Current drug metabolism最新文献

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.

Introduction: Type 2 diabetes management remains challenging because of low bioavailability, side effects, and poor compliance with oral therapies. Transdermal delivery methods offer a non-invasive therapeutic approach with sustained delivery, which avoids first-pass metabolism.

Methods: A total of 207 different phytochemicals were virtually screened using i-dock against the diabetic target, PPAR-γ. Subsequently, three matrix-type transdermal patches were developed: a patch containing pure baicalin, a standard patch containing metformin, and a baicalin-loaded phytosomal patch. Phytosomes loaded with baicalin were optimized by using Central Composite Design and evaluated for their physicochemical properties, drug content, physical strength, in vitro, and ex vivo studies. In vivo antidiabetic efficacy was also studied in diabetic Wistar rats over 21 days, followed by a comparison of all formulations, including histopathological analysis of pancreatic tissue.

Results: Molecular docking studies showed promising results; baicalin has a high binding affinity for PPAR-γ (-9.8 kcal/mol). The optimized phytosomal patch confirmed a uniform drug content (91.4 ± 0.12 %) and showed sustained release over 12 hours. The ex vivo permeation study showed a significantly higher skin flux for the phytosomal patch (83.6%). In vivo studies confirmed that baicalin-loaded phytosomal patches showed significant blood glucose reductions (223 ± 0.32 to 96 ± 0.38 levels by Day 21), a comparable efficacy to standard metformin patches (224 ± 0.37mg/dL to 94 ± 0.34 mg/dL by Day 21).

Discussion: The enhanced skin permeation, penetration, and sustained-release exhibited by the phytosomal transdermal patch can be explained by the phospholipid-based shell structure, leading to better affinity with the skin, facilitating retention of the drug. The comparable glycemic control observed with metformin indicates that baicalin-loaded phytosomal transder-mal patches can achieve effective therapeutic concentrations via transdermal delivery, which is corroborated across two studies. These observations are consistent with previous literature documenting improved solubility and bioavailability of plant-derived actives utilizing phyto-some-based systems, which have applicability for chronic metabolic diseases such as T2DM.

Conclusion: The developed phytosomal transdermal patch showed sustained release, better permeation, and potent antidiabetic activity; thus, it offers an alternative to conventional T2DM therapies.

The liver plays a vital role in regulating normal physiological processes in the body. Liver dysfunction can lead to mild to severe pathological conditions and, in some cases, death. To date, more than 900 drugs, toxins, and herbs have been identified with the potential to cause various liver diseases, including acute liver damage, cholestatic jaundice, hepatic granulomas, active chronic hepatitis, and hepatic tumors. A wide range of liver dysfunction results from drug consumption and is referred to as drug-induced liver injury (DILI). DILI significantly contributes to the immediate withdrawal of drugs from the mar-ket. Due to its numerous advantages, the oral route has long been the preferred method of drug administration, although these medicines increase the risk of liver damage. Novel drug delivery approaches, such as the lymphatic drug delivery system and lipid-based nanofor-mulations-including solid lipid nanoparticles (SLNs) and nanostructured lipid carriers-can bypass the liver, reducing the toxic effects of various drugs. Therefore, SLNs represent a promising strategy for lymphatic drug delivery, particularly for hepatocompromised pa-tients and those taking hepatotoxic drugs. This review summarizes how lymphatic drug delivery systems and lipid-based nanoformulations can benefit hepatocompromised pa-tients and individuals on hepatotoxic medications.

Herbal medicines have gained remarkable popularity due to their natural origins and potential medicinal value. Nevertheless, they are chemically complex and pose signifi-cant pharmacological challenges. This review focuses on the key aspects influencing their clinical use: their variable bioavailability, complex pharmacokinetics (ADME), and potential for interactions. A primary concern is herb-drug interactions, with special emphasis on the modulation of drug-metabolizing enzymes by specific phytoconstituents, which can alter drug concentrations to an extent that may be life-threatening, causing either increased toxicity or therapeutic failure. The pharmacological profile is further complicated by the complex effects of constituents, such as synergistic or antagonistic actions, which make predicting therapeutic response and safety difficult. A critical challenge in this field is the frequent dis-connect between in vitro findings and in vivo outcomes, underscoring the importance of phar-macokinetic data, particularly bioavailability, for accurate clinical risk assessment. Safety is a paramount concern, as it is often compromised by inconsistent standardization and quality control, leading to batch-to-batch variability, potential adulteration, and contamination. The absence of stringent regulation impairs therapeutic consistency and introduces health risks. To address these issues, advanced approaches are being employed to improve bioavailability, including novel drug delivery systems that enhance solubility and stability. This review em-phasizes that a rigorous, phytoconstituent-centric approach is essential for navigating the complexities of herbal medicine. By addressing challenges in pharmacokinetics, interactions, safety, standardization, and bioavailability through rigorous scientific investigation and em-bracing future perspectives, such as in silico modeling and improved regulatory frameworks, the quality, safety, and effectiveness of herbal treatments can be ensured, supporting their responsible integration into modern, evidence-based medical systems.

Introduction: Danio rerio, the zebrafish, serves as an excellent model in neuroprotective drug discovery due to its conserved nervous system organization, neurotransmitter pathways, antioxidant de-fenses, and genomic similarity to mammals.

Methods: A systematic literature search following PRISMA 2020 guidelines was conducted across Pub-Med, Scopus, Web of Science, and Google Scholar. Studies published between 2020 and 2025 were pri-oritized, with earlier key papers included for context. The data on larval, adult, and genetically modified zebrafish models were analyzed for neurotoxic effects, focusing on study design, toxicants, and neurobe-havioral or molecular outcomes.

Results: Neurotoxicants such as chlorpyrifos, bisphenol, triphenyl phosphate, aluminum, ammonium ac-etate, arsenic, zinc, acrylamide, methylmercury, and tris (1,3-dichloro-2-propyl) phosphate were shown to cross the zebrafish blood-brain barrier. These exposures caused significant behavioral alterations, neu-rotransmitter imbalances, oxidative stress, and gene or protein expression changes related to brain func-tion. Analysis of the transgenic zebrafish revealed notable alterations in neuronal development and axonal morphology upon exposure to various neurotoxic chemicals.

Discussion: Zebrafish display neurotoxic responses with a close resemblance to mammals, supporting their translational value in neurotoxicity and drug discovery studies. However, limitations such as a less complex brain compared to mammals, quick neuronal regeneration, limited tissue access, and difficulties in drug absorption quantification warrant refinements in zebrafish models.

Conclusion: Zebrafish offer a versatile, cost-effective, and genetically tractable system for neurotoxicity and neuroprotection research. This systematic review highlights their crucial role in neuroprotective drug discovery while emphasizing the need for improved methodological approaches to enhance translational reliability.

Nanotechnology has been applied to the diagnostic and therapeutic treatment of cancer, with Carbon Nanotubes (CNTs) serving as an effective platform for these processes. In addition to their known physicochemical characteristics, such as high surface area, mechanical strength, and ease of functionali-zation, CNTs possess pharmacokinetic properties that enable their use in targeted drug-delivery and diag-nostic systems. Through functionalization, biodistribution, cellular uptake, and circulatory time can be modulated, thereby overcoming the limitations of traditional therapies, such as low bioavailability and systemic toxicity, and enabling more robust absorption, distribution, metabolism, and excretion profiles. Targeted CNT formulations can reduce off-target exposure and improve therapeutic efficiency through targeted delivery and controlled release. Besides, conjugation of CNTs to imaging or diagnostic agents enables improved assessment of biodistribution and metabolic characteristics, which justify their use as theranostic platforms. This review describes the new developments in CNT-based drug delivery systems for cancer treatment, with particular regard to their interactions with metabolism and the importance of these interactions on drug excretion. The fact that CNTs cross biological barriers and can boost drug bio- availability highlights the importance of these nanoparticles in enhancing the effectiveness of treatment procedures and minimizing toxicity. However, safety issues, including toxicity, long-term safety, and bi- ocompatibility, are also significant impediments to clinical translation. There will be a need to address such issues by systematizing pharmacokinetic and metabolic studies to assist in developing CNT-based solutions for precision oncology.

Bone healing remains a major clinical challenge, especially in conditions such as osteoporosis, delayed unions, and critical-sized defects, where conventional therapies often prove inadequate. Current approaches, including growth factor therapies, autografts, and al-lografts, are limited by complications such as immunological reactions, donor-site morbidity, high cost, and poor long-term outcomes. In recent years, Natural Herbal Medicines (NHMs) have emerged as promising alternatives owing to their osteogenic, antioxidant, and anti-in-flammatory properties. Phytoconstituents such as flavonoids, saponins, polyphenols, alka-loids, and minerals exert significant regulatory effects on key signaling pathways, including BMP/Smad, Wnt/β-catenin, MAPK, and RANK/RANKL/OPG, thereby restoring bone mi-croarchitecture, suppressing osteoclastogenesis, and promoting osteoblast differentiation and mineralization. This review focuses on five medicinal plants with strong evidence in bone regeneration: Cissus quadrangularis, Dalbergia sissoo, Moringa oleifera, Withania somnifera, and Terminalia arjuna. Preclinical and clinical studies demonstrate their ability to enhance bone mineral density, collagen deposition, angiogenesis, and callus formation, while reducing oxidative stress and inflammation. Furthermore, synergistic effects have been reported in pol-yherbal formulations, and recent advances in biomaterials and nanotechnology-based carri-ers, such as scaffolds, hydrogels, and nanoparticles, offer targeted and sustained delivery, thereby improving therapeutic efficacy. Despite these promising findings, major barriers re-main, including poor solubility, variability in phytochemical composition, lack of standardi-zation, and limited large-scale clinical trials. Future research must integrate toxicological pro-filing, pharmacokinetic studies, and regulatory harmonization to ensure safe and effective translation of these therapies. Overall, NHMs represent an affordable, biocompatible, and culturally relevant adjunct or alternative to conventional bone-healing strategies, with the potential to revolutionize orthopedic regeneration when integrated with modern delivery plat-forms.

Background: PCOS is a common endocrine disorder characterized by metabolic irregularities, hormonal imbalance, and ovarian dysfunction. Traditional therapies, including dietary changes, herbal remedies, and lifestyle modifications, offer limited efficacy in addressing the complex pathophysiology of PCOS.

Method: A literature review was conducted using PubMed, Google Scholar, and ScienceDirect to identify studies on gut microbiota and microbiome-based management strategies for PCOS.

Result: Emerging evidence highlights the role of gut bacteria in regulating hormonal and metabolic functions, sparking interest in microbiota-targeted therapies. Microbial flavonoid synthesis by species such as Streptomyces and Escherichia coli may positively influence endocrine and metabolic pathways relevant to PCOS.

Discussion: Modulating the gut microbiome, particularly through microbial flavonoid production, represents a promising therapeutic avenue. However, most evidence remains pre-clinical, with limited clinical validation. Key gaps include mechanistic understanding, safety evaluation, and translational research. Integrating microbiome-targeted interventions with conventional therapies could enhance metabolic and hormonal regulation, offering improved outcomes for women with PCOS.

Conclusion: Microbiome-based medicinal approaches, including microbial flavonoid production, may offer novel strategies for PCOS management. Rigorous preclinical studies and well-designed clinical trials are essential to establish their efficacy, safety, and therapeutic potential.

Introduction: Acyl glucuronides are common phase II metabolites of xenobiotics and can sometimes contribute to idiosyncratic toxicities. Their reactivity is primarily mediated through acyl migration and/or nucleophilic displacement, and shorter acyl glucuronide half-lives are associated with increased reactivity. This reactivity can lead to metabolite-induced toxicity, posing a significant risk during drug development.

Methods: We developed regression models trained on features derived from Density Functional Theory (DFT) calculations to predict the half-lives of acyl glucuronide metabolites. The aim was to provide a computational tool to guide the design of drug candidates with more stable acyl glucuronide metabolites.

Results: The best-performing model achieved a strong correlation between predicted and experimental half-lives, with an R² of 0.67 on the test set. Predicted half-lives for drugs classified as clinically safe were longer than those for drugs in the warning and withdrawn categories, demonstrating a separation comparable to experimentally measured half-lives.

Discussion: The model is sufficiently accurate to support the optimization of acyl glucuronides for longer half-lives. Further analysis indicated that acyl glucuronide stability can be modulated by electron-donating and electron-withdrawing groups, effects that are effectively captured by the model.

Conclusion: This modeling approach can be applied during drug discovery to reduce the risk of metabolite-related toxicity by enabling in silico screening of compound modifications and ranking them based on predicted effects on acyl glucuronide half-life.

Introduction: Human hepatic carcinoma cell lines are widely used in vitro to study lipid and xenobiotic metabolism, as well as glucose regulation in both normal and diseased states. However, their validity is often questioned due to variability in protein expression compared to primary human hepatocytes (cHH). This study aimed to quantify protein abundance in various hepatic cell lines versus cHH and human liver tissue homogenate (HLT) using a data-independent acquisition-based total protein approach (DIA-TPA). We compared the global proteome from the whole cell homogenates of HepaRG, HepG2, and Huh7 cell lines with that of cHH and HLT.

Methods: Proteins in whole cell homogenates were digested in solution using pressure-cycling technology (PCT). DIA was performed via sequential window acquisition of theoretical mass spectra (SWATH-MS), and MS2 spectra were quantified using Spectronaut™, followed by analysis with TPA.

Results: We identified 2715, 2578, 2874, 2717, and 3083 proteins in HepaRG, HepG2, Huh7, cHH, and HLT, respectively, at a 1% FDR. The global proteome of cHH significantly differed from that of the cancer hepatic cell lines. Among the cell lines, the global and ADME protein profile of HepaRG most closely correlated with cHH, with 89 out of 101 ADME proteins identified. Clinically relevant DMEs from the CYP450 family (CYP2C9, CYP2C19, CYP2D6, and CYP3A4) and the UGT family (UGT1A1, UGT1A3, UGT1A6, UGT2B7, and UGT2B15) were quantifiable in human hepatocytes, human liver tissue, and the HepaRG cell line. The Huh7 cell line exhibited a higher abundance of proteins related to gluconeogenesis and glycolysis compared to other groups.

Conclusion: This study highlights the potential of untargeted global proteomics in detecting differences in protein expression among various hepatic cell lines and provides a comprehensive database to inform the choice of the cell line in future studies.