacopan is phase I metabolism, followed by biliary excretion of the metabolites. CYP3A4 is the primary isozyme involved in the in vitro metabolism of avacopan and formation of metabolite M1. CONCLUSION: Study results provide a definitive assessment of the absorption, elimination, and nature of metabolism of avacopan in humans.
The Intricacies of Polypharmacy and Drug Interactions in Schizophrenia Treatment.
Dwivedi J, Seemab M, Wal P … +4 more , Dey P, Rathinam T, Dhamini A, Khan A
Curr Drug Metab · 2025 · PMID 41088977 · Publisher ↗
INTRODUCTION: Polypharmacy is frequently practiced in the management of schizophrenia due to its chronic nature, recurrent relapses, and associated comorbidities. While combining psychotropic medications may benefit pati...
INTRODUCTION: Polypharmacy is frequently practiced in the management of schizophrenia due to its chronic nature, recurrent relapses, and associated comorbidities. While combining psychotropic medications may benefit patients with treatment-resistant symptoms, it poses risks such as drug-drug interactions (DDIs), adverse effects, and reduced medication adherence. The absence of uniform prescribing standards further complicates clinical decision-making. METHODS: This narrative review was conducted using a scoping methodology. Databases including Pub- Med, Scopus, and Web of Science were searched for English-language publications from 2000 to 2024. Search terms included "schizophrenia," "polypharmacy," "drug-drug interactions," "clinical outcomes," and "pharmacogenetics." Eligible sources included clinical trials, observational studies, systematic reviews, and treatment guidelines. Exclusion criteria were non-English articles, gray literature, and individual case reports. RESULTS: Polypharmacy is reported in 30-60% of individuals with schizophrenia, especially in institutionalized or treatment-resistant populations. Treatment regimens often involve multiple antipsychotics along with adjunctive antidepressants or mood stabilizers. This approach is associated with increased risks of metabolic syndrome, cardiovascular events (e.g., QT prolongation), extrapyramidal symptoms, and decreased adherence. Interindividual variability in pharmacogenetics further affects drug efficacy and safety. Innovative approaches like genotype-guided therapy and computerized clinical decisionsupport systems are promising but not yet widely implemented. DISCUSSION: Although polypharmacy may offer symptomatic relief in specific scenarios, it requires careful management due to its potential to cause harm. Rational prescribing, close monitoring, and attention to individual patient factors such as pharmacogenetic profiles are essential to optimize therapy. CONCLUSION: Ensuring a balance between therapeutic benefit and adverse effects is crucial when employing polypharmacy in schizophrenia treatment. Integrating personalized medicine strategies, regular monitoring, and deprescribing practices when feasible can enhance clinical outcomes and patient safety.
Development of Transdermal Drug Delivery Approaches to Combat Diabetes: An Update.
Singhal P, Mazumder R, Rani A … +1 more , Debnath A
Curr Drug Metab · 2025 · PMID 41084243 · Publisher ↗
BACKGROUND: Diabetes mellitus, a widespread and chronic metabolic condition, creates significant challenges for healthcare systems due to complications from inadequate glycemic control, patient non-compliance, and the in...
BACKGROUND: Diabetes mellitus, a widespread and chronic metabolic condition, creates significant challenges for healthcare systems due to complications from inadequate glycemic control, patient non-compliance, and the invasive nature of traditional treatments, including oral medications and insulin injections, which often lead to discomfort, variability in blood glucose levels, and low adherence. OBJECTIVE: To explore the potential of Transdermal Drug Delivery Systems (TDDS) as a non-invasive and effective alternative for diabetes management, highlighting their advantages, recent technological advancements, and associated challenges. METHODS: This review examines the role of TDDS in diabetes treatment, with an emphasis on recent innovations, including microneedles, hydrogels, and sonophoresis. The study also discusses the benefits of TDDS in maintaining stable plasma drug levels, reducing first-pass metabolism, and integrating with continuous glucose monitoring systems. RESULTS: Emerging TDDS technologies improve drug permeability, enhance bioavailability, and offer sustained drug release, potentially addressing limitations of conventional delivery methods. However, barriers such as skin permeability, high manufacturing costs, and patient variability remain significant challenges. DISCUSSION: Multi-drug patches and microneedle-based systems represent innovative approaches that enhance therapeutic efficacy and patient compliance by enabling painless, targeted, and combination drug delivery. With support from nanotechnology and pharmacogenomics, these platforms are evolving toward personalized medicine, offering optimized dosing and reduced side effects. CONCLUSION: TDDS presents a promising alternative for diabetes management by improving patient adherence, ensuring controlled drug release, and reducing discomfort associated with injections. While further research is required to overcome existing limitations, advancements in biomaterials and personalized medicine approaches hold the potential to optimize TDDS for widespread clinical application. This research aims to summarize the advancements and address existing challenges for future development.
Natural Compounds as Potential Therapeutics for Pancreatic Cancer: A Narrative Review.
Lin XD, Li T, Du RX … +2 more , Li GC, Liu Z
Curr Drug Metab · 2025 · PMID 41031495 · Publisher ↗
Pancreatic cancer is a highly lethal malignancy with a low 5-year survival rate. This review focuses on natural compounds as potential therapeutics for it. Different types of natural compounds, such as polyphenols, sapon...
Pancreatic cancer is a highly lethal malignancy with a low 5-year survival rate. This review focuses on natural compounds as potential therapeutics for it. Different types of natural compounds, such as polyphenols, saponins, and alkaloids, have shown anti-pancreatic cancer effects, including inhibiting tumor cell growth, inducing apoptosis, and preventing angiogenesis. They also have indirect impacts on pancreatic cancer through influencing the gut microbiota, glucose and lipid metabolism, and the endocrine system. Additionally, Chinese herbal medicines containing these compounds show promise in clinical applications. However, challenges such as target identification and low bioavailability persist. Future research trends involve interdisciplinary collaboration and the use of advanced technologies to overcome these issues.
Anticancer Potential of Polyphenols in Legumes: Mechanisms and Insights.
Rizwan A, Shaikh H, Farooqi H
Curr Drug Metab · 2025 · PMID 41029922 · Publisher ↗
INTRODUCTION: Cancer poses a tough global health challenge, prompting the exploration of innovative prevention and treatment strategies. Polyphenols, bioactive compounds abundant in various plant-based foods, have gained...
INTRODUCTION: Cancer poses a tough global health challenge, prompting the exploration of innovative prevention and treatment strategies. Polyphenols, bioactive compounds abundant in various plant-based foods, have gained significant attention for their potential anticancer properties. Legumes, characterized by their excellent nutritional profile, offer a promising source of polyphenols such as ferulic acid, caffeic acid, genistein, and kaempferol, which exhibit notable antioxidative and anti-inflammatory effects. METHODS: This review systematically analyzed peer-reviewed literature on the polyphenolic content of various legumes. No original research or experimental work was carried out as part of this study. Databases such as PubMed, Google Scholar, Scopus, SpringerLink, and ScienceDirect were searched for studies focusing on the identification and pharmacokinetic profiles of legume-derived polyphenols. Emphasis was placed on examining the mechanisms of action, including modulation of cell signalling pathways, induction of apoptosis, inhibition of angiogenesis, and influence on detoxification enzymes. The review also assessed the ADME (absorption, distribution, metabolism, and excretion) properties of key polyphenols to evaluate their bioavailability and therapeutic efficacy. RESULTS: The analysis revealed that legumes are significant sources of polyphenols with demonstrated anticancer activity. Compounds like genistein and kaempferol modulate key signalling pathways such as PI3K/Akt, MAPK, and NF-kB, which are involved in cell proliferation, survival, and inflammation. Additionally, these polyphenols can promote apoptosis and inhibit angiogenesis, thereby impeding tumor growth and metastasis. DISCUSSION: The findings underscore the potential of legume-derived polyphenols in cancer prevention and management. By addressing the ADME of Polyphenols, this study aims to deepen our understanding of their pharmacological potential, providing a foundation for developing dietary strategies and functional foods to effectively prevent and manage cancer. Addressing the limitations in bioavailability through novel delivery systems and dietary formulations could enhance their effectiveness. CONCLUSION: Combining polyphenol-rich legume diets with conventional cancer therapies may offer a synergistic therapeutic effect and promote better health outcomes. However, it is essential to first establish through rigorous scientific research that polyphenols do not produce any unwanted adverse effects when used alongside standard medications. Further research focusing on improving bioavailability and validating in vivo efficacy will be crucial for translating these findings into practical cancer prevention treatment approaches.
TOX4 Inhibition in Chronic Hyperglycemia: Effects on Glycation Stress, Hepatic Protection, Epigenetic Mechanisms, Signaling Pathways, and Beta Cell Dynamics.
Varunteja B, Gupta N, Kumari A … +5 more , Mukherjee T, Mohanty S, Nayak N, Chopra MP, Pattnaik A
Curr Drug Metab · 2025 · PMID 41029921 · Publisher ↗
TOX high mobility group box family member 4 (TOX4) has emerged as a critical regulator of Hepatic Glucose Production (HGP), particularly under insulin-resistant conditions seen in Type 2 Diabetes Mellitus (T2DM). Hypergl...
TOX high mobility group box family member 4 (TOX4) has emerged as a critical regulator of Hepatic Glucose Production (HGP), particularly under insulin-resistant conditions seen in Type 2 Diabetes Mellitus (T2DM). Hyperglycemia-induced formation of Advanced Glycation End products (AGEs) exacerbates metabolic dysfunction. While the Akt- FoxO1 axis has been the conventional focus of insulin signaling, recent findings highlight the upregulation of TOX4 in T2DM, obesity, and preclinical models (e.g., db/db mice). The cAMP signaling pathway has been shown to modulate TOX4 expression. This review synthesizes findings from recent and studies investigating the role of TOX4 in hepatic metabolism. The study focuses on its regulatory mechanisms, interaction with insulin signalling pathways, and its modulation through pharmacological inhibition. TOX4 inhibition significantly reduces glucose output in hepatocytes and improves glucose tolerance in animal models. While TOX4 ablation fails to reverse metabolic impairments caused by insulin receptor knockout, it nonetheless attenuates hepatic glucose production under insulin- resistant states. Additionally, TOX4 suppression shows hepatoprotective effects and may offer potential neuroprotection in the context of diabetic complications. TOX4 represents a promising therapeutic target for managing T2DM and its comorbidities. Further investigation into selective TOX4 inhibitors and their long-term safety profiles could facilitate the development of adjunct therapies for metabolic disorders involving hepatic and neuronal dysfunction.
Nanocochleates in Clinical Trials: A Review of Current Status, Challenges, and Future Directions.
Singh A, Verma S
Curr Drug Metab · 2025 · PMID 41029920 · Publisher ↗
Nanocochleates are novel lipid-based nanoparticles with a distinctive, multilayered, rolledup structure that resembles the spirals of a cochlea. They form when bivalent cations, such as calcium, interact with negatively...
Nanocochleates are novel lipid-based nanoparticles with a distinctive, multilayered, rolledup structure that resembles the spirals of a cochlea. They form when bivalent cations, such as calcium, interact with negatively charged lipid bilayers. These structures are gaining popularity in drug delivery due to their stability, biocompatibility, and ability to encapsulate and shield a wide range of bioactive substances, including hydrophobic drugs, peptides, and nucleic acids. Nanocochelates can withstand harsh environmental conditions, such as acidic pH or enzymatic degradation, making them suitable carriers for oral, injectable, and transdermal medication administration. Their unique construction enables the gradual release of encapsulated medicines, thereby increasing bioavailability and therapeutic effectiveness. Additionally, nanocochleates can target specific tissues or cells, allowing for precision medical methods. A recent study demonstrates their promise for overcoming issues in the administration of poorly watersoluble medicines, gene therapy agents, and vaccines. Nanocochleates have shown promise in preclinical trials for the management of inflammatory diseases, cancer, and infectious diseases. Despite their potential, further research is needed to optimize large-scale manufacturing, maintain uniform quality, and address regulatory challenges. This review provides a detailed discussion of nanocochleate preparation methods, with a particular focus on entrapment, hydrogel approaches, and dialysis methods. The paper reviews characterization experiments, including particle size measurements, encapsulation effectiveness, surface morphology, and in vitro release tests. Furthermore, the article discusses the feasibility of industrial-scale formation with pure lipid feedstock.
Metabolomics and Network Pharmacology Analysis of Yiqi Huazhuo Decoction in Regulating EGFR Signaling and Metabolic Pathways in Type 2 Diabetes with Insulin Resistance: Validation.
Li S, Liu J, Weng S
Curr Drug Metab · 2025 · PMID 40999608 · Publisher ↗
INTRODUCTION: Type 2 diabetes mellitus (T2DM), characterized by insulin resistance (IR) and hepatic ectopic lipid deposition (ELD), poses a complex metabolic challenge. This study aimed to elucidate the mechanisms of Yiq...
INTRODUCTION: Type 2 diabetes mellitus (T2DM), characterized by insulin resistance (IR) and hepatic ectopic lipid deposition (ELD), poses a complex metabolic challenge. This study aimed to elucidate the mechanisms of Yiqi Huazhuo Decoction (YD) through an integrated approach combining network pharmacology and metabolomics. T2DM is marked by impaired insulin signaling and disrupted hepatic lipid metabolism, resulting in a vicious cycle that accelerates disease progression. While Traditional Chinese Medicine (TCM), such as YD, demonstrates potential in modulating these dysfunctions, its underlying molecular mechanisms remain to be fully clarified. MATERIALS AND METHODS: A diabetic fat rat model was used to evaluate the efficacy of YD. UPLC-MS characterized the main metabolites found in YD. After an 8-week intervention, physiological indices and hepatic pathology were assessed. Network pharmacology identified bioactive metabolites and targets, which were validated by molecular docking. Untargeted metabolomics was employed to analyze hepatic metabolic changes. RESULTS: YD improved glucose/lipid metabolism, insulin sensitivity, and hepatic function. Network pharmacology revealed that YD acts via the EGFR and PI3K-Akt/IL-17 pathways. Molecular docking confirmed luteolin-EGFR binding. Metabolomics identified 20 altered metabolites in the biosynthesis of unsaturated fatty acids. Multi-omics analysis revealed that YD regulated EGFR and hepatic metabolic networks. DISCUSSION: The multi-metabolite, multi-target mechanism of YD distinguishes it apart from single-target drugs, such as metformin. The binding of luteolin to EGFR may potentially reactivate the PI3K-Akt signaling pathway, thereby enhancing insulin sensitivity. Regulation of metabolic pathways, including the biosynthesis of unsaturated fatty acids, contributes to the reduction of hepatic lipid deposition. These findings underscore the capacity of YD to disrupt the IR-ELD cycle in T2DM. CONCLUSION: YD ameliorates T2DM-IR and hepatic ELD by modulating EGFR signaling and metabolic pathways, providing multi-omics evidence for its clinical application.
An Explicative Review on Nanotechnology-based Drug Delivery Systems for Alleviating Oxidative Stress-driven Pathologies.
Karati D, Gayen S, Mukherjee S … +1 more , Roy S
Curr Drug Metab · 2025 · PMID 40993951 · Publisher ↗
BACKGROUND: Numerous chronic illnesses, including diabetes, cancer, cardiovascular disease, and neurological disorders, are mostly caused by oxidative stress, which is defined as an imbalance between the body's antioxida...
BACKGROUND: Numerous chronic illnesses, including diabetes, cancer, cardiovascular disease, and neurological disorders, are mostly caused by oxidative stress, which is defined as an imbalance between the body's antioxidant defenses and the generation of reactive oxygen species (ROS). The success of traditional treatments for oxidative stress has been limited because antioxidant medications are not well-absorbed, are quickly broken down, and do not target specific areas of the body. METHODS: Drug delivery methods based on nanotechnology offer a viable solution to these issues by providing therapeutic molecules with improved release characteristics, enhanced bioavailability, and targeted capabilities. Recent developments in nanotechnology have enabled the creation of multipurpose carriers that can simultaneously transmit genes for endogenous antioxidant enzymes and antioxidants. RESULTS: This integration promotes a long-term healing response and addresses the immediate oxidative stress. Likewise, functionalizing nanocarriers with particular ligands improves localization to oxidative stress locations, including inflammatory tissues or tumor microenvironments, boosting therapeutic efficacy. The potential of nanotherapeutics in reducing oxidative stress-driven diseases is examined in this article. DISCUSSION: Nanotechnology-based drug delivery approaches offer a novel avenue for the treatment of several oxidative stress-induced diseases. These delivery systems are highly target-specific and have a longer duration of action. Still, more research is needed to address issues, such as safety margins, largescale production, and approval of medicine use. CONCLUSION: We address several nanocarrier platforms, such as liposomes, polymeric nanoparticles, dendrimers, and metallic nanoparticles that have proven more effective in delivering therapeutic drugs and antioxidants to specific sites of oxidative damage. Furthermore, nanotherapeutics may enhance their therapeutic potential by protecting these bioactive substances from premature degradation and clearance.
Targeting Metabolic Dysregulation in Alzheimer's Disease: A Potential Therapeutic Strategy.
Barnwal N, Dubey S, Tiwari P
Curr Drug Metab · 2025 · PMID 40990282 · Publisher ↗
Alzheimer's disease (AD), the most common form of dementia, is characterized by progressive cognitive decline and neuropathological hallmarks, including amyloid-beta plaques and tau tangles. Emerging evidence implicates...
Alzheimer's disease (AD), the most common form of dementia, is characterized by progressive cognitive decline and neuropathological hallmarks, including amyloid-beta plaques and tau tangles. Emerging evidence implicates metabolic dysfunction as a critical contributor to the pathogenesis and progression of AD. Impaired glucose metabolism, mitochondrial dysfunction, oxidative stress, and lipid dysregulation are frequently observed in AD brains, suggesting that metabolic dysfunction may exacerbate neurodegeneration and cognitive deficits. This review explores the therapeutic potential of targeting metabolic pathways to mitigate AD pathology. Key metabolic disruptions, including insulin resistance, reduced cerebral glucose utilization, and mitochondrial inefficiency, are closely linked to neuronal energy deficits and synaptic dysfunction. Therapeutic approaches, such as insulin sensitizers, ketogenic diets, and mitochondrial-targeted antioxidants, have shown promise in preclinical and early clinical studies. Additionally, strategies to modulate lipid metabolism, such as enhancing cholesterol efflux via APOE or reducing neurotoxic ceramides, offer potential avenues for intervention. The review also highlights the roles of neuroinflammation and oxidative stress as mediators of metabolic dysfunction in AD, underscoring the need for multifaceted approaches that target both metabolic and inflammatory pathways. The emerging field of precision medicine offers opportunities to tailor interventions based on individual metabolic profiles, potentially enhancing treatment efficacy. Despite the growing recognition of metabolic dysfunction in AD, translating these insights into effective therapies remains challenging due to the disease's complexity and heterogeneity. Future research must focus on elucidating the interplay between metabolic pathways and AD pathology, identifying reliable biomarkers, and designing targeted interventions. By addressing the metabolic underpinnings of AD, this review underscores the potential of metabolic reprogramming as a novel and integrative therapeutic strategy to slow or prevent disease progression and improve patient outcomes.
Transfer of Intravenous Remimazolam into Milk of Lactating Sheep and Uptake by Breast-fed Lambs.
Schmalix W, Onyuro M, Pesic M … +2 more , Karl-Uwe-Petersen, Stoehr T
Curr Drug Metab · 2025 · PMID 40968423 · Publisher ↗
INTRODUCTION: Remimazolam is a short-acting sedative/anesthetic. For safe breastfeeding, information on the extent and possible risks of remimazolam being passed over to the infant through mother´s milk is needed. The ob...
INTRODUCTION: Remimazolam is a short-acting sedative/anesthetic. For safe breastfeeding, information on the extent and possible risks of remimazolam being passed over to the infant through mother´s milk is needed. The objective of this work was to study the transfer of remimazolam from maternal to infant circulation by mother´s milk in an animal model. METHODS: Three lactating British milk sheep received intravenous remimazolam (0.4 mg/kg bolus plus 4-hrinfusion at 1 or 2 mg/kg/hour). Drug profiles were recorded in plasma and milk. Six suckling lambs were administered remimazolam by intravenous and oral gavage administration for a comparison of plasma concentration profiles of remimazolam and its primary metabolite, CNS7054. RESULTS: Treatment of lactating sheep induced dose-dependent sedation and loss of consciousness. At the end of infusion, the concentration of remimazolam was higher in milk than in plasma. The subsequent elimination of remimazolam from milk was rapid, although somewhat slower than from plasma. DISCUSSION: In lambs, intravenous, but not oral, remimazolam (2 mg) caused different grades of sedation/anesthesia (fully reversible within 8 to 15 min). Mean plasma C was 278.3 ng/mL after intravenous and 1.3 ng/mL after oral administration. Oral gavage resulted in a sizable plasma concentration of CNS7054 (Cmax around 100 ng/mL), indicating efficient intestinal absorption of the parent drug, followed by extensive firstpass metabolic elimination, leading to negligible bioavailability of oral remimazolam. CONCLUSION: In mother´s milk, remimazolam reaches higher concentrations than in plasma and is cleared by redistribution to the central compartment for final hepatic elimination. In lambs, oral remimazolam results in minimal plasma concentrations, suggesting that safety concerns regarding breast-fed infants would be minor and could be completely alleviated by a short nursing interruption.
Application of Physiologically Based Pharmacokinetic Modeling in the Research of Anti-HIV Drugs.
Xie Y, Zhang W, Wang H … +4 more , Hu H, Zhang S, Wang S, Han J
Curr Drug Metab · 2025 · PMID 40968422 · Publisher ↗
Physiologically based pharmacokinetic (PBPK) modeling is a computational technique that uses the physicochemical properties of drugs and physiological information to simulate plasma and tissue concentrations. PBPK modeli...
Physiologically based pharmacokinetic (PBPK) modeling is a computational technique that uses the physicochemical properties of drugs and physiological information to simulate plasma and tissue concentrations. PBPK modeling has become a mainstream approach in drug research and development, frequently employed to support regulatory packages for new drug applications. Understanding the pharmacokinetic characteristics of anti-HIV drugs is essential for successful treatment. In recent decades, PBPK modeling has been commonly used in the development and clinical therapy of anti-HIV medications. This review discusses the prevalence and application of PBPK modeling in the pharmacokinetics of anti-HIV drugs. Among the articles retrieved for this review, PBPK modeling was predominantly employed for anti-HIV drugs in contexts, such as pregnancy, drug-drug interactions, and pediatrics. The most commonly used software programs for this model are Simcyp, MATLAB, and PK-sim. This review will provide insights for researchers in applying PBPK models to manage patients with HIV infection, aiming to enhance the efficacy of anti-HIV drug therapy and prevent undesirable adverse effects.
Advances in Nanomedicine: Transforming Diagnostic Imaging with Novel Contrast Agents.
Das P, Gupta M, Sahu A … +8 more , Mukherjee T, Mohanty S, Nayak N, Kumari S, Singh RP, Lariya D, Chopra MP, Pattnaik A
Curr Drug Metab · 2025 · PMID 40947743 · Publisher ↗
In recent years, the development of medical technologies leveraging nanomedicine has witnessed remarkable progress, particularly in areas such as targeted drug delivery, controlled drug release, tissue engineering, and...
In recent years, the development of medical technologies leveraging nanomedicine has witnessed remarkable progress, particularly in areas such as targeted drug delivery, controlled drug release, tissue engineering, and diagnostics. This review explores the transformative impact of nanotechnology on medical imaging, focusing on developing novel contrast agents. Diagnostic imaging techniques, including Positron Emission Tomography (PET), Computed Tomography, and Magnetic Resonance Imaging, have become indispensable tools in modern healthcare. Contrast agents play an important role in enhancing the sensitivity of these imaging modalities, enabling the detection of previously undetectable anomalies. Nanotechnology offers unprecedented opportunities to revolutionize contrast agent design, leading to improved imaging modalities and diagnostic accuracy. Due to their high X-ray attenuation coefficients, metal-based inorganic nanoparticles, such as gold, bismuth, and lanthanide-based nanomaterials, exhibit significant potential as CT contrast agents. Furthermore, the pharmacokinetic properties and drug metabolism profiles of these nanomaterials are critical in ensuring their safety, efficacy, and optimal performance in clinical applications. Moreover, nanomaterials with integrated diagnostic and therapeutic capabilities are emerging as promising candidates for real-time disease detection and image-guided treatment. This review highlights the properties of nanomaterials that make them suitable for use as contrast agents. It discusses the challenges and opportunities in developing multifunctional nanomaterials for medical and diagnostic purposes. Overall, nanotechnology-enabled contrast agents have the potential to redefine the landscape of medical imaging, paving the way for more precise diagnosis and personalized treatment strategies.
Transcriptomic and Proteomics Analysis of a Lipid-Loaded HepaRG Model for Steatosis Reveals Altered Regulation in Lipid and Xenobiotic Metabolism.
Saravanakumar A, Tierney CA, He W … +6 more , Jamwal R, Barlock B, Bush X, Johnson JG, Rodrigues DA, Akhlaghi F
Curr Drug Metab · 2025 · PMID 40947715 · Publisher ↗
INTRODUCTION: Hepatic lipid accumulation (steatosis) is an early indicator of non-alcoholic fatty liver disease (NAFLD), preceding fibrosis and cirrhosis. Understanding its effects on drug-metabolizing enzymes (DMEs) and...
INTRODUCTION: Hepatic lipid accumulation (steatosis) is an early indicator of non-alcoholic fatty liver disease (NAFLD), preceding fibrosis and cirrhosis. Understanding its effects on drug-metabolizing enzymes (DMEs) and transporters is crucial for assessing potential alterations in drug disposition among NAFLD patients. This study aimed to replicate steatosis in an HepaRG cell model and analyze its impact on DMEs and transporters. METHODS: Differentiated HepaRG cells were treated with a mixture of saturated (palmitate) and unsaturated (oleate) fatty acids (in a 1:2 ratio at 0.5 mM), complexed with BSA for 72 hours to induce lipid accumulation. Confirmation of steatosis was performed using Oil Red O staining and triglyceride (TG) quantification, while cell viability was assessed via the WST-1 assay. RNA sequencing and SWATHMS proteomic analysis were employed to identify differentially expressed transcripts and proteins in lipid-loaded cells compared to controls. RESULTS: Lipid loading resulted in a ~6-fold increase in TG concentration without compromising cell viability. Transcriptomic analysis identified 393 differentially expressed transcripts (89 upregulated, 304 downregulated), while proteomic analysis detected 165 differentially expressed proteins (127 upregulated, 38 downregulated). Notably, key mRNA transcripts related to transcription factors (NR1I2, HNF4α), phase 1 DMEs (CYP1A2, 2B6, 2C8, 2C9, 2C19, 3A4), phase 2 DMEs (UGT1A6, 2B7, SULT2A1, 1E1), and transporters (ABCC11, ABCG5, SLCO2B1, SLC10A1) exhibited significant downregulation. DISCUSSION: The observed alterations in DMEs and transporters suggest a potential shift in drug metabolism pathways under NAFLD conditions. Downregulation of transcription factors and metabolic enzymes could impact drug efficacy and toxicity, necessitating further research into the pharmacokinetic implications. CONCLUSION: The in vitro hepatic steatosis model demonstrated significant changes in the expression of clinically relevant DMEs and transporters. These findings highlight the importance of considering NAFLD-induced metabolic alterations when assessing drug disposition in affected patients.
Mechanism of Tetrandrine in Ameliorating Hypoxic Pulmonary Hypertension Vascular Remodeling through Transcriptomics and Metabolomics.
Gong X, Min F, Guo J … +9 more , Zhang Z, Liu X, Guo W, Wu Y, Li H, Fang X, Yuan Y, Sheng Y, Cui H
Curr Drug Metab · 2025 · PMID 40916438 · Full text
BACKGROUND: Tetrandrine (TET) demonstrates therapeutic potential for hypoxic pulmonary hypertension (HPH); however, its precise pharmacological mechanisms remain unclear. In this study, we aimed to investigate the effect...
BACKGROUND: Tetrandrine (TET) demonstrates therapeutic potential for hypoxic pulmonary hypertension (HPH); however, its precise pharmacological mechanisms remain unclear. In this study, we aimed to investigate the effects of TET on pulmonary vascular remodeling (PVR) in HPH and elucidate the molecular pathways through which TET ameliorates HPH. METHODS: We established a rat model of HPH and evaluated the therapeutic effects of TET by measuring hemodynamic parameters, assessing right ventricular hypertrophy, and analyzing pathological changes in lung tissue. To explore the molecular mechanisms, we carried out comprehensive analyses using transcriptome and untargeted metabolomics technologies to examine the impact of TET on gene expression and metabolite profiles in the lung tissue of HPH rats. Using data from these multiomics analyses, we performed biochemical assays, immunofluorescence staining, and Western blotting to validate the effects of TET on vasoconstriction and angiogenesis-related factors. These experiments provide further evidence of the anti-HPH and anti-PVR properties of TET. RESULTS: TET intervention significantly reduced hemodynamic parameters, including mean pulmonary arterial pressure (mPAP) and right ventricular systolic pressure (RVSP), as well as right ventricular hypertrophy indices, such as the right ventricular hypertrophy index (RVHI) and right ventricle-to-body weight ratio (RV/BW), in HPH rats. TET inhibited smooth muscle cell proliferation and alleviated pathological changes in lung tissue. Transcriptome and metabolome analyses revealed that genes affected by TET intervention were enriched in pathways related to PVR, including those involved in endothelial and smooth muscle cell proliferation, angiogenesis, and blood vessel morphogenesis. Metabolites were predominantly associated with the arachidonic acid (AA) metabolism pathway. Differentially expressed genes included , and . Validation experiments demonstrated that TET upregulated ALOX15 protein expression and downregulated CYP4A and CYP2U1 proteins, modulating levels of arachidonate metabolites 20-HETE and 15(S)-HPETE. We further observed that TET reduced the levels of PVR markers, including endothelin-1 (ET-1) secretion, while increasing nitric oxide (NO) release. TET also decreased the expression of cell proliferation markers PCNA and Ki-67 and elevated the endothelial marker CD31. Moreover, TET intervention suppressed angiogenic and vasoconstrictive factors, such as MMP-9, TGF-β1, IGF2, and PDGF-B, while enhancing levels of FGF9 and NOS3. CONCLUSION: Our findings highlight the protective effects of TET on lung tissue in HPH mediated through the regulation of 15(S)-HPETE and 20-HETE within the arachidonic acid metabolism pathway. This regulation inhibits pulmonary angiogenesis and vasoconstriction, ultimately improving PVR in HPH.
Comparative Pharmacokinetics of Five Major Ingredients in Normal and Atherosclerotic Rats after Oral Administration of Shenlian Formula.
Cai-Ying Y, Xin-Ge W, Linying Q … +7 more , Qing Y, Ying C, Qi L, Xiao-Xin Z, Lihong Y, Long C, Yu D
Curr Drug Metab · 2025 · PMID 40908519 · Publisher ↗
INTRODUCTION: Shenlian formula (SL) has been widely used to treat various diseases, including type 2 diabetes mellitus and atherosclerosis (AS). Pathological states can significantly alter drug pharmacokinetics (PK) comp...
INTRODUCTION: Shenlian formula (SL) has been widely used to treat various diseases, including type 2 diabetes mellitus and atherosclerosis (AS). Pathological states can significantly alter drug pharmacokinetics (PK) compared to normal physiology, primarily by modulating biological membrane permeability and metabolic enzyme activity, thereby affecting drug absorption, distribution, metabolism, and excretion. However, the specific influence of AS on the PK profile of SL remains uncharacterized. OBJECTIVE: To investigate the plasma PK of five components (Salvianolic acid A (SAA), Danshensu (DSS), Andrographolide (AND), Neoandrographolide (NAND), and Dehydrated andrographolide (DDAND),) which were the ingredients of SL, in physiological and AS rats administered SL intragastrically. METHODS: The AS SD rat model was induced with a high-fat diet, carotid balloon injury, and VD3 injections. A validated LC-MS/MS method quantified plasma concentrations to assess PK parameters. RESULTS AND DISCUSSION: The validation parameters were all in accordance with the current standards. Comparative PK analysis revealed significant intergroup disparities between the AS and normal groups. The value of C and AUC for DSS was significantly decreased (P<0.05) in the AS group, which indicated that the absorptive amount in vivo was remarkably attenuated in the pathological state. Additionally, the variation trend of AND under C and AUC values were consistent with the alteration trend of DSS. Furthermore, the T of NAND in the AS group was significantly reduced (P<0.05), confirming that the pathological state accelerated the absorption rate of NAND, thereby shortening the time required for NAND to reach its maximum concentration in the body. CONCLUSION: We established and validated a sensitive LC-MS/MS method for the simultaneous quantification of five bioactive components of SL in rat plasma. This method is applicable to both physiological and pathological states. Comparative pharmacokinetic analysis revealed significant differences in the systemic exposure of all five analytes between AS and normal rats. These findings provide critical PK evidence for optimizing SL dosage regimens in AS patients, underscoring the imperative to consider the disease' status when determining therapeutic strategies for traditional Chinese medicine formulations.
Advances in Controlled Release Formulations for Ocular Diseases: Improving Patient Compliance and Therapeutic Outcomes.
Narwal S, Dushyant, Singh G … +3 more , Grewal N, Chanalia V, Dhingra AK
Curr Drug Metab · 2025 · PMID 40873218 · Publisher ↗
A majority of the global population suffers from eye diseases, but few effective treatment options are available with ophthalmic drug therapies. The reasons that have been identified are (1) lack of awareness about the o...
A majority of the global population suffers from eye diseases, but few effective treatment options are available with ophthalmic drug therapies. The reasons that have been identified are (1) lack of awareness about the options for treatments, drugs, polymeric science, or physiological barriers, (2) limitations in bringing drug therapies to the posterior segment of the eye due to physiological or anatomical limitations, and (3) regulatory and production difficulties of ocular drug products. Innovative ocular medication delivery and therapies are covered in this study, including hydrogels, nano micelles, implants, nanoparticles, microparticles, liposomes, gels, and microneedles. Moreover, due to their potential to capture both hydrophilic and lipophilic medications, increase ocular permeability, prolong the period of residence, enhance drug stability, and increase bioavailability, this review includes nanotechnology-based carriers. The research encompassed various eye disorders, obstacles to ocular delivery, multiple ocular administration routes, a range of nanostructured platforms, characterization approaches, methods to improve ocular delivery, and emerging technologies. This review aims to provide information on the anatomy of the eye, various ocular conditions, and obstacles to ocular delivery. The benefits and drawbacks of various ocular dose forms or delivery techniques are also evaluated. Finally, it describes methods for increasing ocular bioavailability.
Comprehensive Insights into Licochalcone A: its Distribution, Biosynthesis, Metabolism, and Pharmacological Effects.
Wang X, Liu J, Li W … +4 more , Tao X, Yu C, Xie J, Zhang Y
Curr Drug Metab · 2025 · PMID 40873217 · Publisher ↗
Licochalcone A (LCA) is an important secondary metabolite in licorice that has attracted extensive attention due to its unique species-specific distribution characteristics and various pharmacodynamic activities, particu...
Licochalcone A (LCA) is an important secondary metabolite in licorice that has attracted extensive attention due to its unique species-specific distribution characteristics and various pharmacodynamic activities, particularly its anti-inflammatory and anti-cancer effects. LCA was originally considered exclusive to Batal. However, further analyses have shown its distribution in different licorice species, extending its known distribution among licorice species and suggesting a broader role in secondary metabolism. Nevertheless, the complex chemical synthesis of LCA presents challenges in regioselectivity control. The oral bioavailability of LCA is limited due to the intestinal first-pass effect, and its metabolic mechanism has not yet been fully elucidated. These issues restrict the therapeutic effects and practical applications of LCA . In recent years, advancements in optimizing synthetic pathways and developing new delivery systems have significantly improved the efficacy of LCA while also achieving notable breakthroughs in its safety. This review examines the distribution patterns, synthesis methods, metabolic processes, pharmacological activities, and current application status of LCA, while also exploring future research directions. However, its metabolic mechanisms and prospects for clinical application still require further investigation in the future. A multisource database search related literature employed "Licochalcone A"as the anchor term, synergized with species taxonomy (Glycyrrhiza), biogeographic patterns, and phytochemical dynamics (biosynthesis/metabolism).
Emerging Approaches in Data-Driven Drug Discovery for Rare Diseases.
Abbas M, Parayangat M, Al-Hamami MAH … +3 more , Elshafie H, Al-Shamri MYH, Resmi R
Curr Drug Metab · 2025 · PMID 40873216 · Publisher ↗
Rare diseases present unique challenges in drug discovery and development, primarily due to small patient populations, limited clinical data, and significant variability in disease mechanisms. The primary objective of th...
Rare diseases present unique challenges in drug discovery and development, primarily due to small patient populations, limited clinical data, and significant variability in disease mechanisms. The primary objective of this review is to examine the integration of pharmacokinetics (PK) and drug metabolism data into data-driven drug discovery approaches, particularly in the context of rare diseases. By incorporating advanced computational techniques such as Machine Learning (ML) and Artificial Intelligence (AI), researchers can better predict PK parameters, optimize drug candidates, and identify personalized therapeutic strategies. AI integration with genomic and proteomic data reveals previously unidentifiable pathways, fostering collaboration among researchers, clinicians, and pharmaceutical companies. This interdisciplinary approach reduces development timelines and costs while enhancing the precision and effectiveness of therapies for patients with rare diseases. This review highlights the critical role of absorption, distribution, metabolism, and excretion (ADME) in understanding drug behavior in genetically diverse populations, thereby enabling the development of tailored treatments for patients with rare diseases. Additionally, it evaluates the opportunities and limitations of integrating PK/PD (pharmacodynamics) models with multi-omics data to improve drug discovery efficiency. Key examples of enzyme-drug interactions, metabolic pathway analysis, and AIbased PK simulations are discussed to illustrate advancements in predictive accuracy and drug safety. This review concludes by emphasizing the transformative potential of integrating PK and metabolism studies into the broader framework of data-driven drug discovery, ultimately accelerating therapeutic innovation and addressing unmet medical needs in rare diseases.
Biopharmaceutical Factors Involved in the Disposition of Mycophenolic Acid: A Comprehensive Review of ADME Properties and Their Potential Impact on Mycophenolic Acid Plasma Exposure.
Asare E, Du T, Xie H … +2 more , Liang D, Gao S
Curr Drug Metab · 2025 · PMID 40873215 · Full text
Mycophenolic acid (MPA) is an approved drug widely used as an immunosuppressant agent for the prevention of rejection in organ transplant patients and for managing various autoimmune disorders. Pharmacological studies ha...
Mycophenolic acid (MPA) is an approved drug widely used as an immunosuppressant agent for the prevention of rejection in organ transplant patients and for managing various autoimmune disorders. Pharmacological studies have shown that the plasma exposure of MPA is critical to maintaining its efficacy, leading to a significant focus on MPA therapeutic drug monitoring (TDM) in clinical practice. Additionally, many papers have been published regarding MPA's absorption, distribution, metabolism, and elimination (ADME) characteristics, which are the key disposition factors affecting the plasma exposure of MPA. In this paper, we review the current data and information in the literature on the ADME properties of MPA and discuss their implications for MPA's TDM. We also analyze the disposition of MPA major metabolites mycophenolic acidglucuronide (MPAG), and acyl-glucuronide (AcMPAG), highlighting the key factors that affect MPA plasma exposure, including the influence of transporters, namely Multidrug Resistance-Associated Protein 2 (MRP2), Breast Cancer Resistance Protein (BCRP), Organic Anion-Transporting Polypeptides (OATPs), metabolic enzymes (i.e., UDP-Glucuronosyltransferases (UGTs)), enterohepatic recycling (EHR), and protein binding. We expect to provide researchers with a comprehensive understanding of factors that could affect MPA's TDM to ensure its efficacy.
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