Xenobiotica最新文献_第9页

Safflower yellow for injection enhances anti-coagulation of warfarin in rats: implications in pharmacodynamics and pharmacokinetics. 注射用红花黄色素可增强华法林对大鼠的抗凝作用：对药效学和药代动力学的影响

IF 1.8 4区医学

Xenobiotica Pub Date : 2024-02-01 Epub Date: 2024-03-13 DOI: 10.1080/00498254.2024.2326987

Yan Liu, Jiahui Sun, Chunjuan Yang, Mengnan Qin, Shiwei Xu, Yue Zhao, Gaofeng Liu

{"title":"Safflower yellow for injection enhances anti-coagulation of warfarin in rats: implications in pharmacodynamics and pharmacokinetics.","authors":"Yan Liu, Jiahui Sun, Chunjuan Yang, Mengnan Qin, Shiwei Xu, Yue Zhao, Gaofeng Liu","doi":"10.1080/00498254.2024.2326987","DOIUrl":"10.1080/00498254.2024.2326987","url":null,"abstract":"This study investigated whether Safflower Yellow for injection (SYI) would affect the anticoagulation of warfarin in rats.Wistar male rats were divided into six groups randomly and administered with SYI (9 mg/kg, intraperitoneal injection) in single-dose and steady-dose warfarin (0.2 mg/kg, oral gavage), respectively. The pharmacodynamic parameters of PT and APTT were measured by a coagulation analyser. R/S-warfarin concentration was measured by UHPLC-MS/MS, and pharmacokinetic parameters calculated using DAS 2.0 software.The single-dose study demonstrated that SYI, alone or co-administered with warfarin, could significantly increase PT, INR, and APTT values (p < 0.01). R-warfarin Cmax, AUC, and t1/2 values increased by 9.25% (p > 0.05), 25.96% (p < 0.01), and 26.17% (p < 0.01), respectively, whereas the CL/F value reduced by 22.22% (p < 0.01) in the presence of SYI. Meanwhile, S-warfarin Cmax, AUC, and t1/2 values increased by 37.41%, 32.11%, and 31.73% (all p < 0.01), respectively, whereas the CL/F value reduced by 33.33% (p < 0.01). The steady-dose study showed that PT, INR, APTT, and the concentrations of R/S-warfarin increased significantly when SYI was co-administered with warfarin (p < 0.01).SYI can enhance warfarin's anticoagulation intensity and decelerate its metabolism in rats.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"75-82"},"PeriodicalIF":1.8,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140040465","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

Preclinical characterization of the absorption and disposition of the brain penetrant PI3K/mTOR inhibitor paxalisib and prediction of its pharmacokinetics and efficacy in human. 脑穿透性 PI3K/mTOR 抑制剂帕沙利西的吸收和处置的临床前表征及其在人体中的药代动力学和药效预测

IF 1.8 4区医学

Xenobiotica Pub Date : 2024-02-01 Epub Date: 2024-01-15 DOI: 10.1080/00498254.2024.2303586

Laurent Salphati, Jodie Pang, Bruno Alicke, Emile G Plise, Jonathan Cheong, Allan Jaochico, Alan G Olivero, Deepak Sampath, Susan Wong, Xiaolin Zhang

{"title":"Preclinical characterization of the absorption and disposition of the brain penetrant PI3K/mTOR inhibitor paxalisib and prediction of its pharmacokinetics and efficacy in human.","authors":"Laurent Salphati, Jodie Pang, Bruno Alicke, Emile G Plise, Jonathan Cheong, Allan Jaochico, Alan G Olivero, Deepak Sampath, Susan Wong, Xiaolin Zhang","doi":"10.1080/00498254.2024.2303586","DOIUrl":"10.1080/00498254.2024.2303586","url":null,"abstract":"Glioblastoma multiforme (GBM) is the most common primary brain tumour in adults. Available treatments have not markedly improved patient survival in the last twenty years. However, genomic investigations have showed that the PI3K pathway is frequently altered in this glioma, making it a potential therapeutic target.Paxalisib is a brain penetrant PI3K/mTOR inhibitor (mouse Kp,uu 0.31) specifically developed for the treatment of GBM. We characterised the preclinical pharmacokinetics and efficacy of paxalisib and predicted its pharmacokinetics and efficacious dose in humans.Plasma protein binding of paxalisib was low, with the fraction unbound ranging from 0.25 to 0.43 across species. The hepatic clearance of paxalisib was predicted to be low in mice, rats, dogs and humans, and high in monkeys, from hepatocytes incubations. The plasma clearance was low in mice, moderate in rats and high in dogs and monkeys. Oral bioavailability ranged from 6% in monkeys to 76% in rats.The parameters estimated from the pharmacokinetic/pharmacodynamic modelling of the efficacy in the subcutaneous U87 xenograft model combined with the human pharmacokinetics profile predicted by PBPK modelling suggested that a dose of 56 mg may be efficacious in humans. Paxalisib is currently tested in Phase III clinical trials.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"64-74"},"PeriodicalIF":1.8,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139404602","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

Effect of tubeimoside I on the activity of cytochrome P450 enzymes in human liver microsomes. tubeimoside I 对人肝脏微粒体中细胞色素 P450 酶活性的影响。

IF 1.8 4区医学

Xenobiotica Pub Date : 2024-02-01 Epub Date: 2024-01-12 DOI: 10.1080/00498254.2023.2301352

Rui Wang, Kai Zheng, Yunjiao Liu, Shuxia Ji, Yaxin Tang, Jie Wang, Rong Jiang

{"title":"Effect of tubeimoside I on the activity of cytochrome P450 enzymes in human liver microsomes.","authors":"Rui Wang, Kai Zheng, Yunjiao Liu, Shuxia Ji, Yaxin Tang, Jie Wang, Rong Jiang","doi":"10.1080/00498254.2023.2301352","DOIUrl":"10.1080/00498254.2023.2301352","url":null,"abstract":"This study assessed the effect of tubeimoside I on CYP1A2, 2A6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 to reveal the potential of tubeimoside I to induce drug-drug interaction.The evaluation of cytochromes P450 enzyme (CYP) activity was performed in pooled human liver microsomes with probing substrates of CYP1A2, 2A6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4. Typical inhibitors were employed as positive controls and the effect of 0, 2.5, 5, 10, 25, 50, and 100 μM tubeimoside I was investigated.The activity of CYP2D6, 2E1, and 3A4 was significantly inhibited by tubeimoside I with the IC50 values of 10.34, 11.58, and 9.74 μM, respectively. The inhibition of CYP2D6 and 2E1 was competitive with the Ki value of 5.66 and 5.29 μM, respectively. While the inhibition of CYP3A4 was non-competitive with the Ki value of 4.87 μM. Moreover, the inhibition of CYP3A4 was time-dependent with the KI and Kinact values of 0.635 μM-1 and 0.0373 min-1, respectively.Tubeimoside I served as a competitive inhibitor of CYP2D6 and 2E1 exerting weak inhibition and a non-competitive inhibitor of CYP3A4 exerting moderate inhibition.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"57-63"},"PeriodicalIF":1.8,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139080953","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

Metabolite characterisation of the peptide-drug conjugate LN005 in liver S9s by UHPLC-Orbitrap-HRMS. 肽-药物偶联物LN005在肝脏S9s代谢产物的UHPLC-Orbitrap-HRMS表征。

IF 1.8 4区医学

Xenobiotica Pub Date : 2024-01-01 Epub Date: 2024-01-08 DOI: 10.1080/00498254.2023.2289635

Yali Yuan, Weiqiang Wang, Jing Luo, Chongzhuang Tang, Yuandong Zheng, Jinghua Yu, Honghong Xu, Mingshe Zhu, Taijun Hang, Hao Wang, Xingxing Diao

{"title":"Metabolite characterisation of the peptide-drug conjugate LN005 in liver S9s by UHPLC-Orbitrap-HRMS.","authors":"Yali Yuan, Weiqiang Wang, Jing Luo, Chongzhuang Tang, Yuandong Zheng, Jinghua Yu, Honghong Xu, Mingshe Zhu, Taijun Hang, Hao Wang, Xingxing Diao","doi":"10.1080/00498254.2023.2289635","DOIUrl":"10.1080/00498254.2023.2289635","url":null,"abstract":"LN005 is a peptide-drug conjugate (PDC) targeting glucose-regulated protein 78 (GRP78) to treat several types of cancer, such as breast, colon, and prostate cancer.As a new drug modality, understanding its metabolism and elimination pathways will help us to have a whole picture of it. Currently, there are no metabolic studies on LN005; therefore, this study aimed to investigate the metabolism of LN005, clarify its metabolic profile in the liver S9s of different species, and identify the major metabolic pathways and differences between species.The incubation samples were measured by ultra-high performance liquid chromatography combined with orbitrap tandem mass spectrometry (UHPLC-Orbitrap-HRMS).The results showed that LN005 was metabolised by liver S9s, and four metabolites were identified. The main metabolic pathway of LN005 in liver S9s was oxidative deamination to ketone or hydrolysis. Similar metabolic profiles were observed in mouse, rat, dog, monkey, and human liver S9s, indicating no differences between these four animal species and humans.This study provides information for the structural modification and optimisation of LN005 and affords a reference for subsequent animal experiments and human metabolism of other PDCs.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"1-9"},"PeriodicalIF":1.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138478643","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

Dose proportionality and bioavailability of quinoxaline-based JNK inhibitor after single oral and intravenous administration in rats. 基于喹喔啉的 JNK 抑制剂在大鼠口服和静脉注射后的剂量比例和生物利用度

IF 1.8 4区医学

Xenobiotica Pub Date : 2024-01-01 Epub Date: 2024-01-02 DOI: 10.1080/00498254.2023.2299686

Galina A Frelikh, Elena A Yanovskaya, Alexander P Lakeev, Galina A Chernysheva, Vera I Smolyakova, Anastasia R Kovrizhina

{"title":"Dose proportionality and bioavailability of quinoxaline-based JNK inhibitor after single oral and intravenous administration in rats.","authors":"Galina A Frelikh, Elena A Yanovskaya, Alexander P Lakeev, Galina A Chernysheva, Vera I Smolyakova, Anastasia R Kovrizhina","doi":"10.1080/00498254.2023.2299686","DOIUrl":"10.1080/00498254.2023.2299686","url":null,"abstract":"The dose proportionality and bioavailability of the potential anti-inflammatory and neuroprotective JNK inhibitor 11H-indeno[1,2-b]quinoxalin-11-one oxime (IQ-1) were evaluated by comparing pharmacokinetic parameters after single oral (25, 50 and 100 mg/kg) and intravenous (1 mg/kg) IQ-1 administration in rats.IQ-1 and its major metabolite ketone 11H-indeno[1,2-b]quinoxalin-11-one (IQ-18) were isolated from plasma samples by liquid-liquid extraction. IQ-1 (E-isomer) and IQ-18 were simultaneously quantified in plasma by the validated method of liquid chromatography with triple quadrupole mass spectrometry (HPLC-MS/MS).The absolute bioavailability of IQ-1 was < 1.5%. Cmax values were 24.72 ± 4.30, 25.66 ± 7.11 and 37.61 ± 3.53 ng/mL after single oral administration of IQ-1 at doses of 25, 50 and 100 mg/kg, respectively. IQ-1 exhibited dose proportionality at 50-100 mg/kg dose levels, whereas its pharmacokinetics was not dose proportional over the range of 25-50 mg/kg. IQ-18 demonstrated the invariance of the dose-normalized Cmax.In this study we systematically elucidated the absorption characteristics of IQ-1 in rat gastrointestinal tract and provided better understanding of IQ-1 pharmacology for the future development of a new formulations and therapeutic optimisation.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"18-25"},"PeriodicalIF":1.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139049415","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

Synthesis and evaluation of indomethacin prodrugs with a diester structure that are metabolically activated by human carboxylesterases 合成和评估可被人类羧基酯酶代谢活化的具有二酯结构的吲哚美辛原药

IF 1.8 4区医学

Xenobiotica Pub Date : 2023-12-23 DOI: 10.1080/00498254.2023.2298270

Daisuke Takani, Masato Takahashi, Masakiyo Hosokawa

引用次数: 0

CYP-catalysed Cycling of Clozapine and Clozapine-N-oxide Promotes the Generation of Reactive Oxygen Species in vitro. CYP 催化的氯氮平与氯氮平-N-氧化物的体外循环促进了活性氧的生成。

IF 1.8 4区医学

Xenobiotica Pub Date : 2023-12-18 DOI: 10.1080/00498254.2023.2294473

Ellen Kingston, Malcolm Tingle, Brandi L. Bellissima, Nuala Helsby, Kathryn Burns

引用次数: 0

Through a computer monitor darkly: artificial intelligence in absorption, distribution, metabolism and excretion science. 黑暗中的计算机显示器：吸收、分布、代谢和排泄科学中的人工智能。