European Journal of Pharmaceutics and Biopharmaceutics最新文献

{"title":"Enhanced ex vivo skin retention of bicalutamide using a nano-in-micro composite: Drug-loaded lipid vesicles in a dissolving microarray patch","authors":"Miquel Martínez-Navarrete ,&nbsp;Mafalda Correia ,&nbsp;J.Alejandro Bernabeu-Martínez ,&nbsp;Ana Cláudia Paiva-Santos ,&nbsp;Ana Borrego-Sánchez ,&nbsp;Antonio José Guillot","doi":"10.1016/j.ejpb.2025.114728","DOIUrl":"10.1016/j.ejpb.2025.114728","url":null,"abstract":"<div><div>Antiandrogens are a family of drugs that block the biological effects of androgens, which are commonly used to treat a plethora of androgen-dependent conditions. However, their effectiveness highly depends on treatment compliance and their use is not exempt from side effects. Bicalutamide (BIC) is a testosterone blocker that, due to its peripheral tissue selectivity, offers the advantage of fewer side effects compared to other antiandrogens such as finasteride or dutasteride. In this study, BIC-loaded lipid vesicles (LVs) were developed and incorporated into a PVP/PVA-based Dissolving Microarray Patches (BIC-LVs@DMAPs) for BIC skin local delivery. First, the mechanical and insertion properties of the BIC-LVs@DMAPs were assessed. Then, the <em>in vitro</em> biocompatibility of the formulation was determined in keratinocytes. Finally, the effectiveness of the formulation to deliver BIC through skin was explored <em>ex vivo</em> using murine skin. BIC-LVs@DMAPs exhibited optimal mechanical and insertion properties to effectively perforate the <em>stratum corneum</em> and facilitate the passage of BIC-LVs. <em>Ex vivo</em> studies demonstrated the efficacy of BIC-LVs@DMAPs to improve the skin retention of BIC, while <em>in vitro</em> cytotoxicity results ensured their safety profile. Overall, these results pave the way for further <em>in vivo</em> studies and clinical application to improve the current early stages androgenetic alopecia topical treatments.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"212 ","pages":"Article 114728"},"PeriodicalIF":4.4,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143902128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From in vitro to in vivo: The Dominant role of PEG-Lipids in LNP performance","authors":"Ankita Borah ,&nbsp;Valeria Giacobbo ,&nbsp;Burcu Binici ,&nbsp;Ranald Baillie ,&nbsp;Yvonne Perrie","doi":"10.1016/j.ejpb.2025.114726","DOIUrl":"10.1016/j.ejpb.2025.114726","url":null,"abstract":"<div><div>Lipid nanoparticles (LNPs) are widely employed for delivering nucleic acids, such as mRNA, in both vaccines and therapeutic applications. These LNPs generally include an ionisable lipid (typically ∼ 50 %) to facilitate nucleic acid encapsulation and a PEG-lipid (typically ∼ 1.5 %) to enhance nanoparticle stability. To examine how the choice of PEG-lipid impacts LNP performance, we investigated the physicochemical characteristics and potency of LNPs prepared using two PEG-lipids with different acyl chain lengths: DMG-PEG 2000 and DSG-PEG 2000, containing 14 and 18 carbon tail lengths, respectively. These were combined with three commonly used ionisable lipids (ALC-0315, DLin-MC3 and SM-102). We evaluated the efficacy of these LNPs both <em>in vitro</em> (HeLa cells) and <em>in vivo</em> in mice after intramuscular (IM), subcutaneous (SC), and intravenous (IV) administration. <em>In vitro</em> studies showed that all LNP formulations primarily enter cells via clathrin-mediated endocytosis. Irrespective of the choice of ionisable lipid, DMG-PEG LNPs demonstrated higher <em>in vitro</em> mRNA transfection efficacy than DSG-PEG LNPs. These <em>in vitro</em> results aligned with the <em>in vivo</em> outcomes across all routes of administration tested. Our findings emphasise that despite the low percentage content of PEG-lipid, its selection critically influences LNP efficacy across different administration routes, with DMG-PEG-based LNPs outperforming DSG-PEG LNPs, regardless of the ionisable lipid used.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"212 ","pages":"Article 114726"},"PeriodicalIF":4.4,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143902127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring starch-based excipients in pharmaceutical formulations: Versatile applications and future perspectives","authors":"Devesh U. Kapoor ,&nbsp;Anil Pareek ,&nbsp;Mayank Sharma ,&nbsp;Bhupendra G. Prajapati ,&nbsp;Supakij Suttiruengwong ,&nbsp;Pornsak Sriamornsak","doi":"10.1016/j.ejpb.2025.114727","DOIUrl":"10.1016/j.ejpb.2025.114727","url":null,"abstract":"<div><div>Starch, a naturally abundant and biocompatible polysaccharide, serves as a key excipient in pharmaceutical formulations, enhancing drug stability, efficacy, and manufacturability. This review explores the properties, modifications, and diverse applications of starch-based excipients. Native starches from corn, potato, rice, and wheat are commonly used as disintegrants, binders, and fillers. Physical (e.g., pre-gelatinization), chemical (e.g., cross-linking, acetylation), and enzymatic modifications improve their functionality, such as enhanced stability and colon-specific drug delivery. Starch excels as a binder, improving tablet cohesion and strength, and as a disintegrant, promoting rapid drug release. It also supports controlled and sustained-release systems and advanced drug delivery methods, like nanoparticles and microparticles. Compared to other natural and synthetic excipients, starch offers advantages in biodegradability, non-toxicity, and cost-effectiveness, despite challenges like stability and batch variability. Innovations such as starch nanocrystals show promise in boosting drug solubility and bioavailability. Looking ahead, starch-based excipients hold potential for sustainable pharmaceutical development, personalized medicine, and 3D printing.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"212 ","pages":"Article 114727"},"PeriodicalIF":4.4,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143887585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Performance of oral Bosentan-loaded SNEDDS and S-SNEDDS tablets: Biodistribution in mice, echocardiography and histology studies in pulmonary arterial hypertension rat model","authors":"Duygu YILMAZ USTA ,&nbsp;Seval OLGAC ,&nbsp;Murside Ayse DEMIREL ,&nbsp;Serdar KULA ,&nbsp;Cigdem ELMAS ,&nbsp;Perihan SEZGINER ,&nbsp;Akif KAVGACI ,&nbsp;Zeynep Safak TEKSIN","doi":"10.1016/j.ejpb.2025.114725","DOIUrl":"10.1016/j.ejpb.2025.114725","url":null,"abstract":"<div><div>Bosentan monohydrate (BOS) is the most preferred molecule for treating the rare pulmonary arterial hypertension (PAH) disease. BOS shows low solubility and high variability when administered orally. This study evaluated the pharmacodynamic biodistribution, echocardiography, and histology results of BOS-loaded SNEDDS and BOS-loaded S-SNEDDS tablets. Pharmacodynamic biodistribution studies were conducted with male Balb/c mice (8 weeks old, 18–20 g) after oral administration. XenoLight^TM DiR and VivoTag® 680XL fluorescent dyes were used to monitor biological distribution and absorption with the <em>In Vivo</em> Imaging System® (IVIS®). Pharmacodynamic echocardiography and histology studies were carried out with Wistar rats (8–10 weeks old, 250–300 g). The PAH rat model was successfully induced with monocrotaline (MCT), which is one dose (60  mg/kg) was intraperitoneally injected. The reference drug (Tracleer® 125 mg tablet) and BOS-loaded SNEDDS and S-SNEDDS tablets were administered as 50 mg/kg; 2 mL per os to the treatment groups. Pharmacodynamic biodistribution studies showed that real-time biodistribution in the body, <em>ex-vivo</em> region of interest (ROI) values of organs, and total fluorescence emission were increased (p &lt; 0.05). It has been confirmed that the formulations enter the systemic circulation via the lymphatic system, do not have a first-pass effect in the liver, and show no emission in the liver. The echocardiographic study was performed for up to 14 days and no difference was found between the treatment groups which are the reference tablet (Tracleer®), BOS-loaded SNEDDS, and BOS-loaded S-SNEDDS tablet (p &gt; 0.05). Hematoxylin and Eosin (H&amp;E) and Immunohistochemical (IHC) staining were done for the histology studies. These studies showed that the BOS-loaded formulations have a similar therapeutic effect on histopathological phenomena in lung and liver tissues. As the histological evaluation results, lower-dose formulations were found to be more effective than the same dose reference tablet in terms of improvements in histological parameters (p &lt; 0.05). Comprehensive and comparative <em>in vitro</em> and <em>in vivo</em> studies indicate that BOS-loaded formulations could be an alternative oral drug delivery system for PAH treatment compared to the reference product.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"212 ","pages":"Article 114725"},"PeriodicalIF":4.4,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143892111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Incorporating the biphasic system to GIS-α Improves In vivo prediction for low solubility drugs","authors":"Marvin D. Naing,&nbsp;Yasuhiro Tsume","doi":"10.1016/j.ejpb.2025.114724","DOIUrl":"10.1016/j.ejpb.2025.114724","url":null,"abstract":"<div><div>The gastrointestinal simulator alpha (GIS-α) is an in vivo predictive transfer dissolution method that mimics the pH changes and peristalsis in the gastrointestinal tract, factors that are necessary in the biorelevant dissolution of drugs especially those that are under the Biopharmaceutics Classification System (BCS) class II and IV. It can be used to provide increased understanding to the dissolution, precipitation, and supersaturation of various low-solubility drugs, but lacks insights on absorption. Conducting experiments in the GIS-α with a biphasic system to add an absorptive phase in the jejunal compartment increased the observed dissolution and improved the overall in vivo prediction. In this study, the objective was to evaluate the improvement of dissolution on four representative BCS class II drugs using the biphasic format in the GIS-α. A customized double paddle was also used in the jejunal chamber to mix the aqueous buffer and organic layer simultaneously. This paddle floats in the organic layer as the aqueous volume increases and maintains the hydrodynamics in both the aqueous and organic phases. The combination of the biphasic system in the GIS-α and the moving double paddles resulted to increased dissolution profiles of fenofibrate, danazol, and celecoxib while not affecting that of ritonavir. Incorporating these dissolution profiles in a PBPK model using GastroPlus® improved the predictability of bioperformance of those oral medicines. Overall, this methodology considers both dissolution and absorption and proves to be a useful tool in predicting the in vivo performance of low-solubility drugs.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"211 ","pages":"Article 114724"},"PeriodicalIF":4.4,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143868624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Erratum to “Raloxifene HCl – Naringin co-amorphous system: Preparation, characterization and pharmacokinetic studies” [Eur. J. Pharm. Biopharm. 209 (2025) 114667]","authors":"Navya Sree Kola Srinivas ,&nbsp;Dani Lakshman Yarlagadda ,&nbsp;Brahmam Bheemishetty ,&nbsp;Shaila Lewis ,&nbsp;Swapnil Jayant Dengale ,&nbsp;Krishnamurthy Bhat","doi":"10.1016/j.ejpb.2025.114721","DOIUrl":"10.1016/j.ejpb.2025.114721","url":null,"abstract":"","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"211 ","pages":"Article 114721"},"PeriodicalIF":4.4,"publicationDate":"2025-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143900097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting the pharmacokinetics and food effect of oral drug products using the dynamic gastrointestinal model (DGM)","authors":"Matthias Manne Knopp ,&nbsp;Jacob Rune Jørgensen ,&nbsp;Laila Tognarelli Hansen ,&nbsp;Anette Müllertz","doi":"10.1016/j.ejpb.2025.114723","DOIUrl":"10.1016/j.ejpb.2025.114723","url":null,"abstract":"<div><div>The pharmacokinetics (PK) of oral drug compounds are often significantly altered by food intake and evaluating this effect, as required by regulatory agencies, typically involves costly and time-consuming clinical trials. This study used the Dynamic Gastrointestinal Model (DGM), an advanced <em>in vitro</em> system simulating both biochemical and mechanical aspects of the human upper gastrointestinal tract, to predict plasma concentration–time profiles (PK profiles) and food effect of three immediate release oral drug products. The drug products, containing cinnarizine (CIN), diclofenac potassium (DIC) or paracetamol (PAR), were processed in the DGM mimicking the fasted and fed state clinical protocols and the resulting intestinal drug dissolution profiles were modelled (by convolution) to achieve the predicted PK profiles. The predicted PK profiles in both the fasted and fed state were in accordance with the observations in clinical trials, capturing both the positive food effect for CIN and the negative food effects for DIC and PAR. These findings demonstrate the ability of the DGM to provide insights into the PK performance and food effect of oral drug products.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"212 ","pages":"Article 114723"},"PeriodicalIF":4.4,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143903796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Improving accuracy in food effect predictions: Application of in-vitro absorption experiments as a useful tool for the evaluation of ten drug products","authors":"Gobardhan Bal ,&nbsp;Cornelius Harlacher ,&nbsp;Dominic Werthmueller ,&nbsp;Ioannis Loisios-Konstantinidis ,&nbsp;Katarina Vulic ,&nbsp;Marina Statelova ,&nbsp;Martin Hingle ,&nbsp;Pawel Bigos ,&nbsp;Ryan Pelis ,&nbsp;Stephanie Dodd","doi":"10.1016/j.ejpb.2025.114722","DOIUrl":"10.1016/j.ejpb.2025.114722","url":null,"abstract":"<div><div>Predicting the magnitude and direction of food effects on oral drug delivery can be challenging, especially for compounds with absorption limited by changes in the permeation rate. Currently available <em>in-vitro</em> tools assess the impact of increased bile flow and food on drug solubilization, potentially leading to increased absorption under fed conditions. However, the presence of bile can sequester the drug within bile/food colloids, reducing free drug availability and resulting in unanticipated absorption. The aim of this study is to explore the application and outcome of a combined dissolution/permeation (MacroFLUX™) assay of ten drug products for a more accurate prediction of clinical food effects in the context of given dose and formulation. The ratio of the fed-to-fasted dissolution and Flux were used to correlate each experimental model to clinical food effect in humans. Assessing the flux across a biomimetic artificial membrane provided superior predictability over dissolution alone. Food effects were predicted accurately for 60% of compounds within 1.25-fold based on flux analysis, while dissolution analysis only predicted 30% of compounds evaluated. The most interesting outcome is that dissolution did not pick up on any of the negative food effects. Notably, the study revealed that the common assumption of compounds exhibiting a positive food effect due to increased dissolution/solubility from fasted to fed state does not always hold true. This <em>in-vitro</em> absorption experiment proved to be a valuable <em>in-vitro</em> biopharmaceutic tool that can predict clinical food effects, support (pre-)formulation development, and guide the design of dedicated clinical pharmacology studies.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"211 ","pages":"Article 114722"},"PeriodicalIF":4.4,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143852284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predicting the solubility of drugs in supercritical carbon dioxide using machine learning and atomic contribution","authors":"Ahmadreza Roosta ,&nbsp;Feridun Esmaeilzadeh ,&nbsp;Reza Haghbakhsh","doi":"10.1016/j.ejpb.2025.114720","DOIUrl":"10.1016/j.ejpb.2025.114720","url":null,"abstract":"<div><div>The pharmaceutical sector is aware of supercritical CO₂ (SC-CO₂) as a possible replacement for problematic organic solvents. Using a novel artificial intelligence (AI) strategy to predict drug solubility using the SC-CO₂ system mathematically has been deemed an intriguing approach. In this work, the atomic contribution (AC) method and machine learning (ML) models are combined to develop hybrid machine learning models to compute the solubility of several drugs, including anticoagulants, anti-cancers, calcium channel blockers, immunosuppressives, antihistamines, and others. The novelty of the approach lies in using the AC concept to capture molecular details at the atomic level. This enables the model to account for the specific contributions of individual atoms and to provide more precise input features for machine learning. The integration of these molecular insights with ML techniques results in significantly improved predictive performance over traditional ML methods. Throughout the modeling procedure, temperature, pressure, the density of SC-CO₂, and the effect of constituent atoms of the drugs are the input variables, while the solubility of drugs is the output. This study looks into predicting the solubility of these drugs in SC-CO₂ using the least square support vector machine (LSSVM) with radial basis function kernel (RBF) and multilayer perceptron artificial neural network (MLPANN). These models were developed using a database including 2358 experimental solubility data points from 86 solid drugs. The solubility of solid drugs in supercritical CO₂ spans a remarkably wide range in this study, from as high as 3.9 × 10^-2 to as low as 1 × 10^-7. The results demonstrated that this innovative approach could estimate solid drug solubility in SC-CO₂ with <em>AARD%</em> and <em>R²</em> values of 7.20 and 0.99, respectively, under different pressure and temperature conditions. The ability of the models to capture a wide range of solubilities in SC-CO₂ showcases their effectiveness in dealing with both highly and poorly soluble compounds. The developed models, considering their global prediction, accuracy, and being user-friendly, are the best options to be used by researchers for incorporating into software for enabling more efficient design of supercritical extraction processes and reducing the need for trial-and-error experimentation in manufacturing.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"211 ","pages":"Article 114720"},"PeriodicalIF":4.4,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143848127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A comprehensive mechanistic investigation of factors affecting intestinal absorption and bioavailability of two PROTACs in rats","authors":"Janis Niessen ,&nbsp;Nathalie Arendt ,&nbsp;Markus Sjöblom ,&nbsp;Ilse R. Dubbelboer ,&nbsp;Thomas Borchardt ,&nbsp;Mirko Koziolek ,&nbsp;Mikael Hedeland ,&nbsp;Hans Lennernäs ,&nbsp;Anura Indulkar ,&nbsp;David Dahlgren","doi":"10.1016/j.ejpb.2025.114719","DOIUrl":"10.1016/j.ejpb.2025.114719","url":null,"abstract":"<div><h3>Aim</h3><div>Proteolysis targeting chimeras (PROTACs) exhibit a unique and promising pharmacology. However, this comes with molecular properties exceeding the ‘drug-like’ rule of five chemical space, which often limits gastrointestinal absorption. This <em>in vivo</em> study aimed to investigate the contribution of luminal and plasma stability, intestinal effective permeability, P-glycoprotein (P-gp) efflux, and bile excretion, on the rat intestinal absorption and systemic exposure of two PROTACs, ARV-110 (812 Da, LogD_7.4 4.8) and ARV-471 (724 Da, LogD_7.4 4.6).</div></div><div><h3>Methods</h3><div>Luminal stability and effective intestinal permeability were determined directly from luminal disappearance using single-pass intestinal perfusion, with and without a protease inhibitor, or a P-gp/Cytochrome P450 CYP3A inhibitor (ketoconazole) in rats. Plasma stability was tested by <em>in vitro</em> incubations. Intestinal absorption, systemic exposure, and biliary excretion were examined after intraduodenal and intravenous dosing with ketoconazole or the P-gp selective inhibitor (encequidar).</div></div><div><h3>Results and discussion</h3><div>Both PROTACs were degraded in the intestinal lumen and in plasma by peptidases. The intestinal effective permeability in rats was moderate for ARV-110 (0.62 × 10^-4 cm/s) and low for ARV-471 (0.23 × 10^-4 cm/s). P-gp inhibition increased the permeability 1.6- and 2.3-fold for ARV-110 and ARV-471, respectively. After intraduodenal dosing with the P-gp inhibitors a corresponding increase in systemic exposure was observed for both PROTACs. There was only a minor difference in the increased systemic exposure induced by the two inhibitors, suggesting that the mechanisms were primarily P-gp inhibition, rather than gut-wall and hepatic extraction. Biliary excretion was a minor pathway and did not affect the absorption and systemic exposure of the PROTACs to a large extent.</div></div><div><h3>Conclusion</h3><div>In the rat, ARV-110 and ARV-471 were enzymatically degraded in the intestinal lumen and in plasma, and their intestinal permeability and systemic exposure seem to be reduced due to P-gp efflux.</div></div>","PeriodicalId":12024,"journal":{"name":"European Journal of Pharmaceutics and Biopharmaceutics","volume":"211 ","pages":"Article 114719"},"PeriodicalIF":4.4,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143852031","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}