Xenobiotica最新文献_第3页

Meeting report of the 5th European Biotransformation Workshop. 第五届欧洲生物转化研讨会会议报告。

IF 1.3 4区医学

Xenobiotica Pub Date : 2024-09-01 Epub Date: 2024-09-18 DOI: 10.1080/00498254.2024.2400112

M Walles, A Pähler, E M Isin, Marie M Ahlqvist

引用次数: 0

The metabolic activation of and platelet response to vicagrel vary with P-glycoprotein deficiency, rather than P-glycoprotein inhibition, in mice. 在小鼠体内，P-糖蛋白缺乏（而非 P-糖蛋白抑制）会导致维卡格雷的代谢激活和血小板反应发生变化。

IF 1.3 4区医学

Xenobiotica Pub Date : 2024-09-01 Epub Date: 2024-08-21 DOI: 10.1080/00498254.2024.2390972

Xue-Mei Li, Hao-Dong Li, Yuan-Yuan Shao, Jin-Zi Ji, Ke Tang, Zhao-Dong Zheng, Yu Wu, Pei-Jie Ding, Jin Wang, Li-Ping Jiang, Ting Tai, Qiong-Yu Mi, Min Fu, Hong-Guang Xie

{"title":"The metabolic activation of and platelet response to vicagrel vary with P-glycoprotein deficiency, rather than P-glycoprotein inhibition, in mice.","authors":"Xue-Mei Li, Hao-Dong Li, Yuan-Yuan Shao, Jin-Zi Ji, Ke Tang, Zhao-Dong Zheng, Yu Wu, Pei-Jie Ding, Jin Wang, Li-Ping Jiang, Ting Tai, Qiong-Yu Mi, Min Fu, Hong-Guang Xie","doi":"10.1080/00498254.2024.2390972","DOIUrl":"10.1080/00498254.2024.2390972","url":null,"abstract":"This study aimed to determine changes in the hydrolysis of vicagrel, a substrate drug of arylacetamide deacetylase (Aadac) and carboxylesterase 2 (Ces2), in P-glycoprotein (P-gp)-deficient or P-gp-inhibited mice and to elucidate the mechanisms involved.Male wild-type (WT) and P-gp knock-out (KO) mice were used to investigate the systemic exposure of vicagrel thiol active metabolite H4 and platelet response to vicagrel, and the mRNA and protein expression levels of intestinal Aadac and Ces2. Moreover, WT mice were administered vicagrel alone or in combination with elacridar (a potent P-gp inhibitor) to determine drug-drug interactions.Compared with WT mice, P-gp KO mice exhibited significant increases in the systemic exposure of H4, the protein expression levels of intestinal Aadac and Ces2, and inhibition of ADP-induced platelet aggregation by vicagrel. Further, the H4 exposure was positively correlated with intestinal Aadac protein expression levels but did not vary with short-term inhibition of P-gp efflux activity by elacridar.P-gp-deficient mice, rather than elacridar-treated mice, exhibited significant upregulation of intestinal Aadac and Ces2 and thus, enhanced metabolic activation of and platelet response to vicagrel, suggesting that the metabolic activation of vicagrel may vary with P-gp deficiency, not P-gp inhibition, in mice.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"759-769"},"PeriodicalIF":1.3,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141914140","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

Meeting report: DMPK optimisation strategies and quantitative translational PKPD frameworks to predict human PK and efficacious dose of targeted protein degraders. 会议报告：预测靶向蛋白降解剂的人体 PK 和有效剂量的 DMPK 优化策略和定量转化 PKPD 框架。

IF 1.3 4区医学

Xenobiotica Pub Date : 2024-09-01 Epub Date: 2024-07-12 DOI: 10.1080/00498254.2024.2369787

Caroline Rynn, Heide Marika Duevel

引用次数: 0

Improved preclinical drug metabolism and pharmacokinetics of pibothiadine (HEC121210), a novel hepatitis B virus capsid assembly modulator. 新型乙型肝炎病毒囊壳组装调节剂 Pibothiadine (HEC121210) 临床前药物代谢和药代动力学的改进。

IF 1.3 4区医学

Xenobiotica Pub Date : 2024-09-01 Epub Date: 2024-08-12 DOI: 10.1080/00498254.2024.2381223

Ming Li, Xingguo Yan, Li Zhang, Xinchang Liu, Yayi Liu, Qian Wang, Jing Li

{"title":"Improved preclinical drug metabolism and pharmacokinetics of pibothiadine (HEC121210), a novel hepatitis B virus capsid assembly modulator.","authors":"Ming Li, Xingguo Yan, Li Zhang, Xinchang Liu, Yayi Liu, Qian Wang, Jing Li","doi":"10.1080/00498254.2024.2381223","DOIUrl":"10.1080/00498254.2024.2381223","url":null,"abstract":"Pibothiadine (PBD; HEC121120) is a novel hepatitis B virus capsid assembly modulator based on GLS4 (morphothiadine) and has inhibitory activities against resistant strains.To assess the overall preclinical drug metabolism and pharmacokinetics (DMPK) properties of PBD, in vivo pharmacokinetics studies in rats and dogs have been performed along with a series of in vitro metabolism assays.The oral bioavailability of PBD in rats and dogs might be related to its medium permeability in Caco-2 cells and largely be impacted by the pH-dependent solubility. PBD was highly distributed to the liver where the local exposure was 16.4 fold of the system exposure. PBD showed relatively low metabolic rate in recombinant human cytochrome P450 enzymes, whereas low to moderate in vitro clearance in liver microsomes and low (dog) to moderate (rat) in vivo clearance. Furthermore, β-oxidation and dehydrogenation were proposed as the primary metabolic pathways of PBD in rats.Compared to GLS4, the higher systemic exposure of PBD might be attributed to its improved oral absorption and metabolic stability. In addition, the enhanced liver/plasma exposure ratio could further increase the local exposure around the target. These improved DMPK properties might indicate better development of PBD in the clinical phase.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"701-710"},"PeriodicalIF":1.3,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141767604","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

Mechanism-based inactivation of cytochromes P450: implications in drug interactions and pharmacotherapy. 基于机理的细胞色素 P450 失活：药物相互作用和药物治疗的意义》。

IF 1.3 4区医学

Xenobiotica Pub Date : 2024-09-01 Epub Date: 2024-08-28 DOI: 10.1080/00498254.2024.2395557

Boon Hooi Tan, Nafees Ahemad, Yan Pan, Chin Eng Ong

{"title":"Mechanism-based inactivation of cytochromes P450: implications in drug interactions and pharmacotherapy.","authors":"Boon Hooi Tan, Nafees Ahemad, Yan Pan, Chin Eng Ong","doi":"10.1080/00498254.2024.2395557","DOIUrl":"10.1080/00498254.2024.2395557","url":null,"abstract":"Cytochrome P40 (CYP) enzymes dominate the metabolism of numerous endogenous and xenobiotic substances. While it is commonly believed that CYP-catalysed reactions result in the detoxication of foreign substances, these reactions can also yield reactive intermediates that can bind to cellular macromolecules to cause cytotoxicity or irreversibly inactivate CYPs that create them.Mechanism-based inactivation (MBI) produces either irreversible or quasi-irreversible inactivation and is commonly caused by CYP metabolic bioactivation to an electrophilic reactive intermediate. Many drugs that have been known to cause MBI in CYPs have been discovered as perpetrators in drug-drug interactions throughout the last 20-30 years.This review will highlight the key findings from the recent literature about the mechanisms of CYP enzyme inhibition, with a focus on the broad mechanistic elements of MBI for widely used drugs linked to the phenomenon. There will also be a brief discussion of the clinical or pharmacokinetic consequences of CYP inactivation with regard to drug interaction and toxicity risk.Gaining knowledge about the selective inactivation of CYPs by common therapeutic drugs helps with the assessment of factors that affect the systemic clearance of co-administered drugs and improves comprehension of anticipated interactions with other drugs or xenobiotics.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"575-598"},"PeriodicalIF":1.3,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142037076","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

Novel omeprazole delayed release orally disintegrating tablets for enhanced patient compliance: a case of model informed formulation development. 提高患者依从性的新型奥美拉唑缓释口腔崩解片：基于模型的制剂开发案例。

IF 1.3 4区医学

Xenobiotica Pub Date : 2024-09-01 Epub Date: 2024-08-21 DOI: 10.1080/00498254.2024.2391519

Rajkumar Boddu, Sivacharan Kollipara, Veena Kambam, Sohel Mohammed Khan, Soumyajit Behera, Nnvvss Narayana Murty, Nitin Baheti, Anup A Choudhury, Tausif Ahmed

{"title":"Novel omeprazole delayed release orally disintegrating tablets for enhanced patient compliance: a case of model informed formulation development.","authors":"Rajkumar Boddu, Sivacharan Kollipara, Veena Kambam, Sohel Mohammed Khan, Soumyajit Behera, Nnvvss Narayana Murty, Nitin Baheti, Anup A Choudhury, Tausif Ahmed","doi":"10.1080/00498254.2024.2391519","DOIUrl":"10.1080/00498254.2024.2391519","url":null,"abstract":"The advanced in silico simulation tools, such as physiologically based biopharmaceutics models (PBBM) or physiologically based pharmacokinetic models (PBPK), play critical role in model informed formulation development. This approach has been successfully implemented in the present case for development of novel omeprazole delayed-release orally disintegrating tablets (ODT) formulation, aimed to enhance patient compliance.PBBM was developed using physicochemical, biopharmaceutical, and dissolution data. The dissolution studies for pilot formulations were conducted in biopredictive media in fasting (0.1 N HCl followed by pH 6.8) and fed (pH 5 followed by pH 6.8) conditions. The model was extensively validated in three stages: pilot fasted, pilot fed virtual bioequivalence and food effect assessments. Impressively, the model was able to predict both passed and failed batches appropriately.Based on insights from the pilot study, a higher scale pivotal formulation was optimised. Prospective predictions were made for pivotal formulations using validated model and bio results were found to be in line with model predictions in fasting condition.Overall, a rationale and patient compliant formulation was developed using innovative modelling approach and filed to regulatory agency. The novel omeprazole formulation enhanced patient compliance through ease of administration thereby circumventing challenges of conventional formulation.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"629-641"},"PeriodicalIF":1.3,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141914139","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

In vitro ADME, mouse pharmacokinetics of LD14b, and bioanalysis of a novel aβ 17β-HSD10 modulator for the treatment of Alzheimer's disease. 用于治疗阿尔茨海默病的新型 aβ 17β-HSD10 调节剂的体外 ADME、LD14b 的小鼠药代动力学和生物分析。

IF 1.3 4区医学

Xenobiotica Pub Date : 2024-09-01 Epub Date: 2024-09-16 DOI: 10.1080/00498254.2024.2402033

Sohel Daria, Devendra Kumar, Nagsen Gautam, Jawaher Abdullah Alamoudi, Louise F Dow, Paul C Trippier, Yazen Alnouti

{"title":"In vitro ADME, mouse pharmacokinetics of LD14b, and bioanalysis of a novel aβ 17β-HSD10 modulator for the treatment of Alzheimer's disease.","authors":"Sohel Daria, Devendra Kumar, Nagsen Gautam, Jawaher Abdullah Alamoudi, Louise F Dow, Paul C Trippier, Yazen Alnouti","doi":"10.1080/00498254.2024.2402033","DOIUrl":"10.1080/00498254.2024.2402033","url":null,"abstract":"LD14b is an amyloid-β (Aβ) 17β-hydroxysteroid dehydrogenase type 10 (Aβ-17β-HSD10) protein-protein interaction modulator that shows promising in vitro and ex vivo activity to rescue Aβ-induced mitochondrial dysfunction, Aβ-induced toxicity, and Aβ-mediated inhibition of estradiol synthesis.The current study investigated in vitro human S9 fractions metabolic stability, apparent permeability, human and mouse plasma protein binding, in vivo pharmacokinetics, and tissue distribution in Balb/cJ mice. A fast (8-min), sensitive, reliable, and reproducible LC-MS/MS method was developed and validated over the dynamic range of 1-1000 ng/mL for the quantification of LD14b in different biological matrices (plasma, liver, kidney, brain, lungs, heart).LD14b was metabolically stable in human liver S9 fractions with 70% remaining after 90 minutes of incubation, showed intermediate apparent permeability of 3.55 × 10-06 cm/s and 6.16 × 10-06 cm/s for apical-to-basolateral (A-to-B) and basolateral-to-apical (B-to-A), respectively across the Caco-2 monolayer, and was medium/highly bound to human plasma proteins (84.1%), mouse plasma proteins (85.7%), and mouse brain homogenate (95.4%).LD14b showed an in vivo predicted % absorption of 52% in Balb/cJ mice and was well-distributed to the peripheral tissues (liver, kidney, lungs, and heart) including the brain.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"711-722"},"PeriodicalIF":1.3,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142296723","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

A systematic review of allometric scaling exponents for IgG mAbs. 对 IgG mAbs 异速缩放指数的系统回顾。

IF 1.3 4区医学

Xenobiotica Pub Date : 2024-09-01 Epub Date: 2024-08-07 DOI: 10.1080/00498254.2024.2383925

Simon Peter Rowland, Emma Nixon, Krithika Mohan, Qianwen Wang, James W T Yates

引用次数: 0

Human keratinocyte response to 4,4'-methylene diphenyl diisocyanate-glutathione conjugate exposure. 人类角质细胞对 4,4'-亚甲基二苯基二异氰酸酯-谷胱甘肽共轭物暴露的反应。

IF 1.3 4区医学

Xenobiotica Pub Date : 2024-09-01 Epub Date: 2024-10-07 DOI: 10.1080/00498254.2024.2401493

Brandon F Law, Chen-Chung Lin, Justin M Hettick

{"title":"Human keratinocyte response to 4,4'-methylene diphenyl diisocyanate-glutathione conjugate exposure.","authors":"Brandon F Law, Chen-Chung Lin, Justin M Hettick","doi":"10.1080/00498254.2024.2401493","DOIUrl":"10.1080/00498254.2024.2401493","url":null,"abstract":"Workplace exposure to diisocyanates like 4,4'-methylene diphenyl diisocyanate can cause occupational asthma (MDI-OA), and the underlying biological pathways are still being researched.Although uncertainty remains, evidence supports the hypothesis that dermal exposure to MDI plays an important role in the development of MDI-OA.Gene expression, proteomics, and informatics tools were utilised to characterise changes in expression of RNA and protein in cultured human HEKa keratinocyte cells following exposure to conjugates of MDI with glutathione (MDI-GSH).RT-qPCR analysis using a panel of 39 candidate primers demonstrated 9 candidate genes upregulated and 30 unchanged.HPLC-MS/MS analysis of HEKa cell lysate identified 18 540 proteins across all samples 60 proteins demonstrate statistically significant differential expression in exposed cells, some of which suggest activation of immune and inflammatory pathways.The results support the hypothesis that dermal exposures have the potential to play an important role in the development of MDI-OA. Furthermore, proteomic and gene expression data suggest multiple immune (adaptive and innate) and inflammatory pathways may be involved in the development of MDI-OA.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"749-758"},"PeriodicalIF":1.3,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142133935","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

In vitro and in vivo preclinical pharmacokinetic characterization of aficamten, a small molecule cardiac myosin inhibitor. 小分子心肌肌球蛋白抑制剂 Aficamten 的体外和体内药代动力学临床前表征。

IF 1.3 4区医学

Xenobiotica Pub Date : 2024-09-01 Epub Date: 2024-08-09 DOI: 10.1080/00498254.2024.2389407

Rajaa Sukhun, Peadar Cremin, Donghong Xu, Jeanelle Zamora, Jennifer Cheung, Luke Ashcraft, Mark P Grillo, Bradley P Morgan

{"title":"In vitro and in vivo preclinical pharmacokinetic characterization of aficamten, a small molecule cardiac myosin inhibitor.","authors":"Rajaa Sukhun, Peadar Cremin, Donghong Xu, Jeanelle Zamora, Jennifer Cheung, Luke Ashcraft, Mark P Grillo, Bradley P Morgan","doi":"10.1080/00498254.2024.2389407","DOIUrl":"10.1080/00498254.2024.2389407","url":null,"abstract":"Aficamten, a small molecule selective inhibitor of cardiac myosin, was characterised in preclinical in vitro and in vivo studies.Protein binding in human plasma was 10.4% unbound and ranged from 1.6% to 24.9% unbound across species. Blood-to-plasma ratios ranged from 0.69 to 1.14 across species. Aficamten hepatic clearance in human was predicted to be low from observed high metabolic stability in vitro in human liver microsomes. Aficamten demonstrated high permeability in Caco-2 cell monolayers.Aficamten in vivo clearance was low across species at 8.8, 2.1, 3.3, and 11 mL/min/kg in mouse, rat, dog, and monkey, respectively. The volume of distribution was low-to-high ranging from 0.53 in rat to 11 L/kg in dog. Oral bioavailability ranged from 41% in monkey to 98% in mouse.Aficamten was metabolised in vitro to eight metabolites with hydroxylated metabolites M1a and M1b predominating. CYP phenotyping indicated multiple CYPs (2C8, 2C9, 2D6, and 3A4) contributing to the metabolism of aficamten.Human clearance (1.1 mL/min/kg) and volume of distribution (6.5 L/kg) were predicted using 4-species allometry employing 'rule-of-exponents'. A predicted 69 hour half-life is consistent with observed half-life in human Phase-1.No CYP-based drug-drug interaction liability as a precipitant was predicted for aficamten.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"686-700"},"PeriodicalIF":1.3,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141894497","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