European Journal of Pharmaceutical Sciences最新文献

{"title":"Drug Transporter - Enzyme Crossroads: Does OATP2B1 Shape Cyp3a-Driven Midazolam Metabolism in Rats?","authors":"Nikolaos Paloumpis, Marta Rysz, Noemi Bianchi, Isabell Seibert, Jonny Kinzi, Anima M Schäfer, Karin Brecht, Daniel Ricklin, Henriette E Meyer-Zu-Schwabedissen","doi":"10.1016/j.ejps.2025.107343","DOIUrl":"https://doi.org/10.1016/j.ejps.2025.107343","url":null,"abstract":"<p><p>OATP2B1, encoded by SLCO2B1, is an uptake transporter in liver. Humanized SLCO2B1^+/+ rats showed increased hepatic Cyp3a1 expression compared to rSlco2b1^-/- rats. To assess the impact of humanization on Cyp3a activity, we conducted a phenotyping study applying midazolam in SLCO2B1^+/+ and rSlco2b1^-/- rats. Analysis of the serum levels and pharmacokinetic parameters for midazolam, 1'-hydroxymidazolam and 4-hydroxymidazolam revealed no significant differences between humanized and rSlco2b1^-/- rats, indicating minimal impact of genotype on systemic exposure. In contrast, ex vivo experiments with liver microsomes from untreated male SLCO2B1^+/+ and rSlco2b1^-/- rats, showed slightly higher Cyp3a activity in the knockout group. To resolve this apparent discrepancy, we characterized midazolam metabolism using recombinant enzyme systems, where we found Cyp3a2 to exhibit a higher metabolic capacity for midazolam when comparing formation of both metabolites. Determination of transcript levels of Cyp3a isoforms in rat livers revealed consistently higher mRNA expression of Cyp3a2 irrespective of genotype. These findings suggest that Cyp3a2 is the predominant isoform responsible for midazolam metabolism in rats. The modestly elevated microsomal activity in rSlco2b1^-/- rats is therefore most likely attributable to the subtle variation in Cyp3a2 abundance. In conclusion, our findings indicate that even if OATP2B1 affects hepatic abundance of Cyp3a1 this does not translate into relevant changes in pharmacokinetics of midazolam most likely due to the dominance of Cyp3a2 in its metabolism.</p>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":" ","pages":"107343"},"PeriodicalIF":4.7,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145367727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Design of an in situ forming methylcellulose hydrogel as universal vehicle for preclinical intravitreal injection of particulate formulations.","authors":"Marco Block, Grazia Giorgio, Christoph Saal, Remko A Bakker, Achim Gpferich, Achim Grube, Roman Simon","doi":"10.1016/j.ejps.2025.107346","DOIUrl":"https://doi.org/10.1016/j.ejps.2025.107346","url":null,"abstract":"<p><p>Preclinical development of novel intravitreal pharmaceuticals is reliant on the use of animal pharmacokinetic (PK) and pharmacodynamic (PD) models, incipiently performed in small rodents. As most novel molecular entities exhibit fast intravitreal clearance, tailored preclinical extended-release (XR) formulations like microparticle suspensions are required to ensure sufficient exposure in the eye for 1 - 4 weeks which are required for PD experiments. Still, their use is very limited due to three major drawbacks: (i) Limited injectability of high particle concentrations, (ii) high intravitreal mobility, and (iii) attachment to vitreoretinal tissues and the lens. (ii) and (iii) complicate or prohibit PK and PD readouts. We developed a universal hydrogel vehicle to specifically enable microparticulate XR formulations for preclinical intravitreal injection. By optimizing the interplay of methylcellulose and kosmotropic additives, namely Na-citrate and Na-tartrate, rapid thermal gelation at vitreous temperature of 34°C was ensured. The hydrogel vehicle enabled injection of microparticulate XR formulations (Poly-lactide-co-glycolide and silica matrix particles) even when using non-siliconized syringes with small 34 gauge needles. Reduced intravitreal mobility and facilitated separation of formulation from retinal tissues was demonstrated ex vivo in porcine eyes. Rheological examination validated almost complete obstruction of embedded particulate XR formulations. In vitro XR of drugs (small molecules up to full length antibodies) was not altered. Experiments on ARPE-19 cells in vitro showed good tolerability and low toxicity. Furthermore, the hydrogel vehicle masked the cytotoxicity of embedded silica microparticles in high concentration. Our results suggest the hydrogel vehicle as a highly promising universal vehicle for preclinical intravitreal injection.</p>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":" ","pages":"107346"},"PeriodicalIF":4.7,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145367735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Itraconazole Loaded Nanoemulsions: Hansen Solubility & Charge-Driven Permeation and GastroPlus based Predicted In vivo Performance.","authors":"Afzal Hussain, Mohammad A Altamimi, Mudassar Shahid, Bushra Alhabib","doi":"10.1016/j.ejps.2025.107345","DOIUrl":"https://doi.org/10.1016/j.ejps.2025.107345","url":null,"abstract":"<p><p>There is limited in vivo investigation for the permeation profiles of itraconazole (ITZ) loaded cationic nanoemulsion after oral delivery. We reported HSPiP and GastroPlus oriented major formulations (MCNE11 and MNE11) as a state-of-the-art study. HSPiP diffusion module predicted the impact of diffusion coefficients on the % drug absorption and absorption-time across intestinal membrane. In vitro dissolution data were used to predict and simulate in vivo performance (GastroPlus) in humans. Finally, confocal laser scanning microscopy (CLSM) study confirmed the extent of penetration across mucosal layer. GastroPlus simulated in vitro dissolution data (only 32% drug release from suspension than 100% released from MCNE11 at 12 h) at pH 6.8 for in vivo performance in humans, wherein it showed the best fit of Weibull model (β ˂ 0.75), suggesting Fickian diffusion of ITZ from MCNE11. The actual plasma concentration (1.9 × 10² µg/mL) was relatively higher than the suspension (1.5 × 10^-2 µg/mL). Parameter sensitivity analysis (PSA) predicted that the AUC (area under the curve), T_max (the time required to reach C_max), and C_max (maximum plasma drug concentration reached) over the size range of 2.5 - 6.96 µm for oral suspension. The dose greatly affected AUC and C_max as predicted in GastroPlus for MCNE11 due to rapid absorption. The reginal absorption compartment model predicted 33.6 % and 100% as overall absorption from the suspension and MCNE11, respectively (upper intestine). The finding was further supported with the CLSM result as nanocarreir based maximized ITZ absorption to treat systemic fungal infection.</p>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":" ","pages":"107345"},"PeriodicalIF":4.7,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145367716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical evaluation of Manganese-52 labelled cyclodextrin: a prostaglandin E2 affine imaging probe","authors":"Renáta Adél Dienes ,&nbsp;Lili Anna Komor ,&nbsp;Judit P. Szabó ,&nbsp;András Berzi ,&nbsp;Miklós Emri ,&nbsp;Dezső Szikra ,&nbsp;Anikó Fekete ,&nbsp;Gábor Opposits ,&nbsp;István Jószai ,&nbsp;István Kertész ,&nbsp;Ferenc Fenyvesi ,&nbsp;György Trencsényi ,&nbsp;István Hajdu ,&nbsp;Zita Képes","doi":"10.1016/j.ejps.2025.107344","DOIUrl":"10.1016/j.ejps.2025.107344","url":null,"abstract":"<div><div>Prostaglandin E2 (PGE2) is implicated in several tumor-related biological processes, making it a promising biomarker for molecular imaging. In nuclear medicine, radiolabelled cyclodextrins have emerged as potential probes to target PGE2 in various cancer types. Hereafter, we aimed to specify the pharmacokinetics of a novel Manganese-52-labelled randomly methylated β-cyclodextrin ([⁵²Mn]Mn-DOTAGA-RAMEB) by performing multiple time-point positron emission tomography and <em>ex vivo</em> biodistribution studies in PGE2 positive BxPC-3 pancreatic adenocarcinoma xenografts. In line with the <em>ex vivo</em> findings, [⁵²Mn]Mn-DOTAGA-RAMEB showed early and specific tumor uptake (30 and 60 min after injection), followed by rapid wash-out and renal clearance. Our experimental data demonstrate the feasibility of ⁵²Mn-labelled RAMEB cyclodextrin to identify PGE2 expressing tumors, although further pharmacokinetic optimization is required to enhance tumor retention and fully exploit its diagnostic potential.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"215 ","pages":"Article 107344"},"PeriodicalIF":4.7,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145354219","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Risk-Based, Qtpp-Driven Framework For Semi-Solid Extrusion 3d Printing of Personalized Medicines: Integrating Hospital Compounding and Clinical Trial Regulation.","authors":"Maxime Annereau, Philippe-Henri Secretan, Bernard Do","doi":"10.1016/j.ejps.2025.107340","DOIUrl":"https://doi.org/10.1016/j.ejps.2025.107340","url":null,"abstract":"<p><p>Semi-solid extrusion (SSE) 3D printing enables precise, patient-specific oral medicines, yet its uptake is constrained by fragmented regulatory pathways. This study develops an applied, risk-based framework grounded in empirical data from hospital compounding and early-phase clinical trial implementation, integrating both within a unified regulatory model through the concept of the printable ink as a pharmaceutical intermediate. Drawing from three pediatric use cases involving 5 different active pharmaceuticals ingredients (APIs), trimethoprim-sulfamethoxazole (Bactrim®), cyclophosphamide, tamoxifen (OPERA clinical trial) and isoleucine (Maple syrup urine disease) the framework applies quality-by-design principles (ICH Q8-Q11, USP <1220>) to define critical quality attributes (CQAs), critical process parameters (CPPs), and in-process controls (IPCs) suitable for both centralized and point-of-care production. Two complementary tables stratify APIs by risk and map them to actionable quality control strategies, enabling science-based decisions on when IPCs alone suffice versus when full GMP oversight is required. This harmonized model supports reproducible, traceable production across decentralized sites, addressing regulatory ambiguity while preserving flexibility for innovation in paediatric and rare disease care.</p>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":" ","pages":"107340"},"PeriodicalIF":4.7,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145344251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Simultaneous in-line particle size distribution determination of drug and excipient from their powder blend using endoscopic imaging and AI.","authors":"Máté Benczúr, Máté Ficzere, Orsolya Péterfi, Áron Kálnai, Zsombor Kristóf Nagy, Dorián László Galata","doi":"10.1016/j.ejps.2025.107339","DOIUrl":"https://doi.org/10.1016/j.ejps.2025.107339","url":null,"abstract":"<p><p>This paper presents a method capable of simultaneously measuring component-based particle size distribution and API concentration via direct, in situ measurements in bulk powders. The method uses real-time imaging with a probe connected to a digital camera, and machine vision combined with artificial intelligence to process the images. The pharmaceutical processing environment was simulated with a conveyor belt. The blends consisted of acetylsalicylic acid (ASA) and calcium hydrogen phosphate (CHP). The determined component-based particle size distributions were compared to references measured using a microscope, and the results showed good correlation. The method not only proved effective in real-time component-based particle size distribution determination but was also able to provide information about the API concentration of the blends. This technique could provide valuable, real-time information about bulk powders used in pharmaceutical processing environments. Therefore, the method has the potential to play a central role in monitoring product quality in bulk powder processing providing assistance in the development of pharmaceutical quality control.</p>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":" ","pages":"107339"},"PeriodicalIF":4.7,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145344336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enabling Personalised 3D Printed Extended-Release Oral Drug Products: Transmission Raman Spectroscopy as a Rapid Quality Control Tool.","authors":"Anna Kirstine Jørgensen, Julia Griffen, Robert Wills, Maryam Parhizkar, Alvaro Goyanes, Abdul W Basit","doi":"10.1016/j.ejps.2025.107341","DOIUrl":"https://doi.org/10.1016/j.ejps.2025.107341","url":null,"abstract":"<p><p>Decentralised manufacture (DM) of personalised medicines via 3D printing (3DP) is now viable in the United Kingdom under new legislation with regulatory agencies across the globe working to follow suit. Quality control (QC) and ensuring dose accuracy for small-batch production of extended-release (ER) printlets (3DP tablets) remains a challenge. We demonstrate, for the first time, a non-destructive, volumetric method for drug quantification using Transmission Raman spectroscopy (TRS) combined with partial least squares regression (PLSR), suitable for high-throughput QC of individual ER printlets in DM settings. A simple theophylline-based pharma-ink was developed for direct powder extrusion (DPE) 3DP of cylindrical ER printlets in 3 sizes, maintaining a constant surface area-to-volume (SA/V) ratio to ensure comparable release profiles. In vitro dissolution confirmed equivalent ER profiles across all sizes, meeting pharmacopeial requirements. A PLSR model calibrated with only the smallest and largest printlet TRS spectra accurately predicted drug content in all 3 printlet sizes (R² = 0.9948, RMSEP = 0.5611% w/w) with no statistical differences compared to the reference method. These findings establish TRS as a rapid, non-destructive drug content QC tool for personalised, dose-flexible 3DP medicines and support its implementation in decentralised pharmaceutical manufacturing workflows.</p>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":" ","pages":"107341"},"PeriodicalIF":4.7,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145344254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prediction of Small-molecule Pharmaceuticals Solubility Parameters Using a Thermodynamic SAFT-based Equation of State.","authors":"Hashem O Alsaab, Saeed Shirazian","doi":"10.1016/j.ejps.2025.107338","DOIUrl":"https://doi.org/10.1016/j.ejps.2025.107338","url":null,"abstract":"<p><p>Accurate prediction of drug solubility parameters plays a crucial role in optimizing pharmaceutical formulations. In this study, the solubility parameters of pharmaceutical compounds are estimated using the Perturbed Chain Statistical Associating Fluid Theory (PC-SAFT) equation of state (EoS). It should be noted that experimental values of drug solubility parameters are scarce, and group contribution (GC) methods have several significant limitations. Solubility is influenced by factors such as steric hindrance and intramolecular hydrogen bonding, which are not captured by GC approaches. As well, most GC tables are based on common organic functional groups, whereas many drugs contain rare or novel groups, making GC-based estimates either unavailable or unreliable. It is the first attempt to predict the solubility parameter of pharmaceuticals using a SAFT-based EoS. The PC-SAFT EoS parameters were calculated from binary experimental solubility data and subsequently applied to predict drug solubility parameters. To enhance model performance, the association interactions between drug-drug and drug-solvent molecules were explicitly considered. The effect of each contribution (hard-chain, dispersion, and hydrogen bonding) on solubility parameter prediction has been investigated. The results demonstrate that hydrogen-bonding interaction plays a critical role in accurately predicting solubility parameters. In addition to using the PC-SAFT EoS, an unconstrained regression approach (URA) was employed as a complementary method. In the URA, experimental solubility data were incorporated to establish correlations for the Hansen solubility terms. The predictions obtained with PC-SAFT EoS were compared to those from regression model and GC approaches, showing that the PC-SAFT approach provides satisfactory accuracy for drug solubility parameter estimation. This approach provides a tool for pre-designing new drug candidates by optimizing solvent selection in chemical processes.</p>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":" ","pages":"107338"},"PeriodicalIF":4.7,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145344309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the potential of combining menthol-thymol deep eutectic solvent and solid microneedles for cutaneous peptide delivery","authors":"Shabir Ahmad ,&nbsp;Grzegorz S. Czyrski ,&nbsp;Christian Janfelt ,&nbsp;Stéphanie Baud ,&nbsp;Massimo Fresta ,&nbsp;Andrea Heinz","doi":"10.1016/j.ejps.2025.107336","DOIUrl":"10.1016/j.ejps.2025.107336","url":null,"abstract":"<div><div>While cutaneous administration of bioactive molecules like peptides offers advantages over oral delivery by bypassing first-pass metabolism and increasing bioavailability, it also comes with some challenges, primarily due to poor peptide absorption through the lipophilic stratum corneum, as a result of peptide hydrophilicity and high molecular weight. Recently, deep eutectic solvents (DESs) have gained attention as a new subclass of chemical permeation enhancers, facilitating drug delivery across the skin by disrupting the lipid organization within the stratum corneum, thereby significantly improving drug permeation into deeper skin layers. This study investigated the permeation of the pentapeptide GVAPG in porcine skin using a menthol-thymol DES (MT-DES), both alone and in combination with solid microneedles (MNs) as a physical permeation enhancer, to assess whether the combined use of both chemical and physical enhancers offers additional benefits over individual application. The combination of MT-DES and MNs significantly enhanced GVAPG permeation compared to either enhancer alone. Stability testing showed that MT-DES reduced peptide degradation caused by the skin proteolytic enzymes compared to phosphate-buffered saline. Matrix-assisted laser desorption/ionization mass spectrometry imaging revealed an even distribution of GVAPG and its degradation products across the skin. Molecular dynamics simulations indicated that GVAPG adopted an elongated conformation in MT-DES, with fewer hydrogen bonds with MT-DES as compared to water, which may potentially contribute to an enhanced liberation of GVAPG from the formulation and improved permeation. Overall, these findings suggest that combining MT-DES and MNs is a promising strategy to enhance peptide permeation and stability, potentially reducing application frequency. However, further studies with other peptides are needed to confirm these results.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"215 ","pages":"Article 107336"},"PeriodicalIF":4.7,"publicationDate":"2025-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145344303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The fourth-generation EGFR tyrosine kinase inhibitor BLU-945 resensitizes ABCG2-overexpressing multidrug-resistant non-small cell lung cancer cells to cytotoxic anticancer drugs","authors":"Yen-Ching Li ,&nbsp;Bing-Huan Lin ,&nbsp;Megumi Murakami ,&nbsp;Yu-Shan Wu ,&nbsp;Tai-Ho Hung ,&nbsp;Suresh. V. Ambudkar ,&nbsp;Chung-Pu Wu","doi":"10.1016/j.ejps.2025.107337","DOIUrl":"10.1016/j.ejps.2025.107337","url":null,"abstract":"<div><div>ABCG2, a key ATP-binding cassette (ABC) transporter, contributes significantly to multidrug resistance (MDR) by actively effluxing a wide range of chemotherapeutic agents from cancer cells, thereby lowering intracellular drug concentrations and reducing therapeutic efficacy. This mechanism poses a major challenge in treating cancers such as non-small-cell lung cancer (NSCLC). Despite extensive research, no clinically approved agents specifically target ABCG2-mediated MDR. Given the success of combining tyrosine kinase inhibitors (TKIs) with chemotherapy, we explored whether BLU-945, a fourth-generation epidermal growth factor receptor (EGFR) TKI with potent activity against resistant EGFR mutations, could modulate ABCG2 function to reverse MDR. Our findings reveal that BLU-945 stimulates the ATPase activity of ABCG2, indicating direct interaction as a potential substrate or modulator. However, ABCG2-overexpressing NSCLC cells did not display resistance to BLU-945, suggesting that its antitumor activity remains intact despite high ABCG2 expression. Importantly, BLU-945 significantly resensitized these resistant cells to multiple cytotoxic agents in a concentration-dependent manner, with effects evident even at nanomolar levels. Mechanistic studies indicate that this chemosensitizing effect results from functional inhibition of ABCG2-mediated drug efflux, without affecting ABCG2 protein expression, thereby enhancing intracellular drug retention and cytotoxicity. These findings reveal a previously unrecognized pharmacological property of BLU-945 as an inhibitor of ABCG2-mediated drug efflux, supporting its potential role in combination therapies aimed at overcoming MDR in patients with ABCG2-overexpressing tumors. Further preclinical and clinical studies are warranted to validate the translational relevance of this approach and to identify patient populations that may benefit most from this combinatorial strategy.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"215 ","pages":"Article 107337"},"PeriodicalIF":4.7,"publicationDate":"2025-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145344318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}