Current Drug Metabolism - Online First

Type 2 Diabetes (T2D) presents a significant global health challenge, characterized by persistent hyperglycemia and insulin resistance, with effective long-term glycemic control remaining a critical unmet need. Geraniol, a naturally occurring monoterpene alcohol, holds promising antidiabetic potential but is limited by poor water solubility, which restricts its therapeutic application. This study focuses on the formulation and CCD-based optimization of geraniol-loaded niosomes. Additionally, to assess its antidiabetic effect, blood glucose levels were evaluated.

Geraniol-loaded niosomes were formulated using the thin-film hydration technique. A central composite design was generated using Design Expert software to evaluate the impact of Span 40 and cholesterol concentrations on dependent variables such as particle size and encapsulation efficiency. A streptozotocin-induced diabetic model was used to assess the in vivo antidiabetic effect of the geraniol-loaded niosomes.

Using the thin-film hydration technique and CCD optimization, the niosomes demonstrated favorable characteristics, including an average particle size of 287.7 nm, an entrapment efficiency of 80.13%, and a zeta potential of –25.46 mV. Geraniol-loaded niosomes produced a notable hypoglycemic effect, reducing blood glucose levels from 275 ± 0.28 mg/dL to 150 ± 0.20 mg/dL by day 21. Although slightly less potent than metformin (117 ± 0.93 mg/dL), the formulation showed significantly better efficacy than both the diabetic control and plain geraniol solution groups.

Pharmacokinetic analysis revealed that the AUC, AUMC, and MRT of the geraniol-loaded niosomal formulation were approximately 1.5-, 4-, and 3-fold higher, respectively, compared to plain geraniol. These findings indicate that niosomal formulations improve bioavailability while providing sustained and prolonged drug release.

Overall, these results highlight the potential of geraniol-loaded niosomes as an innovative and effective strategy for managing T2D, supporting further clinical research to explore their therapeutic application in addressing this global health challenge.

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.

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.

Eight studies met the inclusion criteria, mostly involving adult gout patients. Pharmacokinetic analyses of oxypurinol employed a one-compartment model, incorporating first-order 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.

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.

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.

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

A systematic literature search following PRISMA 2020 guidelines was conducted across PubMed, Scopus, Web of Science, and Google Scholar. Studies published between 2020 and 2025 were prioritized, 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 neurobehavioral or molecular outcomes.

Neurotoxicants such as chlorpyrifos, bisphenol, triphenyl phosphate, aluminum, ammonium acetate, 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, neurotransmitter imbalances, oxidative stress, and gene or protein expression changes related to brain function. Analysis of the transgenic zebrafish revealed notable alterations in neuronal development and axonal morphology upon exposure to various neurotoxic chemicals.

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.

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.

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.

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.

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.

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.

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.

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

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.

Modulating the gut microbiome, particularly through microbial flavonoid production, represents a promising therapeutic avenue. However, most evidence remains preclinical, 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.

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.

Ricinoleic acid (RA), a fatty acid derived from castor oil (Ricinus communis), exhibits potent antioxidant activity and hepatoprotective properties, primarily attributed to its ability to mitigate oxidative stress. However, its therapeutic application is limited by poor bioavailability due to high metabolism, low intestinal permeability, poor water solubility, rapid urinary and biliary elimination, frequent dosing requirements, and a short half-life. This study aimed to optimize the formulation of ricinoleic acid-loaded chitosan nanoparticles (RA-CSNPs) for improved delivery and bioavailability using the ionic gelation technique.

The formulation was developed using chitosan as the polymer and sodium tripolyphosphate (STPP) as the cross-linking agent. The synthesized nanoparticles were characterized for particle size (PS: 164.15 nm), polydispersity index (PDI: 0.259), zeta potential (ZP: +30.25 mV), and entrapment efficiency (EE: 97.07%) and drug release within 24 hours. Structural and thermal properties were assessed using differential scanning calorimetry (DSC), X-ray diffraction (XRD), and Fourier-transform infrared spectroscopy (FTIR).

The in vitro drug release profile of the RA-CSNPs showed a cumulative release of 92.12%, demonstrating significant controlled release. Additionally, the antioxidant activity was measured at 84.45%, indicating that RA retained its bioactivity in the nanoparticle formulation.

These results highlight the potential of RA-CSNPs as an effective drug-delivery system to overcome the bioavailability challenges of ricinoleic acid. The controlled release and antioxidant activity of the formulation are promising for therapeutic applications in various oxidative stress-related diseases. However, limitations in scaling up nanoparticle production and conducting long-term pharmacokinetic studies need to be addressed in future research.

This study successfully demonstrates the potential of RA-loaded chitosan nanoparticles as a novel and efficient drug delivery system. The formulation provides controlled release, enhancing the bioavailability of ricinoleic acid and offering a promising strategy for improving its therapeutic efficacy in clinical applications.