Journal of Pharmacy and Pharmacology最新文献

Objectives: Pazopanib is an anti-angiogenic small molecule tyrosine kinase inhibitor approved for use in the treatment of advanced renal cell carcinoma and advanced soft tissue sarcoma. This review provides an overview of pazopanib pharmacokinetics and therapeutic drug monitoring.

Key findings: Pazopanib exhibits a multifaceted pharmacokinetic profile characterized by low and pH-dependent solubility, non-linear absorption, and time-dependent decreases in systemic exposure. Research to date has revealed numerous intrinsic and extrinsic factors significantly influencing pazopanib pharmacokinetics, including food interactions, use of gastric acid suppressants, drug-drug interactions with concomitant medications and genetic polymorphisms. Pazopanib plasma trough concentrations > 20.5 and ≥ 27 μg/ml are associated with improved efficacy in patients with renal cell carcinoma and soft tissue sarcoma, respectively, and increased pazopanib systemic exposure is associated with increased incidence of drug-related adverse events (e.g. hypertension).

Conclusion: Pazopanib exhibits large variability in systemic exposure and consequently, achieving systemic exposures within a therapeutic range for optimal efficacy while minimizing toxicity, can be challenging when a fixed dose is used. Therefore, therapeutic drug monitoring may be a promising tool to optimize the efficacy of pazopanib while limiting drug-related toxicities, through personalized dose adjustments guided by monitoring plasma pazopanib concentrations. Further exploration into the influence of additional factors on pazopanib pharmacokinetics is essential for advancing pharmacokinetic-guided dosing strategies and improve treatment outcomes.

Background: Drug resistance critically impedes renal cell carcinoma therapy. A dual-targeted liposomal system that codelivered resveratrol (RES) and paclitaxel (PTX) with αvβ3 integrin-targeting was developed to overcome multidrug resistance (MDR).

Methods: RGDfC peptide-functionalized liposomes (PTX/RES-RGDfC-Lip) were synthesized via film hydration-ultrasound methods. The particle size, zeta potential, drug encapsulation efficiency, and release kinetics were evaluated. P-glycoprotein (P-gp) modulation, cellular uptake, and chemosensitization in PTX-resistant A498 cells (PTX-res-A498) and in vivo antitumor efficacy were studied in xenograft models.

Results: The RGDfC ligand enables selective tumor delivery by binding to αvβ3 integrins that are overexpressed in the renal carcinoma vasculature, whereas RES enhances PTX efficacy by modulating P-gp-mediated drug efflux. Liposomes were synthesized via film hydration-ultrasound methods and systematically characterized for size (109.8 ± 4.2 nm), zeta potential (-8.91 ± 0.75 mV), dual-drug encapsulation efficiency (RES: 90.56 ± 4.30%; PTX: 90.23 ± 4.66%), and sustained release kinetics. In vitro studies demonstrated 3.19-fold greater cellular uptake in resistant renal carcinoma cells (PTX-res-A498 cells) than in nontargeted formulations. In vivo, PTX/RES-RGDfC-Lip resulted in 70.2% tumor reduction in xenograft models. Mechanistic studies confirmed the RES-mediated downregulation of P-gp expression and the restoration of chemosensitivity.

Conclusion: This dual-targeted codelivery system represents a promising strategy for overcoming MDR in advanced renal carcinoma.

Objectives: The primary aim was to characterize the influence of diet-induced obesity on the stereoselective pharmacokinetics of racemic bupivacaine in male and female rats.

Method: Rats were fed either a standard diet (StdD) or high-fat diet (HFD) for 12 weeks. A stereoselective assay was used to measure plasma concentrations after subcutaneous injection of racemic bupivacaine. A rich sampling protocol was initially employed for cannulated rats, while a sparse sampling in non-cannulated rats, coupled with Bayesian forecasting, was used in dietary assessment.

Key findings: Clearance (CL) of both enantiomers was significantly reduced in males fed HFD. StdD females had lower peak concentrations and longer elimination phases than StdD males. Stereoselectivity was modest, with the d-enantiomer displaying marginally higher CL than antipode. There was an apparent late-absorption peak with rich sampling.

Conclusion: Bupivacaine exhibits modest stereoselectivity in rats, with diet and sex influencing CL. The application of Bayesian forecasting in sparse sampling models in rats proved to be a robust tool for pharmacokinetic assessment, aligning with the goals of reducing numbers, refining experimental design and replacing invasiveness of procedures in the use of animals.

Objectives: Although HER2 overexpression is observed in only 2%-3% of colorectal cancer (CRC) patients, its amplification can function as a compensatory mechanism that drives CRC resistance to targeted therapy. 1,2,3,4,6-Penta-O-galloyl-β-d-glucose (PGG) has been reported to possess anti-tumor and anti-metastatic activities in CRC. Nevertheless, the molecular targets through which PGG exerts its effects in CRC remain unclear. This study aimed to evaluate the role of HER2 as a potential molecular target of PGG in CRC.

Methods: Ultra performance liquid chromatography-mass spectrometer (UPLC-MS) was employed to determine the cellular uptake of PGG in HCT116 cells. Potential PGG targets were predicted using STITCH and molecular operating environment platforms. Functional rescue assays were performed with lapatinib, a HER2 inhibitor. Direct PGG-HER2 interactions were validated by drug affinity responsive target stability and thermal shift assays. Downstream signaling effects were examined by assessing HER2 expression and its downstream pathway by Western blotting.

Key findings: UPLC-MS analysis confirmed the accumulation of PGG (204.5 ± 19.1 ng) in HCT116 cells after 40 μM PGG treatment for 12 h. Computational predictions suggested ErbB2 (HER2) as a potential binding target. Rescue experiments showed that the combination of lapatinib and PGG failed to further reduce cell viability when compared with lapatinib alone, implying HER2 as a molecular target of PGG. Both drug affinity responsive target stability and thermal shift assays verified that PGG protects HER2 from pronase-induced degradation and enhances its stability upon thermal challenge, indicating direct binding. Mechanistically, PGG suppressed HER2 expression and inhibited the PI3K-Akt-mTOR pathway, a canonical downstream pathway of HER2.

Conclusions: Our findings provide a strong preclinical rationale for future clinical trials of PGG as a HER2-targeted drug in CRC and highlight its considerable potential as a novel therapeutic for CRC treatment.

Objective: To investigate the mechanism and pharmacological activity of (Xiaoyaosan decoction) XYSD in the treatment of NAFL (nonalcoholic fatty liver) by proteomic techniques.

Methods: C57BL/6 mice NAFL model was induced by HFD (high fat diet), and observed biochemical indicators and histopathological changes. We employed TMT (tandem mass tag) quantitative proteomics and conducted bioinformatics analysis. Additionally, an in vitro model using unsaturated FFA (free fatty acid)-induced lipid accumulation was established to discover the effect of XYSD on lipid accumulation in HepG2 cells.

Results: The results showed that XYSD improved liver index and biochemical indexes, and reversed the characteristics of liver steatosis in NAFL mice. Based on the results of in vivo proteomic enrichment analysis, we hypothesize that the activation of the PPARα signaling pathway may be a potential mechanism underlying the therapeutic effect of XYSD in treating NAFL. XYSD remarkably improved protein and gene expression of Fads2 (fatty acid desaturase 2), Hmgcs2 (3-hydroxymethylglutaryl-CoA synthase 2), Fabp1 (fatty acid-binding protein 1) and PPARα. This hypothesis has been further confirmed in our in vitro experiments.

Conclusion: The study shows that XYSD improves lipid accumulation by activating PPARα signaling pathway, and finally achieves the effect of NAFL.

Objectives: Co-administration of multiple drugs typically induces drug-drug interactions (DDIs). DDIs have the potential to exert significant effects on the pharmacokinetics and therapeutic efficacy of the drugs employed. The treatment for estrogen receptor-positive (ER+) breast cancer is advancing with the incorporation of third-generation selective CDK4/6 inhibitors, such as abemaciclib. Honokiol, a bioactive phytochemical derived from Magnolia species, possesses broad anti-cancer actions. The study aimed to, in vitro and in vivo, investigate the impact of honokiol on the pharmacokinetics of abemaciclib.

Methods: To measure the IC50 values of honokiol on abemaciclib in vitro, rat liver microsomes (RLMs) were used. Eighteen Sprague-Dawley rats were randomly assigned to three groups: honokiol multiple-dose, honokiol single dose and control. All rats received a 10 mg/kg (high energy diet: 1.6 mg/kg) dose of abemaciclib. The plasma concentration of abemaciclib was measured utilizing ultra-performance liquid chromatography-tandem mass spectrometry (UPLC/MS-MS) technique. Molecular docking was performed with AutoDock software to analyse the binding energies of honokiol and abemaciclib to CYP3A4.

Key findings: IC50 values for abemaciclib were determined in vitro in RLMs at 27.6 μM. The results showed that the values of area under the plasma concentration and mean residence time of abemaciclib were significantly increased and the values of Cmax and Tmax were significantly extended when rats were pretreated with honokiol. In contrast, our results revealed that CLz/F values were markedly decreased (P < .05). Honokiol and abemaciclib possess the amino acid residue ALA370 as their binding site, which may explain why they compete for metabolism via the CYP3A4 enzyme.

Conclusions: Honokiol and abemaciclib show significant DDIs in vitro and in vivo and more attention is required when administered synchronously.

Objectives: Formononetin (FMN) is known for its significant neuroprotective effects, this study aims to investigate the antidepressant potential and underlying mechanisms of FMN.

‌methods: Antidepressant efficacy was evaluated in corticosterone (CORT)-induced depression models. In vivo, CORT-exposed mice received FMN to assess behavioral and hippocampal changes (dendritic spine density, synaptic markers: MAP-2/GAP-43). In silico, network pharmacology and molecular docking predicted FMN's binding affinity and enriched pathways. In vitro, HT22 cells pretreated with FMN (10 μM, 6 h) were subjected to CORT injury, with mechanistic validation via ERα antagonist (MPP) and ERK inhibitor (PD98059).

Key findings: FMN alleviated depressive-like behaviors and preserved hippocampal integrity in mice. Bioinformatics analysis revealed FMN's strong binding to ER subtypes and enrichment in estrogen/MAPK pathways. In vitro, FMN pretreatment activated the ERK-CREB-BDNF axis in CORT-injured HT22 cells, enhancing neuronal survival and synaptic function. The activation was ERα/ERK-dependent, as evidenced by the abolition of protective effects following pharmacological inhibition with MPP (ERα antagonist) or PD98059 (ERK inhibitor). Concomitantly, in vivo FMN treatment restored hippocampal p-ERK/ERK ratios in mice, directly corroborating the ERK-CREB-BDNF pathway activation and highlighting its efficacy in reversing CORT-induced signaling deficits.

Conclusion: FMN exerts antidepressant effects via ERα-mediated neurotrophic signaling (ERK-CREB-BDNF), offering a mechanistic foundation for natural antidepressant development.

Objectives: β-Caryophyllene (β-Cary) is known for its anti-inflammatory properties and offers a promising avenue for drug development. This study prepared a lipid-based self-emulsifying system containing clove oil-derived β-Cary and investigated its bioavailability and anti-inflammatory effects upon oral administration in rats.

Methods: The formulation (β-SNEDDS), composed of β-Cary, surfactant, and lipophilic phase, was evaluated as size, morphology, and rheology.

Key findings: β-SNEDDS exhibited Newtonian flow and formed spherical droplets (≈100 nm) in water and phosphate-buffered saline (pH 6.8), with a diameter ~15% higher in PBS, likely due to ionic strength affecting surfactant hydration and interfacial structure. Transmission electron microscopy confirmed spherical particles in simulated gastrointestinal medium. β-SNEDDS showed twice the oral bioavailability of β-Cary. This phenomenon allowed β-SNEDDS to reduce carrageenan-induced paw edema and pleural polymorphonuclear leukocyte recruitment in the pleural cavity of rats, showing greater efficacy than β-Cary. Furthermore, β-Cary reduced N-Formyl-Met-Leu-Phe (fMLP)-induced leukocyte chemotaxis in vitro, and oral β-SNEDDS or β-Cary reduced rolling and adherent leukocytes in situ in rat microvascular endothelium. Notably, β-SNEDDS exhibited a more pronounced effect on rolling behavior.

Conclusions: β-Cary showed significant anti-inflammatory activity by inhibiting leukocyte migration to the inflamed site. Its β-SNEDDS formulation improved oral bioavailability and additional anti-inflammatory parameters in vivo, beyond those achieved by β-Cary, supporting this approach as a promising oral strategy.

Objectives: This study investigated the effects of pigment epithelium-derived factor (PEDF) on bone homeostasis in a glucocorticoid-induced osteoporosis (GIOP) rat model, focusing on prostaglandin E2 receptors EP2 and EP4.

Methods: Male Sprague-Dawley rats were divided into six groups. Dexamethasone (DEX, 1 mg/kg) was administered intramuscularly twice weekly for 90 days to induce osteoporosis. PEDF (50, 100, 200 mg/kg) was then given subcutaneously for 30 days. Bone mineral density (BMD) and bone morphology were assessed by computed tomography. Bone turnover markers-C-terminal telopeptide of type I collagen (CTX-1), tartrate-resistant acid phosphatase 5b (TRAP-5b), and bone-specific alkaline phosphatase-as well as EP2/EP4 mRNA expressions were evaluated using qRT-PCR.

Key findings: Immunohistochemical analysis was performed for ALP, osteopontin, osteocalcin, and VEGFR1. PEDF partially mitigated DEX-induced weight loss and dose-dependently restored BMD. Histopathological analyses showed improved bone architecture in all PEDF-treated groups. PEDF increased bone formation markers, reduced bone resorption markers, and upregulated EP2/EP4 expression.

Conclusion: These findings indicate that PEDF exerts protective effects against GIOP and may modulate bone metabolism through EP2/EP4 signalling pathways. PEDF shows promise as a potential therapeutic agent for preventing bone loss in GIOP.