Current drug metabolism最新文献

Traditional treatment methods for the management of diabetes, such as oral hypoglycemic med-ications and insulin injections, include drawbacks like systemic adverse effects, inconsistent medication levels, and low compliance. To avoid difficulties, glycemic levels in diabetic patients, a long-term meta-bolic condition, must be precisely and consistently controlled. Smart therapeutic systems allow for precise, on-demand medication release in response to local physiological or environmental cues, such as glucose levels, pH, temperature, or enzyme activity. They provide a possible substitute for conventional diabetic therapies. As these systems only administer medications when and where needed, they reduce side effects while simultaneously increasing therapeutic efficacy and patient compliance. These systems are designed to respond to signals from external sources (such as light, ultrasound, or magnetic fields) or stimuli like temperature, pH, glucose levels, and enzymes. As they use glucose-sensitive substances like phenyl-boronic acid, glucose oxidase, or polymers to precisely release insulin in hyperglycemic circumstances, glucose-responsive delivery methods are essential for diabetes. This review discusses a stimuli-responsive drug delivery system designed for diabetes treatment, with a focus on the developments in biomaterials, nanotechnology, and engineering that improve its effectiveness and biocompatibility. Along with the pos-sibility of combining a stimuli-responsive drug delivery system with wearable technology for continuous glucose monitoring and intelligent insulin delivery, issues, such as manufacturing complexity, stability, and patient safety, are also addressed. The stimuli-responsive drug delivery system has the potential to revolutionize diabetes management by bridging the gap between physiological needs and therapeutic de-livery, providing better glucose control, fewer side effects, and an enhanced standard of living for patients.

Objective: The objective of this study was to investigate the mechanism of anti-cerebral ischemia-reperfusion injury (anti-CIRI) of Ai pian by using the network pharmacology approach combined with serum metabolomics technique based on UPLC-MS.

Methods: The cerebral ischemia-reperfusion injury (CIRI) model was established by middle cerebral artery occlusion (MCAO). The therapeutic effect of Ai pian on CIRI rats was evaluated by behavioral test, 2,3,5-triphenyltetrazolium chloride (TTC) staining, Nissl staining, and hematoxylin-eosin (HE) staining. The active compound-potential target-disease network for Ai Pian in the treatment of CIRI was established using network pharmacology methods. Rat serum was detected by the metabolomics technique based on UPLC-MS. A Western blot was used to validate common targets of the network pharmacology approach combined with serum metabolomics.

Results: The process of treating CIRI with Ai Pian involved regulating enzyme, nuclear receptor, and transcription factor activity, managing the inflammatory response, and participating in biofilm composition. Twenty endogenous potential biomarkers were screened and submitted to MetaboAnalyst 6.0 for pathway and enrichment analysis. Four metabolic pathways were identified: butanoate metabolism, fructose and mannose metabolism, alanine, aspartate, and glutamate metabolism, and pyrimidine metabolism. Fructose and mannose metabolism and pyrimidine metabolism were two key pathways. Western blot analysis suggested that DHODH, TYMS, and AKR1B1 may be targets through which therapeutic effects are exerted.

Conclusion: This research contributed to the development of Ai pian as an adjunctive drug for treating CIRI and provided a basis for further research on CIRI.

Objectives: As a long-acting DPP-4 inhibitor administered orally once a week, trelagliptin can address the issues of frequent medication and poor compliance associated with traditional hypoglycemic drugs. Revealing the pharmacokinetic changes of trelagliptin is particularly important for populations in high-altitude hypoxic environments.

Methods: The Hypoxia model in rats was constructed at an altitude of approximately 4300 meters. The plasma concentration of trelagliptin was determined by LC-MS/MS. The biochemical indices and the pro-tein expression levels of P-gp and OCT2 in the kidneys of rats were determined to explain the possible reasons for the pharmacokinetic changes of trelagliptin.

Results: This study demonstrated that the pharmacokinetic parameters of trelagliptin were significantly changed in high-altitude hypoxic environments. Compared with the control group, the AUC, MRT, t1/2, and Vd were remarkably increased during acute and chronic hypoxia, while the CL and Ke were de-creased. Additionally, the biochemical indexes and protein expression of P-gp and OCT2 were signifi-cantly altered.

Conclusion: The study demonstrated that high-altitude hypoxia significantly altered trelagliptin's phar-macokinetics, slowing clearance, prolonging elimination half-life and residence time, and increasing bio-availability. These changes suggested that the optimal therapeutic dosage of trelagliptin should be reas-sessed under hypoxic exposure.

Purpose: This research aimed to establish a population pharmacokinetic (PPK) model for busulfan (Bu) in Chinese pediatric patients with thalassemia major. We analyzed pharmacokinetic (PK) parameter variability and explored potential covariates affecting Bu disposition using patient data. These findings are intended to support the optimization and personalization of Bu dosage regimens for children with thalassemia major.

Methods: Concentration-time samples were collected retrospectively from 62 pediatric patients with thalassemia major. These patients had previously received intravenous Bu as a preparatory regimen for allogeneic hematopoietic stem cell transplantation (allo-HSCT). A PPK model of Bu was developed through nonlinear mixed-effects modeling. This modeling process, conducted using NONMEM software, concurrently involved data analysis and examination of the effect of covariates on Bu pharmacokinetics. For validation purposes, the resulting model was evaluated against an external dataset consisting of 20 individuals.

Results: The pharmacokinetic results were optimally analyzed using a model that incorporated a one-compartment model with first-order elimination. Body surface area (BSA) was subsequently identified as the most significant factor influencing both Bu clearance (CL) and volume of distribution (V). Diagnostic evaluations, encompassing goodness-of-fit plots, normalized prediction distribution errors, and visual predictive checks, confirmed the satisfactory fit and predictability of the final PPK model. Moreover, prediction-based diagnostic indices (MDPE%, 15.75; MAPE%, 22.26; F20%, 45.71; and F30%, 58.57) from external validation showed that no significant bias was detected when comparing the model's predicted concentrations against the observed data.

Conclusion: The present study developed the first PPK model characterizing the pharmacokinetics of Bu specifically in children with thalassemia major. This study's final PPK model demonstrated that BSA was the key predictive covariate for CL and V.

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. 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 the nature of metabolism of avacopan in humans.

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 PubMed, 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 decision-support 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.

Background: Diabetes mellitus, a widespread and chronic metabolic condition, creates signif-icant 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 ad-vancements, and associated challenges.

Methods: This review examines the role of TDDS in diabetes treatment, with an emphasis on recent in-novations, 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 con-tinuous glucose monitoring systems.

Results: Emerging TDDS technologies improve drug permeability, enhance bioavailability, and offer sus-tained drug release, potentially addressing limitations of conventional delivery methods. However, barri-ers such as skin permeability, high manufacturing costs, and patient variability remain significant chal-lenges.

Discussion: Multi-drug patches and microneedle-based systems represent innovative approaches that en-hance 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 ad-herence, ensuring controlled drug release, and reducing discomfort associated with injections. While fur-ther 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 re-search aims to summarize the advancements and address existing challenges for future development.

Pancreatic cancer is a highly lethal malignancy with a low 5-year survival rate. This review fo-cuses 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. Ad-ditionally, Chinese herbal medicines containing these compounds show promise in clinical applications. However, challenges such as target identification and low bioavailability persist. Future research trends in-volve interdisciplinary collaboration and the use of advanced technologies to overcome these issues.

Nanocochleates are novel lipid-based nanoparticles with a distinctive, multilayered, rolled-up 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 ena-bles 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 water-soluble medicines, gene therapy agents, and vaccines. Nanocochleates have shown promise in preclin-ical 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 prepa-ration methods, with a particular focus on entrapment, hydrogel approaches, and dialysis methods. The paper reviews characterization experiments, including particle size measurements, encapsulation effec-tiveness, surface morphology, and in vitro release tests. Furthermore, the article discusses the feasibility of industrial-scale formation with pure lipid feedstock.