Current drug metabolism最新文献

Cirrhosis is a very serious, gradual liver disease characterized by the overproduction of collagen and scarring, which together may result in liver failure or hepatocellular cancer. It typically develops based on fibrosis, which may be reversible when diagnosed in its initial stages. Viral hepatitis, alcohol, non-alcoholic fatty liver disease, and drug-induced hepatotoxicity are some of the etiologies of the disease. It is worth noting that about half of the cases of hepatic damage in patients are known to be caused by drug-induced liver injury. The existence of the pathophysiological complexity and therapeutic reactions of cirrhosis requires experimental models that are reliable. This review gives insight into the different in vivo, ex vivo, and operative animal models employed to cause hepatic injury by application of chemicals, drugs, dietary, and bile duct ligation particulars. The focus is on the mechanistic understanding of the actions of hepatotoxic substances, their involvement in oxidative stress, mitochondrial pathology, and the inflammatory process. Each model is critically discussed in terms of its advantages, limitations, and translational relevance.Additionally, this work highlights emerging alternatives, such as organ-on-a-chip systems, 3D co-cultures, and hepatic bioengineered tissues, as solutions that aim to reduce animal use and increase physiological relevance. The review also discusses biomarkers, histopathological endpoints, and important molecular players in hepatic fibrosis and cirrhosis. The review also examines data from preclinical studies of hepatoprotective substances and modulators of fibrosis, as it facilitates the integration of data from various experimental platforms. The next steps involve personalized pathology based on decellularized liver scaffolding and patient cells, aiming to better determine clinical outcomes and treatment responses.

Background: Vincosamide, an indole alkaloid extracted from Nauclea officinalis, exhibits a range of pharmacological activities, such as anti-tumor, antibacterial, and anti-inflammatory properties. However, despite its promising therapeutic applications, there is a notable gap in research focused on the metabolic pathways of vincosamide.

Objectives: This study aims to investigate the metabolism of vincosamide both in vitro and in vivo in rats, and to elucidate its metabolic pathways.

Methods: Samples of liver microsomal incubation, plasma, bile, urine, and feces following vincosamide administration were analyzed by ultra-high performance liquid chromatography-quadrupole-Exactive Orbitraphigh resolution mass spectrometry (UHPLC-Q-Exactive Orbitrap HRMS). The collected data were analyzed using Compound Discovery 3.2 software and the molecular network method. The metabolites identified through these methodologies were subsequently validated using Xcalibur 4.1 software, which provided information on retention times, parent ions, and characteristic fragment ions.

Results: A total of 37 metabolites were identified, including 8 in vitro and 32 in vivo (3 in plasma, 7 in bile, 22 in urine, and 17 in feces). While the metabolism of vincosamide differs in vitro and in vivo in rats, the type of metabolic reaction that occurs is well-defined. The predominant metabolic pathways are oxidation, reduction, deglycosylation, hydration, glucuronidation, methylation, sulfation, glycine conjugation, cysteine conjugation, taurine conjugation, and complex reactions.

Conclusion: This study elucidates the metabolism of vincosamide in vitro and in vivo in rats, thereby expanding the metabolite profile of vincosamide. These findings provide a foundation for the potential development of new drugs based on vincosamide.

Introduction: Lornoxicam is a non-steroidal anti-inflammatory drug belonging to the oxicam class. This study aimed to develop a niosomal gel containing orange oil for improving the anti-inflammatory effect of lornoxicam.

Methods: Lornoxicam-loaded niosomes (LOR-OR-NIO) were prepared using film hydration followed by the sonication method. Particle size, entrapment efficiency, and ex vivo permeation were all considered during the optimization of the niosomal gels by employing the Box-Behnken design. Dermatokinetics and in vivo anti-inflammatory studies were performed using male Wistar rats.

Results: The particle size, entrapment efficiency, and skin permeation ability of the optimized LOR-ORNIO formulation were found to be 354.3 nm, 83.56 %, and 105.63 μg/cm2, respectively. The ex vivo studies indicated that the optimized LOR-OR-NIO gel demonstrated superior drug penetration properties (105.43 μg/cm²) compared to both the LOR-NIO gel (69.23 μg/cm²) and the LOR gel (35.34 μg/cm²). The activation energy values of LOR gel, LOR-NIO gel, and LOR-OR-NIO gel were 2.74 Kcal mol^-1, 1.93 Kcal mol^-1, and 0.94 Kcal mol^-1, respectively.

Discussion: The lower activation energy of the LOR-OR-NIO gel contributed to more skin penetration of the drug. Dermatokinetics investigation demonstrated that the LOR-OR-NIO gel had superior penetration in the epidermal and dermal areas compared to the LOR gel. In vivo anti-inflammatory studies indicated that the LOR-OR-NIO gel exhibited greater edema inhibition compared to both the LOR-NIO gel and LOR gel. These results demonstrated the enhanced anti-inflammatory activity of the LOR-ORNIO gel.

Conclusion: The study concluded that orange oil enhanced skin permeability and influenced the dermatokinetics of the LOR-OR-NIO gel, leading to an improvement in in vivo anti-inflammatory properties.

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.

Introduction: This review aims to explore the therapeutic potential and safety of herbal bioactive compounds in the treatment of various liver disorders. As the liver plays a critical role in digestion, detoxification, energy storage, and protein synthesis, any impairment in its function can lead to significant health complications. The study aims to identify effective herbal agents that may support liver health.

Methods: A comprehensive literature search was conducted using scientific databases and platforms including Web of Science, Scopus, PubMed, HINARI, ScienceDirect, and Google Scholar. The review includes studies that investigate the hepatoprotective potential of herbal bioactives, while research related to hepatic cancers was excluded to maintain a focus on non-malignant liver disorders.

Results: The review identifies several medicinal plants and their active constituents that exhibit hepatoprotective properties. These bioactives function through various pharmacological mechanisms at the molecular level. Common liver conditions addressed include fatty liver, hepatitis, fibrosis, steatosis, and cirrhosis. The reviewed compounds demonstrate antioxidant, anti-inflammatory, and antifibrotic activities, supporting their role in liver disease management.

Discussion: The findings support growing evidence that herbal bioactives can modulate key molecular pathways involved in liver disorders. These results align with existing studies highlighting the benefits of plant-based treatments. However, the limitations include a lack of clinical trial data, poor bioavailability of some compounds, and the need for standardized formulations. Further research is necessary to validate these results in human populations.

Conclusion: Herbal bioactives such as flavonoids, polyphenols, alkaloids, glycosides, saponins, vitamins, and essential oils show promising hepatoprotective effects. This review emphasizes the importance of understanding their precise molecular mechanisms and ADME (absorption, distribution, metabolism, and excretion) profiles. These insights are crucial for developing safe, effective, and standardized herbal therapies for liver disease management.

Venetoclax is a first-in-class B-cell lymphoma/lymphoma-2 (BCL-2) inhibitor that induces apoptosis in malignant cells through the inhibition of BCL-2. The clinical response to venetoclax exhibits heterogeneity, and its sensitivity and resistance may be intricately linked to genetic expression. Pharmacokinetic studies following doses of venetoclax (ranging from 100 to 1200mg) revealed a time to maximum observed plasma concentration of 5-8 hours, with a maximum blood concentration of 1.58-3.89 μg/mL, and a 24-hour area under the concentration-time curve of 12.7-62.8 μg·h/mL. Population-based pharmacokinetic investigations highlighted that factors such as low-fat diet, race, and severe hepatic impairment play pivotal roles in influencing venetoclax dose selection. Being a substrate for CYP3A4, P-glycoprotein, and breast cancer resistance protein, venetoclax undergoes primary metabolism and clearance in the liver, displaying low accumulation in the body.The significance of dose modifications (a 50% decrease with moderate and a 75% reduction with strong CYP3A inhibitors) and a cautious two-hour interval when co-administered with P-glycoprotein inhibitors are highlighted by insights from clinical medication interaction studies. Moreover, an exposure-response relationship analysis indicates that venetoclax exposure significantly correlates not only with overall survival and total response rate but also with the occurrence of ≥ 3-grade neutropenia. In real-world studies, common or severe side effects of venetoclax include tumor lysis syndrome, myelosuppression, nausea, diarrhea, constipation, infection, autoimmune hemolytic anemia, and cardiac toxicity, among others. In this review, we summarize the current clinical pharmacology studies and side effects of venetoclax, which showed that the approved dosage of venetoclax is relatively wide, and the dosage for different hematologic populations can be streamlined in the future.

The well-established calcineurin inhibitor, tacrolimus, as an immunosuppressive agent, is widely prescribed after organ transplantation. Cytochrome P450 (CYP 450) isoforms are responsible for the metabolism of many features associated with food parameters like phytochemicals, juices, and fruits. This review article summarizes the findings of previous studies to help predict the efficacy or side effects of tacrolimus in the presence of food variables. From the commencement of databases associated with the topic of interest to 26 October 2024, all relevant articles were searched through PubMed, Scopus, and Web of Science. The suggested therapeutic range for tacrolimus trough concentration (C₀ ) was reported as 5-15 ng/ml blood. Tacrolimus interaction with food variables could significantly change C₀ after organ transplantation. For example, grapefruit juice could increase tacrolimus C₀ due to CYP enzyme inhibition. Toxicity such as nephrotoxicity could result from turmeric and other herbal or food products. By inhibiting tacrolimus-metabolizing enzymes and transporters, a high intake of vegetables could increase the risk of adverse effects. Secondary metabolites of vegetables could lead to toxicity in patients with tacrolimus. Furthermore, grapefruit juice, citrus fruits, turmeric, and pomegranate juice could change clinical pharmacokinetics parameters such as T_max, C_max, AUC, and C₀ of tacrolimus after organ transplantation. Bioavailability of tacrolimus might be decreased by induction of the CYP450 system and P-gp efflux pump due to cranberry, rooibos tea, and boldo. Increased inhibitory effect on CYP450 system and/or P-gp efflux pump by grapefruit juice, schisandra, berberine, turmeric, pomegranate juice, pomelo, and ginger could increase bioavailability of tacrolimus. A vigilant immunosuppressive strategy accompanied by scheduled therapeutic drug monitoring is recommended before and after transplant surgery.

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.

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 in vivo and in vitro 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.

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.