Current drug metabolism最新文献

Introduction: This systematic review aimed to identify, evaluate, and critically an-alyze pharmacokinetic models of vancomycin in adult populations published in PubMed and EMBASE between 2020 and 2024.

Materials and methods: Twenty-two studies were included, describing 24 models character-ized by substantial heterogeneity in terms of study populations, methodological design, and covariate selection. Most models were developed in Asia and focused on hospitalized patients, particularly those in intensive care units (ICUs). Data from 2150 patients were analyzed, with an average of 93 patients per model.

Results: The models demonstrated high variability in pharmacokinetic parameters, such as vancomycin clearance (Cl) and volume of distribution (Vd), influenced by factors, such as renal function, weight, age, and comorbidities. The meta-analysis conducted on clearance and interindividual variability in clearance (IIV Cl) revealed high heterogeneity among the ana-lyzed studies. The average vancomycin clearance was 4.23 L/h, with higher values observed in neurosurgical, oncohematologic patients, and those with increased renal function. The vol-ume of distribution showed greater variability in obese patients and those undergoing continu-ous renal replacement therapy. Creatinine clearance (ClCr) was identified as a significant co-variate in 66% of the models, while weight was significant in 33%. Other important covariates included age, sex, serum creatinine, serum urea, and the hospital admission unit. The meta-analysis of Cl and IIV Cl showed high heterogeneity among the studies, with I² values of 0.83 for Cl and 0.98 for IIV Cl, indicating substantial variability.

Discussion: The limitations of this study included the diversity of the analyzed populations, which made it challenging to assess the model's suitability. While the models showed advances in precision, challenges, such as the lack of external validation and discrepancies in dosing recommendations, remain.

Conclusion: This review paper has highlighted the need to validate models in diverse popula-tions and clinical settings to optimize personalized vancomycin therapy in adults. The findings have highlighted the importance of validating or adapting pharmacokinetic models to the spe-cific characteristics of each hospital population.

Drug-induced hepatotoxicity (DIH) poses a significant clinical challenge due to its unpredicta-ble nature and diverse manifestations. The liver, with its central role in metabolism and close association with the gastrointestinal tract, is particularly susceptible to drug-induced toxicity. DIH encompasses a spectrum of liver injuries, including hepatocellular, cholestatic, and mixed patterns, which may increase the risk of other liver diseases. This review examines diverse examples and molecular mechanisms under-lying DIH, highlighting the influence of genetic predisposition, drug interactions, and pre-existing liver conditions. Given the complexity and variability of hepatotoxic responses to numerous medications, un-derstanding these mechanisms is crucial for improving the diagnosis and management of DIH.

Systemic Lupus Erythematosus (SLE) is a multifactorial autoimmune disorder in-fluenced by genetic predisposition, immune dysregulation, environmental triggers, and epi-genetic modifications. Despite advances in treatment, many patients experience recurrent symptoms and adverse effects. Recent large-scale studies have revealed significant alterations in proteins, glycopeptides, and metabolites in SLE, deepening our understanding of its path-ogenesis. Emerging omics technologies, such as proteomics, glycomics, and metabolomics, enable the high-throughput identification of disease-related biomarkers. However, biological processes are typically driven by the interplay among multiple molecular layers. Therefore, integrative multi-omics approaches have become essential for uncovering potential bi-omarkers and risk factors. This review summarizes the classification of SLE biomarkers and recent advances in diagnostic applications across proteomics, glycomics, and metabolomics, aiming to support the development of more precise diagnostic strategies for SLE.

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.