Xenobiotica最新文献_第7页

Beyond hemorrhagic cystitis: unraveling the multifaceted protective roles of sodium 2-mercaptoethanesulfonate. 超越出血性膀胱炎：揭示2-巯基乙磺酸钠的多方面保护作用。

IF 1.5 4区医学

Xenobiotica Pub Date : 2026-04-01 Epub Date: 2026-04-17 DOI: 10.1080/00498254.2026.2653829

Prathap Srirangan, Muthukumar Balakrishnan, Shalini Magesh, Mukul Shyam, Abilash Valsala Gopalakrishnan, Sabina Evan Prince

{"title":"Beyond hemorrhagic cystitis: unraveling the multifaceted protective roles of sodium 2-mercaptoethanesulfonate.","authors":"Prathap Srirangan, Muthukumar Balakrishnan, Shalini Magesh, Mukul Shyam, Abilash Valsala Gopalakrishnan, Sabina Evan Prince","doi":"10.1080/00498254.2026.2653829","DOIUrl":"10.1080/00498254.2026.2653829","url":null,"abstract":"Sodium 2-mercaptoethanesulfonate (MESNA) is widely used as a uroprotective agent to prevent haemorrhagic cystitis (HC) associated with oxazaphosphorine chemotherapy; however, emerging evidence suggests broader cytoprotective potential beyond the urinary system.This review systematically compiles and evaluates preclinical and clinical evidence on the multi-organ protective effects of MESNA, including its roles in mitigating nephrotoxicity, hepatotoxicity, cardiotoxicity, neurotoxicity, pulmonary injury, gastrointestinal damage, and reproductive toxicity.The protective mechanisms of MESNA are primarily attributed to its thiol-mediated detoxification, antioxidant activity, and anti-inflammatory effects, including scavenging of reactive oxygen species (ROS), reduction of lipid peroxidation, modulation of cytokine responses, and maintenance of cellular redox balance.In addition to its established clinical use in oncology, MESNA demonstrates potential applications in surgical procedures, ischemia-reperfusion injury, and combination therapies, although current clinical evidence supporting its systemic protective effects remains limited.Despite its promising therapeutic profile, factors such as short plasma half-life, limited systemic bioavailability, and variability in clinical outcomes highlight the need for further mechanistic studies and well-designed clinical trials to establish its role as a multi-organ cytoprotective agent.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"318-338"},"PeriodicalIF":1.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147610143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Advances in new approach methodologies for assessing ADME properties of nano-formulations. 评价纳米配方ADME性能的新方法方法研究进展。

IF 1.5 4区医学

Xenobiotica Pub Date : 2026-04-01 Epub Date: 2026-04-09 DOI: 10.1080/00498254.2026.2653145

Aishwarya Jain

引用次数: 0

Pulmonary pharmacokinetics of riociguat following solution and suspension dosing in mice. 利奥西奎特溶液和混悬液给药后小鼠肺药动学。

IF 1.5 4区医学

Xenobiotica Pub Date : 2026-04-01 Epub Date: 2026-05-04 DOI: 10.1080/00498254.2026.2654199

Shengnan Zhang, Qihan Xu, Jiankang Chen, Bing Zhu, Zhenghui He, Qi Pei, Yu Lin

{"title":"Pulmonary pharmacokinetics of riociguat following solution and suspension dosing in mice.","authors":"Shengnan Zhang, Qihan Xu, Jiankang Chen, Bing Zhu, Zhenghui He, Qi Pei, Yu Lin","doi":"10.1080/00498254.2026.2654199","DOIUrl":"10.1080/00498254.2026.2654199","url":null,"abstract":"Pulmonary hypertension is a life-threatening condition with limited therapeutic options. Riociguat, a soluble guanylate cyclase stimulator, is approved for pulmonary arterial and chronic thromboembolic pulmonary hypertension, but oral administration results in variable systemic exposure and adverse effects. This study aimed to evaluate the intratracheal pharmacokinetics and pulmonary retention of riociguat in mice, comparing a suspension and a dimethyl sulfoxide (DMSO)-based solution.Pharmacokinetic parameters, including maximum concentration (Cmax), time to maximum concentration (Tmax), half-life (t1/2), mean residence time (MRT), systemic exposure, and tissue distribution (lung, kidney, and liver), were determined. Lung histology was also assessed.The solution demonstrated higher dose-corrected plasma Cmax/D (0.278 vs. 0.128 ng/mL/μg) and shorter systemic retention (MRT0-∞: 3.57 vs. 4.43 h) compared with the suspension, while systemic exposure remained similar. In lung tissue, the suspension exhibited prolonged retention with longer t1/2 (13.54 vs. 5.17 h) and MRT0-∞ (13.37 vs. 7.82 h), indicating sustained pulmonary exposure. No histological changes were observed with the DMSO-based formulation. The suspension provided extended lung retention but contained large particles (10-100 μm) unsuitable for inhalation. Particle engineering to develop optimised suspension or dry powder formulations may enable efficient lung deposition and improve riociguat inhalation therapy.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"272-281"},"PeriodicalIF":1.5,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147595248","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Behavioural toxicodynamics and kinetic profiling of PCB congeners in Swiss Albino mouse dosed with Aroclor 1232 through inhalational route: a pivotal risk assessment study. 吸入Aroclor 1232对瑞士白化小鼠多氯联苯同系物的行为毒性动力学和动力学分析：一项关键风险评估研究。

IF 1.5 4区医学

Xenobiotica Pub Date : 2026-03-01 Epub Date: 2026-02-24 DOI: 10.1080/00498254.2026.2621365

Sivaselvakumar Muthusamy, Ramanujam Narayanan

{"title":"Behavioural toxicodynamics and kinetic profiling of PCB congeners in Swiss Albino mouse dosed with Aroclor 1232 through inhalational route: a pivotal risk assessment study.","authors":"Sivaselvakumar Muthusamy, Ramanujam Narayanan","doi":"10.1080/00498254.2026.2621365","DOIUrl":"10.1080/00498254.2026.2621365","url":null,"abstract":"Polychlorinated Biphenyls pose hazards to humans as environmental and occupational workplace pollutants, despite which, though they are regulated in India, their use is not yet banned.A whole-body inhalational chamber has been utilised to expose mice to different doses of Aroclor 1232 for single 6-h durations. The plasma and brain samples were used to estimate the corresponding congeners of PCBs (PCB 77 and PCB 180) and calculate their pharmacokinetic parameters. These variables were then correlated with mouse behaviour using Irwin scale, and monoamine levels at 4 h, which is the Tmax.A definite dose-dependence of PCB kinetic parameters was identified in plasma and brain. PCB 77 exhibited more accumulation in brain than plasma, whereas PCB 180 accumulated more in plasma than brain. The changes in the mood and miscellaneous domains on the Irwin scale were due to higher brain PCB 77; changes in autonomic functions were due to higher plasma PCB 180 levels. Behaviour scores were statistically significant at Tmax (3-5 h).Generally, DA reduced at Tmax for each dose level; 5-HT increased exponentially as Tmax approached for each dose level; and NA followed U-shaped dose response, the dip being correlated at Cmax.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"179-191"},"PeriodicalIF":1.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146087480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Neuroprotective and antidepressant potential of S-adenosyl-L methionine (SAMe) and coenzyme Q10 in a corticosteroid-induced depression model. s -腺苷- l蛋氨酸（SAMe）和辅酶Q10在皮质类固醇诱导的抑郁模型中的神经保护作用和抗抑郁作用

IF 1.5 4区医学

Xenobiotica Pub Date : 2026-03-01 Epub Date: 2026-03-28 DOI: 10.1080/00498254.2026.2651323

Archana Panigrahy, Shakti Ketan Prusty, Jajnadatta Panda

{"title":"Neuroprotective and antidepressant potential of S-adenosyl-L methionine (SAMe) and coenzyme Q10 in a corticosteroid-induced depression model.","authors":"Archana Panigrahy, Shakti Ketan Prusty, Jajnadatta Panda","doi":"10.1080/00498254.2026.2651323","DOIUrl":"10.1080/00498254.2026.2651323","url":null,"abstract":"S-adenosyl-L-methionine (SAMe) and Coenzyme Q10 (CoQ10) are known to support brain health through roles in methylation, neurotransmitter synthesis, and reduction of oxidative stress, suggesting potential antidepressant benefits.This experimental study evaluated the antidepressant and antioxidant effects of SAMe, alone and in combination with CoQ10, in a dexamethasone-induced depression model in rats.Thirty-six male Wistar rats were divided into six groups and received dexamethasone (20 mg/kg, orally) for 21 days to induce depressive-like behaviour. SAMe, CoQ10, or their combination were administered 30 minutes prior to dexamethasone. Behavioural assessments were conducted to evaluate depressive-like features, and oxidative stress markers (NOx, MDA, TOS, TAS, GSH, RSH) were measured in the cerebral cortex and plasma. Histopathological examination of the hippocampus was also performed. Dexamethasone produced marked depressive behaviours and increased oxidative stress. Treatment with SAMe and CoQ10, individually, improved behavioural outcomes and enhanced antioxidant status, indicating antidepressant and neuroprotective effects. The combined treatment yielded the most pronounced benefits, almost normalising oxidative markers and preserving hippocampal architecture.Overall, the findings support the utility of dexamethasone-induced depression as a valid experimental model and suggest that SAMe and CoQ10, particularly in combination, may offer promising antidepressant and neuroprotective potential.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"249-263"},"PeriodicalIF":1.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147515217","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The protective effect of linalool against carbon tetrachloride-induced testicular toxicity in rats. 芳樟醇对四氯化碳致大鼠睾丸毒性的保护作用。

IF 1.5 4区医学

Xenobiotica Pub Date : 2026-03-01 Epub Date: 2026-03-09 DOI: 10.1080/00498254.2026.2641519

Mohammadreza Khalkhali, Shiva Rahimi, Aliakbar Fazaeli, Ramin Salimnejad, Reza Alipanah-Moghadam, Masoud Ojarudi, Mohammad Mazani, Pouria Sobhi, Lotfollah Rezagholizadeh

{"title":"The protective effect of linalool against carbon tetrachloride-induced testicular toxicity in rats.","authors":"Mohammadreza Khalkhali, Shiva Rahimi, Aliakbar Fazaeli, Ramin Salimnejad, Reza Alipanah-Moghadam, Masoud Ojarudi, Mohammad Mazani, Pouria Sobhi, Lotfollah Rezagholizadeh","doi":"10.1080/00498254.2026.2641519","DOIUrl":"10.1080/00498254.2026.2641519","url":null,"abstract":"Infertility related to men is a major global issue. Due to the high costs and side effects of chemical drugs, interest has shifted towards medicinal bioactive compounds. Linalool, a terpenoid found in many plants, shows potential in reducing inflammation and oxidative stress. This study investigated the protective effects of linalool against CCl4-induced testicular toxicity in rats.Twenty-four rats were divided into four groups: normal control, linalool only, CCl4 only, and linalool plus CCl4 treatment. Linalool (25 mg/kg) was administered for 14 days, with CCl4 given as a single dose on day 14. Forty-eight hours later, testes were collected to assess oxidative stress markers and histopathological changes.CCl4 significantly reduced antioxidant enzyme activity and total antioxidant capacity, while increasing malondialdehyde (MDA) levels (p < 0.001). Linalool treatment significantly improved antioxidant markers (p < 0.01) and decreased MDA levels (p < 0.001) compared to the CCl4 group. Histological analysis showed that linalool ameliorated CCl4-induced structural damage in testicular tissue.These findings suggest linalool protects against testicular toxicity by preventing excessive free radical accumulation and subsequent oxidative damage, highlighting its potential as a therapeutic agent for male infertility associated with oxidative stress.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"222-227"},"PeriodicalIF":1.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147370397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Therapeutic effect of oleanolic acid on hyperthyroid rats through TLR4/NF-κB pathway. 齐墩果酸通过TLR4/NF-κB通路对甲状腺功能亢进大鼠的治疗作用。

IF 1.5 4区医学

Xenobiotica Pub Date : 2026-03-01 Epub Date: 2026-03-15 DOI: 10.1080/00498254.2026.2641507

Jian Zhong, Xiali Zhou, Jing Zhang, Bo Zou

{"title":"Therapeutic effect of oleanolic acid on hyperthyroid rats through TLR4/NF-κB pathway.","authors":"Jian Zhong, Xiali Zhou, Jing Zhang, Bo Zou","doi":"10.1080/00498254.2026.2641507","DOIUrl":"10.1080/00498254.2026.2641507","url":null,"abstract":"Hyperthyroidism is primarily characterised by excessive secretion of thyroid hormones and abnormal proliferation of thyroid follicular cells. Graves' disease is the most prevalent and is classified as an autoimmune thyroid disorder. However, as a typical triterpenoid compound, the mechanism of oleanolic acid in treating hyperthyroidism remains unclear. Therefore, this study aims to explore the effects and mechanisms of oleanolic acid on hyperthyroidism.The rats were divided into six groups. During the experiment, the body weight of the rats was measured weekly, and their clinical signs were monitored daily. After the administration was completed, the changes in various indicators of the rats were detected through ELISA, HE staining, immunohistochemistry, TUNEL assay, and Western blot experiments.After treatment with methimazole or oleanolic acid, it was found that the rats' body weight increased, their clinical symptoms returned to normal basically, the pathological damage of the thyroid tissue in hyperthyroid rats was significantly reduced, and the adverse effects were also reversed. Furthermore, LPS treatment can reverse the therapeutic effect of oleanolic acid on hyperthyroidism in rats.Oleanolic acid could regulate hormone levels and alleviate oxidative stress in rats with hyperthyroidism by inhibiting the TLR4/NF-κB pathway.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"228-239"},"PeriodicalIF":1.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147356857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Identification, structural elucidation and nonclinical characterisation of oxMET1: a further major metabolite of xevinapant? oxMET1的鉴定、结构解析和非临床特征：xevinapant的另一个主要代谢物？

IF 1.5 4区医学

Xenobiotica Pub Date : 2026-03-01 Epub Date: 2026-02-25 DOI: 10.1080/00498254.2026.2630754

Benedikt Lang, Hanno Schieferstein, Holger Scheible, Martina Foerster, Jonny Nachtigall, Christina Esdar, Kathrin Glaeser, Yulia Vugmeyster, Annick Menetrey, Frederic Massiere, Andreas Marx, Marko Hermsen, Jan G Brandenburg, Felix Rohdich

{"title":"Identification, structural elucidation and nonclinical characterisation of oxMET1: a further major metabolite of xevinapant?","authors":"Benedikt Lang, Hanno Schieferstein, Holger Scheible, Martina Foerster, Jonny Nachtigall, Christina Esdar, Kathrin Glaeser, Yulia Vugmeyster, Annick Menetrey, Frederic Massiere, Andreas Marx, Marko Hermsen, Jan G Brandenburg, Felix Rohdich","doi":"10.1080/00498254.2026.2630754","DOIUrl":"10.1080/00498254.2026.2630754","url":null,"abstract":"Xevinapant, an oral IAP (inhibitor of apoptosis protein) inhibitor, was clinically investigated for the treatment of various cancers. A novel metabolite of xevinapant, oxidated D-1143-MET1 (oxMET1), was identified in the human mass balance study, which had not been detected in previous non- and clinical studies but represented almost 10% of the total drug exposure after single-dose administration and was therefore pinpointed for its structural and initial nonclinical characterization.Using high-resolution mass spectrometry (HRMS) and nuclear magnetic resonance (NMR) spectroscopy after a semi-preparative isolation of oxMET1 it was possible to determine its definitive structure.OxMET1 exhibited only negligible inhibitory activity on cIAP1 in vitro, and thus, taking the low unbound fraction in human plasma into account, contribution to in vivo efficacy was considered low.In addition, coverage of human exposure could be shown in plasma samples from toxicity studies performed with preclinical species, so oxMET1, although likely major, was not a disproportionate circulating metabolite in humans. Based on these findings, this metabolite did not raise safety concerns according to the MIST guidelines, however it warrants further characterisation of its drug-drug interaction (DDI) potential. The integrated workflow presented here highlights the importance of metabolite characterization in drug development.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"192-203"},"PeriodicalIF":1.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146202631","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Inhibition of human liver cytochrome P450 2D6 (CYP6D2) by tetrahydropalmatine, protopine, and dehydrocorydaline and their oxidative metabolism. 四氢巴马汀、原托碱和脱氢堇青碱对人肝细胞色素P450 2D6 （CYP6D2）的抑制作用及其氧化代谢。

IF 1.5 4区医学

Xenobiotica Pub Date : 2026-03-01 Epub Date: 2026-04-12 DOI: 10.1080/00498254.2026.2650150

Jinyi Zhao, Xin He, Shan Feng, Shanshan Cao

{"title":"Inhibition of human liver cytochrome P450 2D6 (CYP6D2) by tetrahydropalmatine, protopine, and dehydrocorydaline and their oxidative metabolism.","authors":"Jinyi Zhao, Xin He, Shan Feng, Shanshan Cao","doi":"10.1080/00498254.2026.2650150","DOIUrl":"10.1080/00498254.2026.2650150","url":null,"abstract":"The inhibition and metabolism kinetics of tetrahydropalmatine (THP), protopine (PRO), and dehydrocorydaline (DHC), three major biologically active components of Corydalis yanhusuo W. T. Wang, which has been used for thousands of years in China, were evaluated in human liver microsomes (HLMs) to determine their potential for drug-drug interactions.THP acted as a mechanism-based inhibitor of cytochrome P450 2D6 (CYP2D6), with a Kinact of 0.053 min⁻1 and a Ki of 0.26 µM. It was metabolised by HLMs with a Km of 7.62 μM, Vmax of 0.071 nmol/min/mg, and intrinsic clearance (CLint) of 9.27 × 10⁻6 L/min/mg. The oxidative metabolism of THP involved CYP2C19, CYP3A4, CYP1A2, and CYP2D6.PRO was a mixed inhibitor (both competitive and non-competitive) of CYP2D6, with Ki of 0.023 µM and Kis of 0.042 µM. HLMs metabolised PRO with a Km of 3.99 μM, Vmax of 0.033 nmol/min/mg protein, and CLint of 8.20 × 10⁻⁶ L/min/mg. Its oxidative metabolism involved CYP2C19, CYP2D6, and CYP3A4.DHC was a weakly competitive inhibitor of CYP2D6 (Ki = 20.1 µM) and was no longer metabolised by HLMs.These findings indicate that CYP2D6 is a potential target for drug-drug interaction involving THP and PRO, whereas DHC exhibits minimal interaction potential.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"240-248"},"PeriodicalIF":1.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147515228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Model-based steady state pharmacokinetic predictions using high throughput cassette infusion approach in mice. 高通量盒式输注方法在小鼠体内基于模型的稳态药代动力学预测。

IF 1.5 4区医学

Xenobiotica Pub Date : 2026-03-01 Epub Date: 2026-04-09 DOI: 10.1080/00498254.2026.2637031

Saivishal Daripelli, Amol Achyutrao Raje, Vishwottam Kandikere, P R Anand Vijaya Kumar

{"title":"Model-based steady state pharmacokinetic predictions using high throughput cassette infusion approach in mice.","authors":"Saivishal Daripelli, Amol Achyutrao Raje, Vishwottam Kandikere, P R Anand Vijaya Kumar","doi":"10.1080/00498254.2026.2637031","DOIUrl":"10.1080/00498254.2026.2637031","url":null,"abstract":"Achieving and characterising steady-state drug concentrations is an essential objective for evaluating exposure-response relationships in preclinical pharmacology.This study assessed the pharmacokinetics (PK) of Fulvestrant, Imipramine, and Brivaracetam using cassette dosing. In vitro liver stability assays with mouse liver microsomes and hepatocytes, both individually and in combination, showed no significant drug-drug interactions.Single-dose subcutaneous (SC) PK studies in CD-1 mice provided absorption, clearance, and distribution parameters to model infusion rates targeting steady-state concentrations (Css). A 168-h SC cassette infusion via Alzet osmotic pumps was used to validate predictions.Brivaracetam had the highest exposure and lowest clearance, while Imipramine showed rapid elimination. Compartmental modelling accurately predicted infusion doses, targeting Css of 60 ng/mL. Observed Css values were lower than predicted, with Imipramine showing the closest match. All compounds reached steady-state within 24-36 h, and clearance/exposure rankings were consistent across models and experiments.This integrated approach combining SC pharmacokinetic (SC PK) profiling, modelling, and cassette infusion enabled model-informed dose prediction and qualitative validation, which can support early PK evaluation and formulation development in drug discovery.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"204-213"},"PeriodicalIF":1.5,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147291281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0