European Journal of Pharmaceutical Sciences最新文献

{"title":"Fluoroquinolones as versatile scaffolds: Potential for targeting classical and novel mechanisms to combat antibacterial resistance","authors":"Ahmed M. Kamal El-sagheir ,&nbsp;Michaela Wenzel ,&nbsp;Jari Yli-Kauhaluoma","doi":"10.1016/j.ejps.2025.107247","DOIUrl":"10.1016/j.ejps.2025.107247","url":null,"abstract":"<div><div>Antibiotics play an essential role in combating infectious diseases. Due to the emergence of multidrug-resistant bacteria, the efficacy of antibiotic therapy is continually decreasing. Consequently, there is an urgent need for the development of novel antibiotics, preferably with novel targets that have not yet been clinically exploited and/or multiple mechanisms of action, reducing the probability of fast resistance development. Recently, several new promising antibacterial targets have been identified, including <em>N</em>-acetylglucosamine-6-phosphate deacetylase, glucosamine-6-phosphate synthase, metal-dependent deacetylase, and carbonic anhydrase. Additionally, inhibition of biofilm formation enhances bacterial susceptibility to antibiotics and potentially minimizes the risk of resistance development. This review discusses fluoroquinolones as versatile scaffolds, covering their structure-activity relationships, recent modifications and their role in inhibiting multiple bacterial targets. Multi-target fluoroquinolone derivatives exhibit enhanced activity against multidrug-resistant bacteria, including Gram-positive, Gram-negative, and mycobacterial species. Therefore, the continued optimization of fluoroquinolone structures represents an attractive approach to combat antibacterial resistance and achieve better therapeutic outcomes.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"214 ","pages":"Article 107247"},"PeriodicalIF":4.7,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144947829","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":"Modeling and ex vivo evaluation of electrostatic precipitation-enhanced intraperitoneal aerosol drug delivery","authors":"Mohammad Rahimi-Gorji ,&nbsp;Yiwen Long ,&nbsp;Amrit Sareen ,&nbsp;Charlotte Debbaut ,&nbsp;Ghader Ghorbaniasl ,&nbsp;Wouter Willaert ,&nbsp;Wim Ceelen","doi":"10.1016/j.ejps.2025.107244","DOIUrl":"10.1016/j.ejps.2025.107244","url":null,"abstract":"<div><div>Peritoneal metastases (PM) remain a significant clinical challenge due to their resistance to systemic chemotherapy. Intraperitoneal aerosolized drug delivery (IPADD) has shown promise as a localized treatment option; however, its efficacy is often limited by inadequate aerosol droplet distribution and poor tissue penetration. In this study, we enhance IPADD using electrostatic precipitation (eIPADD) and evaluate its performance through computational simulations and <em>in vitro</em>/<em>ex vivo</em> experiments. A realistic 3D reconstruction of the human peritoneal cavity was used to simulate the effects of electrostatic fields on droplet distribution and deposition. The results demonstrated that multiple electrodes improved aerosol homogeneity and tissue penetration depth. These findings were validated in vitro, where eIPADD significantly increased droplet coverage and tissue penetration, particularly in anatomically challenging regions. Importantly, increasing the number of electrodes from one to three further enhanced droplet distribution uniformity and tissue penetration depth. While raising the electrical potential improved deposition in key areas, benefits plateaued beyond 10 kV, suggesting a threshold in efficacy. Nevertheless, optimizing voltage within this range, in conjunction with the increased electrode count, remains critical for achieving consistent drug delivery across the peritoneal surfaces and maximizing therapeutic outcomes. Our findings suggest that eIPADD has the potential to address the limitations of conventional IPADD, providing a more effective and uniform drug delivery method for treating PM.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"213 ","pages":"Article 107244"},"PeriodicalIF":4.7,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144902264","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":"Controlled release and extended pulmonary retention of inhaled therapeutics: A review","authors":"Sorawee Yanwinitchai,&nbsp;Robert O. Williams III","doi":"10.1016/j.ejps.2025.107242","DOIUrl":"10.1016/j.ejps.2025.107242","url":null,"abstract":"<div><div>The advancement of controlled release systems for pulmonary therapeutic products has become a significant focus in pharmaceutical research. Various strategies have been employed to regulate the release rate of therapeutic agents, targeting both the release enhancement of poorly water-soluble drugs and prolonging the release of highly water-soluble compounds. These efforts primarily focus on chemical modifications of the active pharmaceutical ingredients (APIs) and the creation of innovative formulations that incorporate biodegradable natural or synthetic excipients. This review offers a comprehensive overview of advancements in controlled release inhalable drugs, beginning with the overview of pulmonary drug delivery. It addresses the classification of current inhalable products, the advantages of pulmonary administration, and the mechanisms involved in the particle deposition within the lungs. This review explores controlled release techniques, which are primarily divided into two main approaches: (i) chemical modification of active pharmaceutical ingredients (APIs) and (ii) specialized formulations.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"213 ","pages":"Article 107242"},"PeriodicalIF":4.7,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144931601","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":"Pharmacokinetics and pharmacodynamics studies of Relugolix long-acting microcrystalline formulation in male Beagle dogs","authors":"Chunxian Li ,&nbsp;Jingxian Wang ,&nbsp;Jianxin Wang ,&nbsp;Miao Yu ,&nbsp;Pei Zhao ,&nbsp;Jing Yu ,&nbsp;Xiaohong Guo ,&nbsp;Zhanling Luo ,&nbsp;Xiaolai Yang","doi":"10.1016/j.ejps.2025.107245","DOIUrl":"10.1016/j.ejps.2025.107245","url":null,"abstract":"<div><div>Relugolix is the first oral GnRH receptor antagonist. However, its oral formulation requires daily administration, leading to poor patient adherence and suboptimal treatment outcomes for long-term users. To address these issues, we developed a long-acting microcrystalline formulation of relugolix administered once every 28 days.This study systematically evaluated the pharmacokinetics (PK), pharmacodynamics (PD), and safety profile of the drug following intramuscular administration in male Beagle dogs. In this study, we established a HPLC-MS/MS method for blood concentration detection, used a highly specific and stable ELISA method to measure serum testosterone levels, and assessed the safety of the drug in male Beagle dogs. The HPLC-MS/MS method showed good linearity (R²=0.9991). The intra-day precision varied between 2.8 % and 10.9 %, while the inter-day precision ranged from 1.6 % to 5.4 %. In terms of accuracy, the intra-day values ranged from -7.3 % to -3.2 %, and the inter-day accuracy ranged from -10.2 % to 0.8 %. Furthermore, key parameters such as stability, extraction recovery, and matrix effects met the FDA bioanalytical method validation guidelines. PK studies showed that the AUC and Tmax exhibited significant sustained-release characteristics, and the half-life was notably extended compared to Orgovyx. PD analysis showed a significant negative correlation between blood drug concentration and testosterone suppression (testosterone levels began to decline after administration, and castration levels were maintained between 504–1008 h). Safety assessments revealed that although no treatment-related deaths or significant weight changes were observed, some hematological parameters (RBC, HGB increases), liver function indicators (ALT, AST increases), and triglyceride (TG) levels showed statistically significant changes (<em>p</em> &lt; 0.05). This suggests potential concerns regarding hemodynamic effects, hepatotoxicity, and lipid metabolism abnormalities. This study is the first to systematically evaluate the PK/PD characteristics of the long-acting micronized formulation of relugolix, providing key data for its clinical translation, but further validation through large sample and cross-species studies is needed.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"213 ","pages":"Article 107245"},"PeriodicalIF":4.7,"publicationDate":"2025-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144902265","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":"Prevalence and risk assessment of drug allergies in hospitalized patients: Potential for allergy delabeling","authors":"Robert Nacsa ,&nbsp;Maria Matuz ,&nbsp;Erika Papfalvi ,&nbsp;Helga Hambalek ,&nbsp;Roxana Ruzsa ,&nbsp;Ni Made Amelia Ratnata Dewi ,&nbsp;Edit Hajdu ,&nbsp;Fruzsina Reka Ambrus ,&nbsp;Zsoka Szikora ,&nbsp;Ria Benko","doi":"10.1016/j.ejps.2025.107240","DOIUrl":"10.1016/j.ejps.2025.107240","url":null,"abstract":"<div><h3>Background</h3><div>Drug allergy prevalence is high and predicted to rise in the future. Although allergy labels are essential for patient safety, evidence supports the fact that incorrectly recorded drug allergy labels might lead to suboptimal treatments, increased healthcare costs, prolonged hospital stays, and the emergence of antimicrobial resistance (AMR). Drug allergy risk assessment and subsequent delabeling could be <strong>a</strong> solution for this problem. Despite the importance of this subject, the number of studies on the prevalence of drug allergies or delabeling is low, especially from Eastern European countries.</div></div><div><h3>Aims</h3><div>This study aimed to determine the prevalence and characteristics of drug allergies in hospitalized patients and assess the associated risk of future exposure to the reported culprit drugs to evaluate the potential for allergy delabeling.</div></div><div><h3>Methods</h3><div>A cross-sectional study was conducted at the tertiary care teaching hospital of University of Szeged in Hungary, involving adult inpatients across multiple surgical wards. Data collection included patient interviews using a structured questionnaire and subsequent risk assessment. Adverse drug reactions were categorized as high or low risk based on the history of the reported reaction.</div></div><div><h3>Results</h3><div>Of the 1522 study participants, 242 (15.90 %, 95 % CI: 14.14 - 17.82 %) patients reported at least one drug allergy, resulting in a total of 384 reported allergy cases. Among these, 277 cases were included in the risk assessment, with 252 (90.97 %) classified as low risk and eligible for potential allergy delabeling. Antibiotics were the most frequently reported culprit drug, followed by analgesics and anti-inflammatory drugs. Skin manifestations were the most common symptoms.</div></div><div><h3>Conclusion</h3><div>This study highlights the high prevalence of self-reported drug allergies and the significant proportion of low-risk cases suitable for delabeling. Systematic allergy evaluation and delabeling should be a key element of (antibiotic) stewardship programs.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"213 ","pages":"Article 107240"},"PeriodicalIF":4.7,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144913014","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":"Towards model-informed precision dosing of cyclosporine in adult renal transplantation: Assessing population pharmacokinetic models and multi-model strategies","authors":"Feiyan Liu ,&nbsp;Junjun Mao ,&nbsp;Zeneng Cheng ,&nbsp;Luyang Xu ,&nbsp;Shan Huang","doi":"10.1016/j.ejps.2025.107241","DOIUrl":"10.1016/j.ejps.2025.107241","url":null,"abstract":"<div><h3>Background</h3><div>Cyclosporine’s narrow therapeutic index and pharmacokinetic variability challenge its optimal dosing in renal transplantation. Model-informed precision dosing (MIPD), utilizing population pharmacokinetic (popPK) models and Bayesian forecasting, can enhance dosing optimization and improve clinical outcomes. This study evaluated the predictive performance of published popPK models and multi-model strategies for cyclosporine, using therapeutic drug monitoring (TDM) data and full pharmacokinetic (PK) profiles.</div></div><div><h3>Methods</h3><div>We evaluated 15 published popPK models and 2 multi-model strategies (averaging/selection) using TDM data (1,856 concentrations from 114 patients) and full-PK profiles (259 concentrations from 24 patients). Bayesian forecasting with objective function value (OFV)- and Akaike information criterion (AIC)-based weighting was applied to predict cyclosporine peak concentration (C₂) and area under the curve (AUC). Predictive accuracy and precision were assessed using relative bias (rBias) and relative root mean square error (rRMSE).</div></div><div><h3>Results</h3><div>The two-compartment model with first-order absorption and transit compartments (Press et al., 2010) provided the best prediction for C₂ (rBias = -1.40%, rRMSE = 5.38%), while the model with lag time and covariates postoperative days, age, and weight (Baek et al., 2014) excelled in AUC prediction (rBias = 4.82%, rRMSE = 1.92%). Multi-model averaging/selection performed comparably to top-performing single popPK models for C₂ (rBias &lt;10% with OFV-based weighting) but underperformed for AUC prediction (rBias &gt;20%).</div></div><div><h3>Conclusion</h3><div>While single popPK models provide reliable predictions for specific PK endpoints, multi-model strategies do not consistently outperform individual models. The optimal model selection for MIPD should be fit-for-purpose to ensure optimal cyclosporine dosing and improved clinical outcomes in renal transplantation.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"214 ","pages":"Article 107241"},"PeriodicalIF":4.7,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144947880","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":"Quality by digital design for accelerated sustainable nanomedicine development","authors":"Yousef Ijjeh ,&nbsp;Nowar Alsarayreh ,&nbsp;Alaa Rifai ,&nbsp;Hiba Abdelnabi ,&nbsp;Sara Al-Mahamid ,&nbsp;Dana A. Alqudah ,&nbsp;Hamdi Nsairat ,&nbsp;Zainab Lafi ,&nbsp;Mohamad Ak Mousa ,&nbsp;Yusuf Al-Hiari ,&nbsp;Walhan Alshaer","doi":"10.1016/j.ejps.2025.107239","DOIUrl":"10.1016/j.ejps.2025.107239","url":null,"abstract":"<div><div>Drug delivery systems, diagnostics, and treatments are all being revolutionized by nanomedicine, greatly improving contemporary healthcare. However, traditional nanomedicine development relies on extensive experimental testing, which is costly, time-consuming, and environmentally harmful. To address these challenges, the Quality by Digital Design (QbDD) concept and framework have been developed, integrating digital technologies such as substantial data analytics, Artificial Intelligence (AI), Machine Learning (ML), and computational modeling to transform nanoparticle design. QbDD enables smart digital simulations and predictive analytics to improve nanoparticles with precise bio-physicochemical properties, thereby enhancing batch reproducibility while reducing reliance on resource-intensive physical experiments, lowering costs, and minimizing environmental impact. This digital infrastructure not only optimizes nanoparticle design and efficacy but also ensures compliance with regulatory standards. This review examines the fundamentals of nano-informatics and its integration with QbDD in nanomedicine, focusing on AI-powered molecular simulations and in silico screening to pre-select nanoparticle candidates, thereby reducing dependence on labor-intensive experimental validation. Furthermore, it discusses digital innovations in nanopharmaceuticals, including real-time monitoring systems and digital twins for process verification, highlighting how these advancements enhance nanoparticle synthesis, making it more efficient, cost-effective, and sustainable.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"213 ","pages":"Article 107239"},"PeriodicalIF":4.7,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144889942","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":"Photodegradation of the antibacterial, antifungal and antiprotozoal drug candidate 2-(2-nitrovinyl) furan (G-0) in solid inclusion complexes with β-cyclodextrin derivatives: Characterization by NMR spectroscopy and in silico toxicity screening","authors":"Vivian Ruz Sanjuan ,&nbsp;Antonio Gilberto Ferreira ,&nbsp;Enoel Hernández Barreto ,&nbsp;Guy Van den Mooter ,&nbsp;Mirtha Mayra González Bedia ,&nbsp;Eryvaldo Socrates Tabosa do Egito ,&nbsp;Anselmo Gomes de Oliveira","doi":"10.1016/j.ejps.2025.107238","DOIUrl":"10.1016/j.ejps.2025.107238","url":null,"abstract":"<div><div>This work aimed to evaluate the effect of inclusion complex (IC) formation between the drug candidate 2-(2-nitrovinyl) furan (G-0) and hydroxypropyl β-cyclodextrin (HP-β-CD) or sulfobutylether β-cyclodextrin (SBE-β-CD) on the drug’s photostability under light exposure. Freeze-dried cyclodextrin inclusion complexes (ICs) and their corresponding physical mixtures were subjected to standardized forced irradiation and light exposure conditions according to ICH guidelines. Kinetic analysis suggested potential alterations in photodegradation pathways. The HPLC chromatographic profile of the ICs exhibited a distinct impurity pattern compared to the physical mixtures, while the profiles of the two ICs were similar. The main photodegradation product (PD1) was identified with a retention time of 5.4 min and a maximum absorption wavelength (λ_max) of 330 nm. PD1 was isolated using High-Performance Liquid Chromatography with diode array detection (HPLC-DAD) and further characterized through Nuclear Magnetic Resonance (NMR) spectroscopy. Combining 1D (¹H NMR, ¹³C {¹H}) and 2D (COSY, HSQC and HMBC) NMR measurements revealed the presence of two substances in equilibrium, identified as (2Z,4Z)-5-nitropenta-2,4-dienoic acid (NPDA) and its corresponding salt. The hazard classification of NPDA was assessed following ICH M7 guidelines using QSAR and expert rule-based toxicity screening methods, providing insights into its potential risk profile.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"213 ","pages":"Article 107238"},"PeriodicalIF":4.7,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144904266","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":"Evaluating drug absorption from enteric capsules in pigs: Impact of capsule size on gastric emptying","authors":"Sophia V. Hoffmann ,&nbsp;Brendan T. Griffin ,&nbsp;Vincent Jannin ,&nbsp;Joseph P. O’Shea","doi":"10.1016/j.ejps.2025.107237","DOIUrl":"10.1016/j.ejps.2025.107237","url":null,"abstract":"<div><div>The development of novel drug delivery systems is contingent on the availability of reliable preclinical animal models and their translatability to humans. The pig model is of particular interest in predicting dosage form-related factors in humans based on similar anatomical and physiological features. However, it has been reported that large non-disintegrating capsules show prolonged retention in the porcine stomach, which questions the utility of the pig model for exploring enteric dosage forms. The present study examined the gastric emptying of gastro-resistant Capsugel® Enprotect® capsules (sizes 0, 1, and 2). The prokinetic agent metoclopramide was evaluated for its potential to enhance gastric emptying. Paracetamol and caffeine were used as marker drugs. Pharmacokinetic parameters were employed to assess gastric emptying, with blood samples collected over a 24-hour period. The study demonstrated that Capsugel® Enprotect® capsules were cleared from the stomach, with mean absorption times ranging from 3.9 to 8.1 hours. There was no statistically significant difference between the tested capsule sizes. However, a trend toward slower gastric emptying with increasing capsule size was observed. In general, gastric emptying appeared to be slower than what is typically seen in humans, which limits the direct translatability of the findings. The administration of metoclopramide did not accelerate gastric emptying or improve consistency between individuals. Although the capsules emptied from the stomach more quickly than large monolithic dosage forms, the longer gastric residence compared to humans remains a limitation and should be taken into account when interpreting and extrapolating the data.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"213 ","pages":"Article 107237"},"PeriodicalIF":4.7,"publicationDate":"2025-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144872065","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":"Pharmacokinetics, metabolism, and toxicity of anisomelic acid and ovatodiolide: Guiding route of administration in preclinical studies","authors":"Navid Delshad ,&nbsp;Preethy Paul ,&nbsp;Michael Santos Silva ,&nbsp;Emrah Yatkin ,&nbsp;Mikko Voipio ,&nbsp;Senthil Kumar Rajendran ,&nbsp;John E. Eriksson","doi":"10.1016/j.ejps.2025.107235","DOIUrl":"10.1016/j.ejps.2025.107235","url":null,"abstract":"<div><div>Despite extensive progress in cancer therapeutic research, translating promising anticancer compounds into clinical treatments often fails due to suboptimal pharmacokinetic and safety profiles. These shortcomings underscore the critical need for comprehensive pharmacokinetic (PK) analyses in the early stages of drug development. Among the compounds that have shown promising anticancer effects in multiple preclinical studies are anisomelic acid (AA) and ovatodiolide (OVT) — two diterpenoids from plant <em>Anisomeles malabarica</em>. However, their pharmacokinetic and toxicity profile remain poorly characterized. To explore their potential as chemotherapy agents, we first evaluated their key <em>in vitro</em> pharmacokinetic (PK) parameters, followed by an acute oral toxicity assessment and complementary <em>in vivo</em> PK analyses. <em>In vitro</em> experiments showed that both AA and OVT exhibited near-complete solubility in phosphate buffer, high stability, and strong permeability across MDR1-MDCK cell monolayer, and were not substrates of multidrug resistance protein (MDR1). However, OVT underwent rapid metabolism in liver microsomes in the presence of NADPH, whereas AA showed comparatively greater stability under the same conditions. Subsequent <em>in vivo</em> pharmacokinetic (PK) analyses in mice also demonstrated rapid clearance and low systemic bioavailability for both compounds following intravenous (IV) or transdermal (TD) administration. Metabolite identification revealed extensive conjugation to cysteine, and no acute toxicity or mortality was observed at high oral doses. Collectively, these data underscore the distinct metabolic and clearance patterns that limit systemic bioavailability but highlight the favorable safety of AA and OVT. Moreover, while topical administration may offer therapeutic advantages for localized conditions, additional formulation strategies will be crucial to overcome limited bioavailability for systemic use of AA or OVT.</div></div>","PeriodicalId":12018,"journal":{"name":"European Journal of Pharmaceutical Sciences","volume":"213 ","pages":"Article 107235"},"PeriodicalIF":4.7,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144854992","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}