Introduction: Allopurinol and its active metabolite, oxypurinol, reduce uric acid concentrations through xanthine oxidase inhibition by suppressing the conversion of hypoxanthine and xanthine. Oxypurinol plays a prominent role in allopurinol’s pharmacological activity due to its longer elimination half-life. Despite decades of clinical use, establishing an optimal dosing strategy to consistently achieve the target serum uric acid concentration lower than 0.36 mmol L-1 remains challenging. This review aimed to summarize the development of population pharmacokinetic modeling for oxypurinol and analyze factors influencing its pharmacokinetic variability. Methods: PubMed, Web of Science, and Scopus were systematically searched from database inception until January 2025, adhering to the PRISMA guideline. Studies were eligible if they involved oxypurinol population pharmacokinetic analyses in adults receiving allopurinol and employed nonlinear mixed-effects modeling Results: Eight studies met the inclusion criteria, mostly involving adult gout patients. Pharmacokinetic analyses of oxypurinol employed a one-compartment model, incorporating firstorder absorption and elimination, reporting clearance value of 0.60−1.74 L h-1 and volume of distribution 38.1−59.3 L. Covariates associated with oxypurinol clearance included creatinine clearance, body weight, normal fat mass, fat-free mass, ethnicity, genetic polymorphisms, and concomitant diuretics; whereas, total body weight was found as significant predictors for volume of distribution. Discussions: Reported values for oxypurinol clearance and volume of distribution varied across studies. The small sample sizes and underrepresentation of certain populations, particularly Asians, restrict the generalizability of these findings. Conclusion: Further research involving larger, more diverse cohorts is needed to refine therapeutic drug monitoring and identify potential covariates across different populations to optimize allopurinol therapy.
Tetrahedral framework nucleic acids (tFNA) are specialised three-dimensional DNA nanostructures with precise self-assembly, structural rigidity, programmability, and excellent biocompatibility. Their resistance to enzymatic degradation is enabled by their unique tetrahedral geometry, which also facilitates efficient cellular internalisation without the need for transfection agents. Thus, establishing tFNA as both a versatile regulator and a nanocarrier. Healing in orthopaedics is often stalled by limited tissue regeneration, unpredictable inflammation and infection, and suboptimal drug localisation within complex microenvironments. This review summarises recent advances in the application of tFNA across key orthopaedic domains, including bone and cartilage regeneration, angiogenesis, immunomodulation, anti-microbial therapy, and bone cancer treatment. tFNA have been shown to enhance osteogenic and chondrogenic differentiation of multiple mesenchymal stem cell populations by indirectly activating the Wnt/β-catenin and PI3K/AKT pathways. When functionalised with peptides, small molecules, nucleic acids, or natural compounds, tFNA promote angiogenesis, suppress oxidative stress, inhibit inflammatory and pyroptotic signalling, and restore extracellular matrix homeostasis in degenerative joint diseases. Furthermore, integration of tFNA with antibiotics, antimicrobial peptides, hydrogels, and implant surfaces demonstrates promising efficacy in combating orthopaedic infections and biofilm formation while supporting tissue regeneration. Emerging tFNA-based delivery systems for osteosarcoma therapy further illustrate their translational versatility. Despite these encouraging findings, several challenges hinder clinical translation: large-scale synthesis, long-term biosafety, immune responses, pharmacokinetics, and controlled degradation within mechanically and biologically complex orthopaedic environments. Interdisciplinary research and optimisation are ongoing to advance tFNA-based platforms toward safe, effective, and personalised nanotherapeutic strategies in orthopaedics. These developments may ultimately redefine precision therapies for the global management of musculoskeletal diseases.
This study summarizes the chemical features, pharmacological effects, pharmacokinetic profiles, and current limitations arising from the limited natural distribution of Jujuboside A (JuA). Since demand for JuA is increasing while natural resources are scarce, our review focuses is its biosynthetic pathway and production challenges. Recent advances and perspectives on alternatives for production are also discussed, such as directed glycosylation based on structurally related homologs, metabolic pathway regulation of sour jujuba (Ziziphus jujububa var. spinosa (Bunge) Hu ex H.F.Chou), microbial cell factory development, and plant callus culture. This review summarizes the pharmacological activities, pharmacokinetics, and biosynthesis of JuA, and discusses current limitations and potential production strategies. Collectively, these insights highlight the pharmacological potential of JuA and provide a theoretical basis for future mechanistic studies and sustainable large-scale production.
Drug-induced liver injury remains a principal trigger of acute hepatic failure, late-stage drug attrition, and post-marketing withdrawal, reflecting persistent limitations in mechanistic prediction and translational safety assessment. Owing to its central role in xenobiotic biotransformation, the liver is highly vulnerable to metabolic bioactivation and reactive intermediate formation. This review presents a metabolism-centered; systems level framework that integrates Phase-I and Phase-II enzymatic processes with downstream cellular stress responses governing hepatocellular fate. Cytochrome 450-mediated oxidation and subsequent conjugative pathways determine the balance between detoxification and electrophilic burden; disruption of this equilibrium initiates oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress, bile-acid transport impairment, immune-inflammatory activation, and regulated cell death. Emphasis is placed on the dynamic crosstalk among these pathways, which explains interindividual variability, idiosyncratic susceptibility and preclinical-clinical discordance. Emerging insights from network toxicology, transcriptomics, metabolomics and computational modelling have enhanced mechanistic resolution beyond conventional biomarkers. Concurrently, advanced experimental systems including three-dimensional hepatic cultures, organoids, micro-physiological liver-on-chip platforms, humanized animal models and integrative in vitro-in silico approaches are improving translational fidelity. Collectively, this synthesis advances a cohesive mechanistic perspective and highlights integrative strategies to strengthen early risk stratification, mechanistically informed evaluation and predictive safety assessment in drug development.
Bioactivation and clearance of anticancer agents are crucial factors in the efficacy and toxicity of anticancer drugs. Exosomes are membrane-bound vesicles secreted by tumor cells and the tumor microenvironment. These vesicles contain drug-metabolizing enzymes, transporters, and RNA. Exosomes can be non-invasively collected from the blood. This article has been prepared by combining the evidence of the role of exosomal cytochrome P450 isoforms, such as cytochrome P450 family 2 subfamily C member 19, cytochrome P450 family 2 subfamily D member 6, and cytochrome P450 family 3 subfamily A member 5, in the oxidation of anticancer drugs in the first phase of drug metabolism. Exosomal UDP-glucuronosyltransferase 1A1 has been found to help in the conjugation of anticancer drugs in the second phase of drug metabolism. Exosomal ATP-binding cassette transporters, P-glycoprotein, multidrug resistance-associated protein 1, and breast cancer resistance protein have been found to act as intercellular conveyors of drug efflux capacity. These transporters can modulate the efficacy of chemotherapy. Exosomal microRNAs, such as microRNA-21, microRNA-155, and microRNA-1246, have been found to modulate apoptosis, DNA repair, metabolic adaptation, and chemotherapy resistance through the PI3K/AKT pathway, EZH2/STAT3 pathway, and PDCD4 pathway. Long non-coding RNAs, such as UCA1 and HOXA antisense RNA, can reprogram the chromatin structure. These long non-coding RNAs can suppress tumor suppressor genes, thus leading to chemotherapy resistance. Bioinformatics pipelines have been designed to bridge the gap between exosomal RNA and protein levels in the profile of dynamic metabolic states. The challenges in the field of exosomal therapy drug monitoring have been discussed in the article. The article has recommended the use of artificial intelligence in the integration of omics with microfluidic technology for the improvement of exosomal therapy drug monitoring.
