Oral bioavailability of fenofibrate from melt-extruded phospholipid-containing solid dispersions: A rat study.

Characteristics of asymmetric microcrystalline solidification pellets and a better prediction for bioequiavailability based on solubility-permeability theory.

Determination of fenofibric acid in saliva and exhaled breath condensate samples using metal- organic frameworks based dispersive micro solid phase extraction coupled to HPLC-PDA.

Artocarpin alleviates fenofibrate-induced hepatic dysfunction via regulating NLRP3/caspase-1, oxidative stress and bile acids synthesis: A biochemical, histological, and computational investigation.

Co‐administration of atorvastatin and fenofibrate has demonstrated clinical benefits in patients with dyslipidemia. To improve convenience and adherence, a fixed‐dose combination (FDC) of the two agents has gained interest. This study aimed to compare the pharmacokinetics (PKs) and safety of an FDC of atorvastatin/fenofibrate 20/145 mg with the corresponding individual components. A randomized, open‐label, single‐dose, two‐sequence, two‐treatment, four‐period full replicated crossover study was conducted. Participants were randomly assigned to one of the two sequences and received FDC or individual components. PK parameters were estimated using a non‐compartmental method. The geometric mean ratio (GMR) and its 90% confidence interval (CI) of the FDC to the individual components were calculated using mixed effect model. A total of 36 participants completed the study. The GMRs (90% CIs) for maximum plasma concentration and area under the time‐concentration curve from zero to the last measurable point were 1.1038 (0.9985‐1.2202) and 1.0148 (0.9745–1.0567) for atorvastatin, 1.0032 (0.9261‐1.0867) and 0.9882 (0.9520–1.0258) for 2‐OH atorvastatin. For fenofibric acid, the corresponding values were 0.9896 (0.8810‐1.1116) and 0.9871 (0.8869‐1.0986), respectively. The FDC of atorvastatin/fenofibrate 20/145 mg showed comparable PK profiles to the corresponding individual components, supporting its potential as an alternative therapeutic option for dyslipidemia with convenience.

Abstract This work develops and validates a green reverse-phase “high-performance thin-layer chromatography (HPTLC)” methodology for measuring fenofibrate (FEN) and rosuvastatin (ROS) concurrently in commercially available fixed-dose combination (FDC) tablets. A green developing system comprising ethanol, water, and ammonia solution (25 % for HPLC) in a 65:30:5 (v/v/v) ternary ratio was used to analyze FEN and ROS concurrently. At a wavelength of 265 nm, FEN and ROS were both concurrently measured. The method’s greenness profile was evaluated using three different greenness methodologies: the analytical eco-scale (AES), chloroform toxicity (ChlorTox), and the analytical GREEnness (AGREE). The developed method was linear for both drugs in the 20–1,200 ng/band range. The developed method was validated and shown to be reliable, sensitive, accurate, precise, and eco-friendly. The results of every greenness tool, such as AES (87), ChlorTox (0.78 g), and AGREE (0.78) demonstrated that the proposed method had an exceptionally greenness profile. The levels of FEN and ROS in two different marketed FDC products were found to be within the 100 ± 2 % limit using the current methodology. The study’s findings demonstrated that the suggested technique could reliably evaluate FEN and ROS in commercially available products.

Nanoparticles-mediated mitochondrial relocation of lipid-lowering drugs shape energy metabolism to conquer acquired immune resistance.

Osteoarthritis (OA) progresses via a destructive cycle involving cartilage damage, friction, lubrication loss, and chondrocyte senescence. Current therapies, limited to temporary lubrication or pain relief, fail to halt OA due to their inability to repair cartilage or restore innate lubrication. To address this challenge, an asymmetric Janus graphene oxide (MGO) nanoplatform is engineered and functionalized with the anti-senescence agent Fenofibrate (FN), creating the MGO-FN system. This integrated design features one side providing robust cartilage adhesion and the opposing side offering superior lubrication, while simultaneously delivering the therapeutic FN. Critically, the nanoscale MGO-FN effectively infiltrates and fills micro-damage on the cartilage surface, enabling localized and sustained FN release. This maximizes drug bioavailability at the target site by minimizing diffusion distances. In vitro, MGO-FN demonstrated potent synergistic effects, significantly enhancing chondrocyte proliferation and extracellular matrix synthesis, reducing senescence, and upregulating the lubrication marker PRG4 more effectively than either component alone. In vivo OA rat studies, supported by transcriptomics analysis, validated MGO-FN's potent therapeutic effects, including reduced cartilage degradation, mitigated inflammation, promoted matrix regeneration, and restored innate lubrication. These findings underscore MGO-FN as a promising multifaceted therapeutic strategy to halt OA progression by concurrently restoring cartilage integrity and lubricating function.

Carrageenan-based multi-unit spheroidal tablets for fenofibric acid: A strategy to minimize food effect via mucoadhesive gel interfaces

Dietary modification in early life can either increase susceptibility or improve resistance to metabolic diseases in adulthood. This study evaluated the potential of lycopene to mitigate metabolic derangements caused by a high-fructose diet in rats mimicking adolescents fed a high-fructose diet. Ninety-six weanling Wistar rats (male and female, aged 21 days) were randomly allocated to six treatment groups: (1) standard rat chow (SRC), plain drinking water (PDW), and plain gelatin cubes (PG); (2) SRC + PDW + 20% fructose solution (FS); (3) SRC + FS + 100 mg/kg fenofibrate (FENO) + PG; and (4-6) SRC + FS with lycopene at 30, 60, and 100 mg/kg/day, respectively, for 12 weeks. Body mass, feed, and fluid intake were measured twice weekly. At termination, rats were fasted overnight, weighed, euthanized, and assessed for gastrointestinal viscera, femora, and tibiae parameters, including mass and length, with bone mass-to-length ratios computed. The rats grew significantly (P < .05) during the trial. Control males had higher mean weekly body mass than medium-dose lycopene-supplemented rats (weeks 3-4) and fenofibrate-treated rats (weeks 10-12), and higher terminal body mass than fructose-fed and fenofibrate groups (P < .05). In both sexes, controls had greater total feed intake (TFI) than all groups (P < .05). Lycopene reduced TFI but increased fluid intake compared with control and fenofibrate-treated groups (P < .05). Fenofibrate increased total calorie intake in females compared with all groups and in males compared with fructose-fed and lycopene-supplemented groups (P < .05). Lycopene-supplemented males had heavier femora and longer tibiae than fenofibrate-treated counterparts (P < .05). Medium- and high-dose lycopene increased stomach mass in males compared with controls, while low-dose lycopene reduced small intestine mass compared with fenofibrate (P < .05). Lycopene may support bone health, enhance gastric function, and prevent fenofibrate-induced bone loss in male Wistar rats.

Objective: This study aimed to improve the solubility and dissolution rate of a fixed-dose combination of atorvastatin (ATR) and fenofibrate (FEN) characterized by poor solubility via solid dispersion techniques. Methods: Soluplus and Kollidon were used for formulating binary solid dispersion (BSD), and PVP and Kollidon were used for ternary solid dispersion (TSD) employing the solvent evaporation technique. Saturation solubility studies and in vitro drug release were done to quantify improvements in solubility and drug dissolution. Further characterization of solid dispersions was carried out by differential scanning calorimetry (DSC), scanning electron microscopy (SEM), X-ray diffraction (XRD), and Fourier-transform infrared spectroscopy (FTIR). Results: Among binary systems, the SF8 formulation (drug-to-Soluplus® ratio of 1:4) showed an edge in solubilization enhancement, dissolution rate, and other physicochemical properties. The ternary composition KDF11 exhibited the best performance in terms of solubility and dissolution rate. In vivo, pharmacokinetic studies reaffirmed that drug bioavailability was greatly improved. SF8 BSD increased solubility by 17-fold. ATR solid dispersion produced 2.87 times more Cmax and 2.56 times more AUC₀–₂₄ₕ while FEN nanoformulation produced 3.56 times more Cmax and 3.44 times more AUC₀–₂₄ₕ after their pure drug counterparts. Cmax increased 2.87-fold for ATR. These increases can be understood to be attributed to the conversion of the crystalline structure into an amorphous state, thereby enhancing solubility and facilitating a more favorable concentration gradient across gastrointestinal and systemic barriers. Conclusion: The study demonstrated that in the ternary system, solid dispersion formulations were very much better than binary dispersions in improving the solubility and dissolution of poorly soluble drug combinations. TSD offers a viable strategy for enhancing FDC bioavailability with potential application in the effective management of hyperlipidemia.

BackgroundNon-alcoholic fatty liver disease (NAFLD) is a prevalent chronic hepatic condition that can progress to non-alcoholic steatohepatitis (NASH) through inflammatory processes.ObjectivesThis research aimed to examine the impact of an aqueous extract of Capparis spinosa fruit and the lipid-lowering agent fenofibrate (FENO) on hepatic inflammation and steatosis in rats subjected to a high-fat emulsion.MethodsMale Wistar rats were given a high-fat diet (HFD) to develop NASH. The high-fat treated rats were categorized into three groups and administered either C. spinosa, FENO, or a vehicle control. Histopathological analyses, Liver Index computation, and measurements of body and liver weights were conducted. Serum levels of liver enzymes, adiponectin, and leptin were also assessed. Additionally, the expression of hepatic genes for monocyte chemoattractant protein 1 (MCP-1), transforming growth factor-beta (TGF-β), interleukin 6 (IL-6), and tumor necrosis factor-alpha (TNF-α) was evaluated.ResultsThe administration of C. spinosa extract to the NASH model rodents significantly increased their adiponectin levels while substantially decreasing their levels of leptin, alanine aminotransferase (ALT), and aspartate transaminase (AST). Hepatic steatosis, liver inflammation, and collagen deposition were significantly reduced by C. spinosa treatment. Furthermore, the hepatic mRNA expression of the proinflammatory cytokines TNF-α, IL-6, and MCP-1, as well as the hepatic fibrogenic marker TGF-β1, was significantly reduced by C. spinosa treatment. The FENO exhibited a comparable pattern of response.ConclusionsOur findings suggest that C. spinosa has a positive anti-inflammatory effect and may protect the liver against hepatic fibrosis, inflammation, and steatosis. These findings demonstrate the promising therapeutic potential of C. spinosa in the management of NASH.

This study provides insights into the in vivo performance of amorphous solid dispersion (ASD) formulations of a poorly water-soluble drug through deconvolution analysis using a surrogate marker for drug release. Carbamazepine (CAR) and fenofibrate (FEN) were used as surrogate markers of drug release from formulations and as a model of a poorly water-soluble drug, respectively. Three ASDs containing CAR (3 wt %) and FEN (30 wt %) were prepared using hydroxypropyl methylcellulose (HPMC) with immediate-release characteristics (ASD-HPMC) and two HPMC derivatives (HPMC acetate succinate, HPMCAS) exhibiting different pH-dependent drug release profiles (ASD-HPMCAS-LF and ASD-HPMCAS-HF). The in vitro drug release profiles of FEN for each ASD were comparable to those of CAR, with both compounds demonstrating polymer-dependent release behavior (release rate: ASD-HPMC > ASD-HPMCAS-LF > ASD-HPMCAS-HF). Slower FEN release prolonged the time to reach the maximum concentration; however, the maximum concentration itself was not affected. The improved oral FEN absorption in rats ranked as follows: ASD-HPMC > ASD-HPMCAS-HF > ASD-HPMCAS-LF, while CAR was completely absorbed regardless of the polymer used. Plasma CAR profile deconvolution analysis revealed that the in vivo drug release profiles corresponded to the in vitro release results. In the FEN absorption rate time-profiles, a hybrid parameter combining the drug concentration and absorption clearance, derived from deconvolution analysis, showed that ASD-HPMC maintained a relatively high and stable absorption rate until complete absorption. Conversely, ASD-HPMCAS-LF exhibited a half absorption rate compared to ASD-HPMC over 1.5 h, which then declined rapidly, resulting in limited FEN absorption improvement. For ASD-HPMCAS-HF, the absorption rate gradually increased and remained at half the rate compared to ASD-HPMC over 6 h, leading to an intermediate improvement in FEN absorption in three ASDs. These differences in absorption rate profiles indicate that drug release profiles significantly affect the amount of dissolved FEN, its retention time in the gastrointestinal tract, and the effective surface area available for absorption. This study demonstrates that the proposed method enables reliable evaluation of the in vivo performance of ASD formulations.

We evaluated the effects of fenofibrate (FF) in a SU5416/hypoxia model of pulmonary arterial hypertension (PAH) with a specific focus on its influence on the renin–angiotensin system (RAS). We assessed right ventricular systolic pressure (RVSP), mean pulmonary artery pressure (mPAP), medial pulmonary artery wall thickening, right ventricular (RV) hypertrophy, systolic pulmonary artery pressure (SPAP), pulmonary artery effective elastance (PAEa), RV diastolic pressure (RVDP), RV developed pressure (RVDevP), right ventricular–pulmonary arterial coupling index (RVPAC), RV dp/dt max and dp/dt min. Levels of angiotensin II, angiotensin (1–7), angiotensin-converting enzyme 2 (ACE2), Bmpr2, Smad5 and nitrite (NO2−) and nitrate (NO3−) in the lung and RV were evaluated. The expression of AT1R, MAS receptors, and ACE2 in lung tissue was assessed. FF prevented the increase in RVSP, mPAP, RV hypertrophy, reduced pulmonary arterioles remodeling, and attenuated the rise in SPAP, mPAP, and PAEa. In the RV, it reduced RVDevP and prevented the decrease in dp/dt min, without affecting RVDP. RVPAC showed partial improvement. In lung tissue, FF decreased angiotensin II levels, the Ang II/Ang-(1–7) ratio, and reduced angiotensin II receptor type 1 (AT1R) expression, while preserving the receptor for the angiotensin-(1–7) (MAS) and ACE2. FF tended to restore Bmpr2/Smad5 expression. NO2− levels were preserved and tended to preserve (NO3−) levels. In the RV, Ang-(1–7) increased, ACE2 was preserved, and NO2− and NO3 levels were maintained. FF exerts protective effects in Su/Hx-induced PAH.

BackgroundHeart failure (HF) pathology is complex and seriously life-threatening. SGLT2 inhibitors, as one of the new quadruple drugs for HF treatment, have a complex mechanism for improving HF. Energy metabolism is one of the important aspects of HF pathology, and the PPARα signaling pathway plays an important role in energy metabolism. Therefore, this study aims to observe changes in the PPARα signal transduction pathway in chronic HF by 18F-FDG MicroPET/CT imaging. Based on the myocardial metabolic imaging of 18F-FDG MicroPET/CT, this study aims to verify the mechanism of SGLT2 inhibitor treatment in rats with HF through the PPARα signal transduction pathway of energy metabolism and provide an imaging diagnostic basis.ResultsIn 18F-FDG PET/CT myocardial metabolic imaging, pretreatment myocardial glucose metabolism rate (MRGlu) levels in the HC group of HF rats were significantly higher than that in the other three groups. Post-treatment, MRGlu and glucose uptake decreased markedly in the empagliflozin (EMPG) group, while no significant changes were observed in the fenofibrate (FF) group. Compared with normal healthy rats, HF model rats showed a significant increase in MRGlu, and the expression of the lipid metabolism pathway proteins (PPARα, RXRα, CPT1α, and CD36) and the energy metabolism pathway proteins (AMPKα and sirt1) were significantly inhibited, while the expression of the glycolytic pathway protein (GLUT4) was enhanced. After 4 weeks of drug treatment in HF model rats, EMPG showed the same lipid metabolism pathway proteins (PPARα, RXRα, and CPT1α) and energy metabolism pathway proteins (AMPKα and sirt1) as FF, but only EMPG showed a significant decrease in MRGlu, inhibition of glycolytic pathway protein (GLUT 4) expression, and decreased cardiac fibrosis in HF rats.ConclusionThis study led to the following conclusions. 1) Rats with HF showed a significant increase in MRGlu compared with healthy rats. 2) Empagliflozin can improve the energy supply efficiency of the heart in rats with chronic HF by inhibiting glucose metabolism and promoting lipid metabolism, thereby ameliorating energy metabolism in chronic HF. 3) 18F-FDG MicroPET/CT can observe the energy metabolism changes of HF, and the MRGlu can provide quantitative data for the changes of HF energy metabolism.

PTPN14 is a non-receptor tyrosine phosphatase that functions as a tumor suppressor through negative regulation of the Hippo signaling pathway, making it a potential therapeutic target for cancer. Despite its therapeutic potential, no PTPN14-targeting drugs have been developed to date. In this study, we discovered fenofibrate (FF), a small-molecule commonly used as a lipid-lowering agent, exhibits potent anti-proliferative and anti-migratory properties. Mechanistically, FF was found to directly bind the PPxY motif of PTPN14, facilitating formation of a complex with LATS1 and MARK3, which promotes cytoplasmic sequestration of YAP. Furthermore, genetic knockdown of PTPN14 or pharmacological inhibition of MARK3 substantially abolished the FF-mediated inhibition of malignant phenotypes, indicating the critical role of the PTPN14/MARK3/Hippo signaling axis in tumor progression. Notably, our findings demonstrate that FF enhances the antitumor effects of conventional chemotherapeutics in melanoma, colorectal carcinoma, and ovarian carcinoma. These results establish PTPN14 as a therapeutically actionable target and expand the clinical potential of FF beyond its metabolic applications, offering a novel strategy for cancer treatment.

Background/Objectives: This study aimed to develop a novel amorphous solid dispersion (ASD) platform using poly(2-ethyl-2-oxazoline) (PEtOx) for the solubility enhancement of poorly water-soluble drugs. Fenofibrate (FB), a Biopharmaceutics Classification System (BCS) Class II drug, was selected as the model drug. The novelty of this work lies in the formulation of dual-matrix systems by blending PEtOx of varying molecular weights (50 kDa, 200 kDa, 500 kDa) with solubility-enhancing polymers, Soluplus® and Kollidon® VA64, to investigate component compatibility, synergistic solubility enhancement, and the influence of PEtOx molecular weight on drug release. Methods: ASDs were prepared via hot-melt extrusion (HME) and characterized using differential scanning calorimetry (DSC), scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), and Fourier transform–infrared spectroscopy (FTIR) to confirm FB amorphization and evaluate drug–polymer interactions. In vitro dissolution testing was performed to assess drug release performance, and stability studies were conducted at ambient conditions for one month to evaluate physical stability. Results: DSC, PXRD, and FTIR confirmed the successful amorphization of FB and good miscibility between PEtOx and the selected excipients. In vitro dissolution studies showed an 8–12-fold increase in FB release from ASDs compared to crystalline drug. Lower-molecular-weight PEtOx grades yielded faster release profiles, while binary blends with Soluplus® or Kollidon® VA64 enabled tailored drug release. Stability testing indicated that all formulations maintained their amorphous state over one month. Conclusions: PEtOx-based ASDs represent a versatile platform for enhancing the solubility and dissolution of poorly water-soluble drugs. By adjusting polymer molecular weight and combining with complementary excipients, release profiles can be optimized to achieve improved performance and stability.

The presence of pharmaceuticals in water poses emerging environmental risks to aquatic ecosystems and potentially human health. This study investigates the occurrence and ecological threat of antiepileptic drugs and lipid-lowering agents in surface water, specifically in the Cauca River, one of the most important rivers in Colombia. Quantification was conducted using liquid chromatography coupled with mass spectrometry. Additionally, conventional physicochemical parameters were evaluated. The hazard associated with the compounds was assessed using the persistence, bioaccumulation, and toxicity (PBT) index. The ecological threat was determined via the Hazard Quotient (HQ) and Toxic Units (TU). A literature review was also performed to evaluate existing treatment systems for their removal. Among a total of 11 pharmaceutical compounds analyzed, 5 were detected. The findings revealed the presence of antiepileptic drugs such as carbamazepine (CBZ), 10,11-dihydro-10,11-dihydroxycarbamazepine (CBZ-Diol), and gabapentin (GBP). Detected lipid-lowering agents included fenofibric acid (FFA) and gemfibrozil (GFZ). Concentrations of up to 92ng.L-1 were found for GFZ and CBZ-Diol. Physicochemical alterations were observed near wastewater discharge points. The PBT index indicated medium hazard for CBZ, CBZ-Diol, FFA, and GFZ, whereas the HQ revealed medium ecological risk for CBZ, with TUs corroborating these findings. Findings underscore the need for pharmaceutical monitoring and management in water sources. Removing these compounds remains challenging due to their variable removal patterns, necessitating the development of effective mitigation strategies.

ObjectiveThis study aimed to investigate the growth-inhibitory effects of fibrate lipid-lowering drugs on bladder cancer cells and their underlying mechanisms, with a focus on exploring how fenofibrate (FNF) exerts antitumor effects by regulating mitochondrial function, the AMPK/mTOR signaling pathway, and the immune regulatory molecule CD276.MethodsThe CCK-8 assay was used to determine the growth inhibition rates of FNF, bezafibrate (BZF), and clofibric acid (CLF) on MB49 cells and calculate their half-maximal inhibitory concentration (IC50). Mitochondrial respiratory chain complex activity assays, ADP/ATP ratio analysis, DCFH-DA fluorescent probe staining, and JC-1 staining were employed to evaluate the effects of FNF on mitochondrial function and oxidative stress. Western blot analysis, immunofluorescence (IF) staining, and treatment with the AMPK inhibitor Compound C were used to investigate the regulation of the AMPK/mTOR signaling pathway and CD276 expression by FNF. T cell cytotoxicity assays and cytokine detection were performed to validate the impact of FNF on T cell antitumor activity. CD276-knockdown stable MB49 cell lines and nude mouse xenograft models were constructed to assess the inhibitory effect of CD276 depletion. Hepatorenal biochemical indices (creatinine, blood urea nitrogen, alanine transaminase, aspartate transaminase) were measured to evaluate the safety of FNF in mice. Histological characteristics, CD276 expression, and T cell infiltration in tumor tissues were analyzed via H&E staining, immunohistochemistry (IHC), and IF staining.ResultsAll three fibrate drugs inhibited MB49 cell growth in a concentration-dependent manner, with FNF exhibiting the strongest inhibitory activity (IC50 = 129.23 ± 9.38 µM). FNF suppressed mitochondrial complex I activity, leading to impaired ATP synthesis, reactive oxygen species (ROS) accumulation, and mitochondrial membrane damage. It activated the AMPK/mTOR pathway and downregulated CD276 expression in a concentration-dependent manner, an effect reversible by the AMPK inhibitor. TIMER database analysis revealed a positive correlation between CD276 expression and genes encoding mitochondrial complex I subunits. FNF treatment enhanced the secretion of IFN-γ and TNF-α by T cells and significantly improved T cell-mediated killing of bladder cancer cells. Knockdown of CD276 suppressed bladder cancer cell proliferation in vitro and tumor growth in vivo without affecting mouse body weight. FNF showed no significant hepatorenal toxicity and exhibited a higher tumor inhibition rate (64.1%) than anti-CD276 monoclonal antibody (44.7%) in vivo, accompanied by increased infiltration of CD3+, CD4+, and CD8 + T cells in tumor tissues.ConclusionFibrate drug FNF exerts antitumor effects by targeting the mitochondrial complex I-AMPK/mTOR-CD276 axis, inducing mitochondrial dysfunction, and downregulating the immunosuppressive molecule CD276 to activate T cell-mediated antitumor immunity. This study provides a potential strategy for drug repurposing and identifies a novel target for immunotherapeutic combination strategies in bladder cancer.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12885-025-14855-w.

Immune regulation of TLR4/MYD88/ NF-κB/AP1/IL-6 pathway and modulation of aldosterone/PPARα receptors by eplerenone and fenofibrate in ovarian ischemia reperfusion induced injury.