Xenobiotica最新文献_第10页

Prediction of pharmacokinetics of an anaplastic lymphoma kinase inhibitor in rat and monkey: application of physiologically based pharmacokinetic model as an alternative tool to minimise animal studies. 预测大鼠和猴子体内一种非典型淋巴瘤激酶抑制剂的药代动力学：应用基于生理学的药代动力学模型作为尽量减少动物实验的替代工具。

IF 1.8 4区医学

Xenobiotica Pub Date : 2023-12-01 Epub Date: 2023-12-26 DOI: 10.1080/00498254.2023.2292725

Gobardhan Bal, Lakshmi Kanakaraj, Bibhash Chandra Mohanta

{"title":"Prediction of pharmacokinetics of an anaplastic lymphoma kinase inhibitor in rat and monkey: application of physiologically based pharmacokinetic model as an alternative tool to minimise animal studies.","authors":"Gobardhan Bal, Lakshmi Kanakaraj, Bibhash Chandra Mohanta","doi":"10.1080/00498254.2023.2292725","DOIUrl":"10.1080/00498254.2023.2292725","url":null,"abstract":"The pharmacokinetic (PK) and toxicokinetic profile of a drug from its preclinical evaluation helps the researcher determine whether the drug should be tested in humans based on its safety and toxicity.Preclinical studies require time and resources and are prone to error. Moreover, according to the United States Food and Drug Administration Modernisation Act 2, animal testing is no longer mandatory for new drug development, and an animal-free alternative, such as cell-based assay and computer models, can be used.Different physiologically based PK models were developed for an anaplastic lymphoma kinase inhibitor in rats and monkeys after intravenous and oral administration using its physicochemical properties and in vitro characterisation data.The developed model was validated against the in vivo data available in the literature, and the validation results were found within the acceptable limit. A parameter sensitivity analysis was performed to identify the properties of the compound influencing the PK profile.This work demonstrates the application of the physiologically based PK model to predict the PKs of a drug, which will eventually assist in reducing the number of animal studies and save time and cost of drug discovery and development.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"621-633"},"PeriodicalIF":1.8,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138801834","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

Evaluation of the non-linearity of NA808 in liver not reflected in plasma using a rat pharmacokinetic study and PBPK modelling. 使用大鼠药代动力学研究和PBPK模型评估血浆中未反映的NA808在肝脏中的非线性。

IF 1.8 4区医学

Xenobiotica Pub Date : 2023-12-01 Epub Date: 2023-11-03 DOI: 10.1080/00498254.2023.2267107

Mizuki Yamane, Kazuhisa Ozeki, Ken Okano, Toshiyuki Kudo, Kiyomi Ito

{"title":"Evaluation of the non-linearity of NA808 in liver not reflected in plasma using a rat pharmacokinetic study and PBPK modelling.","authors":"Mizuki Yamane, Kazuhisa Ozeki, Ken Okano, Toshiyuki Kudo, Kiyomi Ito","doi":"10.1080/00498254.2023.2267107","DOIUrl":"10.1080/00498254.2023.2267107","url":null,"abstract":"When NA808, a potent HCV replication inhibitor, was intravenously administered to rats, it was distributed to the liver. The AUC ratio in the liver of 20 mg/kg to 2 mg/kg was greater than the dose ratio, whereas exposure in plasma was increased in a dose-proportional manner. Saturation of biliary excretion was also shown at 20 mg/kg.NA808 was revealed to be a substrate for both OATP1B and MRP2 transporters by an in vitro study using OATP1B1-MRP2 expressing cells. [14C]NA808 was taken up into the cells by OATP1B1 and excreted from cells by MRP2 efficiently (Papp ratio: 24.2-70.2). The Papp ratio decreased with increasing NA808 concentration.PBPK modelling was constructed to display the blood and liver concentration time profile and biliary excretion of NA808. This model analysis was able to reproduce the pharmacokinetics in rats; the degree of increase in the liver exposure from 2 to 20 mg/kg was more than dose-proportional and was greater than the increase in the blood exposure due to saturation of efflux transporters.In drug development, to avoid unexpected toxicity in tissues, it is important to consider the potential for tissue non-linearity with linear plasma exposure based on pre-clinical data and PBPK modelling.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"498-506"},"PeriodicalIF":1.8,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41239102","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 pharmacokinetic exploration of a novel osteoporotic quinazolinone-benzopyran-indole hybrid (S019-0385) using LC-MS/MS. 新型骨质疏松症喹唑啉酮-苯并吡喃吲哚杂合物（S019-0385）的LC-MS/MS临床前药代动力学研究。

IF 1.8 4区医学

Xenobiotica Pub Date : 2023-12-01 Epub Date: 2023-11-03 DOI: 10.1080/00498254.2023.2265475

Mukesh Kumar, Mridula Chauhan, Sarvesh Kumar Verma, Arpon Biswas, Alisha Ansari, Anjali Mishra, Sachin Nashik Sanap, Amol Chhatrapati Bisen, Koneni V Sashidhara, Rabi Sankar Bhatta

{"title":"Preclinical pharmacokinetic exploration of a novel osteoporotic quinazolinone-benzopyran-indole hybrid (S019-0385) using LC-MS/MS.","authors":"Mukesh Kumar, Mridula Chauhan, Sarvesh Kumar Verma, Arpon Biswas, Alisha Ansari, Anjali Mishra, Sachin Nashik Sanap, Amol Chhatrapati Bisen, Koneni V Sashidhara, Rabi Sankar Bhatta","doi":"10.1080/00498254.2023.2265475","DOIUrl":"10.1080/00498254.2023.2265475","url":null,"abstract":"1. The current investigation was to develop and validate the LC-MS/MS method in order to analyse the various pharmacokinetic parameters of S019-0385. A sensitive, selective, and robust LC-MS/MS approach was established and validated for measuring S019-0385 in female mice plasma and tissue, using optimal multiple reaction monitoring (MRM) transition m/z 488.25/329.12 on positive mode. On a Waters Symmetry Shield C18 column, the analyte was separated using acetonitrile and deionised water with formic acid within 6 min at 0.7 mL/min. Linearity (R2 ≥ 0.99) was observed across 0.195-100 ng/mL concentration range using linear least-squares regression.2. Blood-to-plasma ratio and plasma protein drug binding (%) in mice and human was assessed and found to be less than 1 and >83%, respectively. Absolute bioavailability (%F) of S019-0385 in female Swiss mice was exhibited to be 6.90%. Percent dose excreted S019-0385 in unchanged form through urine and faecal was found to be less than 2% and 0.5%, respectively.3. Following oral administration at 5 mg/kg, the concentration of S019-0385 in tissue distribution was found to be in the order of C small intestine > C bone > C lung > C spleen > C kidney > C liver > C heart > C brain.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"484-497"},"PeriodicalIF":1.8,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41151553","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

4,4'-Methylene diphenyl diisocyanate exposure induces expression of alternatively activated macrophage-associated markers and chemokines partially through Krüppel-like factor 4 mediated signaling in macrophages. 4,4′-亚甲基二苯基二异氰酸酯暴露通过kr<s:1> ppel样因子4介导的信号传导部分诱导巨噬细胞选择性活化的巨噬细胞相关标志物和趋化因子的表达。

IF 1.3 4区医学

Xenobiotica Pub Date : 2023-12-01 Epub Date: 2023-12-26 DOI: 10.1080/00498254.2023.2284867

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

{"title":"4,4'-Methylene diphenyl diisocyanate exposure induces expression of alternatively activated macrophage-associated markers and chemokines partially through Krüppel-like factor 4 mediated signaling in macrophages.","authors":"Chen-Chung Lin, Brandon F Law, Justin M Hettick","doi":"10.1080/00498254.2023.2284867","DOIUrl":"10.1080/00498254.2023.2284867","url":null,"abstract":"Occupational exposure to the most widely used monomeric diisocyanate (dNCO), 4,4'-methylene diphenyl diisocyanate (MDI), may lead to the development of occupational asthma (OA). Alveolar macrophages with alternatively activated (M2) phenotype have been implicated in allergic airway responses and the pathogenesis of asthma. Recent in vivo studies demonstrate that M2 macrophage-associated markers and chemokines are induced by MDI-exposure, however, the underlying molecular mechanism(s) by which this proceeds is unclear.Following MDI exposure (in vivo and in vitro) M2 macrophage-associated transcription factors (TFs), markers, and chemokines were determined by RT-qPCR, western blots, and ELISA.Expression of M2 macrophage-associated TFs and markers including Klf4/KLF4, Cd206/CD206, Tgm2/TGM2, Ccl17/CCL17, Ccl22/CCL22, and CCL24 were induced by MDI/MDI-GSH exposure in bronchoalveolar lavage cells (BALCs)/THP-1 macrophages. The expression of CD206, TGM2, CCL17, CCL22, and CCL24 are upregulated by 3.83-, 7.69-, 6.22-, 6.08-, and 1.90-fold in KLF4-overexpressed macrophages, respectively. Endogenous CD206 and TGM2 were downregulated by 1.65-5.17-fold, and 1.15-1.78-fold, whereas CCL17, CCL22, and CCL24 remain unchanged in KLF4-knockdown macrophages. Finally, MDI-glutathione (GSH) conjugate-treated macrophages show increased chemotactic ability to T-cells and eosinophils, which may be attenuated by KLF4 knockdown.Our data suggest that MDI exposure may induce M2 macrophage-associated markers partially through induction of KLF4.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"653-669"},"PeriodicalIF":1.3,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11323807/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138446411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Comparative study on ABCB1-dependent efflux of anthracyclines and their metabolites: consequences for cancer resistance. 蒽环类药物及其代谢产物ABCB1依赖性流出的比较研究：对癌症耐药性的影响。

IF 1.8 4区医学

Xenobiotica Pub Date : 2023-12-01 Epub Date: 2023-11-03 DOI: 10.1080/00498254.2023.2264391

Kamil Piska, Paulina Koczurkiewicz-Adamczyk, Marek Jamrozik, Adam Bucki, Marcin Kołaczkowski, Elżbieta Pękala

{"title":"Comparative study on ABCB1-dependent efflux of anthracyclines and their metabolites: consequences for cancer resistance.","authors":"Kamil Piska, Paulina Koczurkiewicz-Adamczyk, Marek Jamrozik, Adam Bucki, Marcin Kołaczkowski, Elżbieta Pękala","doi":"10.1080/00498254.2023.2264391","DOIUrl":"10.1080/00498254.2023.2264391","url":null,"abstract":"1. ABCB1 (P-glycoprotein, MDR1) is one of the most important transporter involved in cancer multi-drug resistance. It also plays a significant role in cancer resistance against anthracyclines, an anticancer group of drugs, including doxorubicin and daunorubicin. Several intracellular enzymes metabolise anthracyclines to carbonyl-reduced, hydroxy metabolites, which have impaired cytotoxic properties. However, metabolite efflux by ABCB1 transporter is not well characterised, while it may be the mechanism responsible for the metabolites' lack of activity.2. In this study recombinant ABCB1 ATPase transporter assay; anthracyclines accumulation assay in resistant cells overexpressing ABCB1; and molecular modelling were used to investigate anthracyclines: doxorubicin and daunorubicin and their carbonyl-reduced metabolites (doxorubicinol, daunorubicinol) susceptibility for ABCB1-dependent efflux.3. Based on the kinetics parameters of ATPase activity of ABCB1, it was found that daunorubicinol exerted an exceptionally high potential for being effluxed by the ABCB1 transporter. ABCB1 significantly affected the accumulation pattern of studied chemicals in resistant cancer cells. Doxorubicin and daunorubicinol accumulation were influenced by the activity of ABCB1 modulator - valspodar.4. Results indicate that ABCB1 activity affects not only anthracyclines but also their metabolites. Therefore crosstalk between the process of anthracyclines metabolism and metabolite efflux may be the mechanism of impairing anticancer properties of anthracyclines metabolites.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"507-514"},"PeriodicalIF":1.8,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41180007","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

Cytochrome P450 1A2 and 2C enzymes autoinduced by omeprazole in dog hepatocytes and human HepaRG and HepaSH cells are involved in omeprazole 5-hydroxylation and sulfoxidation. 奥美拉唑在狗肝细胞和人HepaRG和HepaSH细胞中自身诱导的细胞色素P450 1A2和2C酶参与奥美拉唑5-羟基化和硫氧化。

IF 1.8 4区医学

Xenobiotica Pub Date : 2023-12-01 Epub Date: 2023-11-03 DOI: 10.1080/00498254.2023.2266840

Yasuhiro Uno, Shotaro Uehara, Genki Ushirozako, Norie Murayama, Hiroshi Suemizu, Hiroshi Yamazaki

{"title":"Cytochrome P450 1A2 and 2C enzymes autoinduced by omeprazole in dog hepatocytes and human HepaRG and HepaSH cells are involved in omeprazole 5-hydroxylation and sulfoxidation.","authors":"Yasuhiro Uno, Shotaro Uehara, Genki Ushirozako, Norie Murayama, Hiroshi Suemizu, Hiroshi Yamazaki","doi":"10.1080/00498254.2023.2266840","DOIUrl":"10.1080/00498254.2023.2266840","url":null,"abstract":"The induction assay for the cytochromes P450 (P450s) is an important tool in drug discovery and development. The inductions of dog P450 1A2 and 3A12 by omeprazole and rifampicin were functionally characterised in dog hepatocytes and were compared with induction in human HepaRG and HepaSH cells.P450 1A2-dependent ethoxyresorufin O-deethylation was induced by R,S-omeprazole and P450 3 A-dependent midazolam 1'-hydroxylation was induced by rifampicin, and both reactions were significantly enhanced in cultured dog hepatocytes and human HepaRG and HepaSH cells.Recombinant dog P450 1A2 exhibited activities towards R- and S-omeprazole 5-hydroxylation with low Km values of 23-28 µM, whereas dog P450 2C21 and 3A12 efficiently mediated S-omeprazole 5-hydroxylation and sulfoxidation, respectively, with high Vmax values of 12-17 min-1.Although omeprazole 5-hydroxylation by human P450 2C19 (and sulfoxidation by P450 3A4) in human HepaSH cells were slightly (∼2-fold) induced by R,S-omeprazole, dog P450 1A2 was autoinduced by omeprazole in dog hepatocytes and showed enhanced R-omeprazole 5-hydroxylation activity (∼5-fold).These results indicate that omeprazole can be an autoinducer of P450 1A2 in hepatocytes, and this enzyme was found to be involved in omeprazole 5-hydroxylation and sulfoxidation in dog hepatocytes and human HepaRG and HepaSH cells.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"465-473"},"PeriodicalIF":1.8,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41135357","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

Study on the transport and internalisation mechanism of dietary supplement nattokinase in the small intestine using animal and Caco-2 cell monolayer models. 利用动物模型和Caco-2细胞单层模型研究膳食补充剂纳豆激酶在小肠内的转运和内化机制。

IF 1.8 4区医学

Xenobiotica Pub Date : 2023-12-01 Epub Date: 2023-12-26 DOI: 10.1080/00498254.2023.2284249

Huawei Feng, Chang Liu, Qingqing Liu, Jie Wang, Yingyue Zeng, Yue Sun, Man Zhang, Hui Zhang, Zhikui Liu, Jian Zhao, Hongsheng Liu

{"title":"Study on the transport and internalisation mechanism of dietary supplement nattokinase in the small intestine using animal and Caco-2 cell monolayer models.","authors":"Huawei Feng, Chang Liu, Qingqing Liu, Jie Wang, Yingyue Zeng, Yue Sun, Man Zhang, Hui Zhang, Zhikui Liu, Jian Zhao, Hongsheng Liu","doi":"10.1080/00498254.2023.2284249","DOIUrl":"10.1080/00498254.2023.2284249","url":null,"abstract":"Maintaining proper blood flow is critical to promoting good health. Nattokinase is a serine protease from Bacillus subtilis that has significant in vitro thrombolytic activity, but its mechanism as a dietary supplement to prevent thrombosis through intestinal absorption and transport is still unclear.The purpose of this study is to study the transport and internalisation mechanism of NK in the small intestine using animal models and Caco-2 cell monolayer models.This study first evaluated the preventive effect of supplementing low dose (4000 FU (Fibrin Unit)/kg, n = 6), medium dose (8000 FU/kg, n = 6), and high dose (12000 FU/kg, n = 6) of nattokinase on carrageenan induced thrombosis in mice. Subsequently, we used the rat gut sac model, ligated intestinal loop model, and Caco-2 cell uptake model to study the intestinal transport mechanism of NK.Results indicate that NK is a moderately absorbed biomolecule whose transport through enterocytes is energy- and time-dependent. Chlorpromazine, nystatin and EIPA all inhibited the endocytosis of NK to varying degrees, indicating that the endocytosis of NK in Caco-2 cells involves macropinocytosis, clathrin-mediated and caveolae-mediated pathway. These findings offer a theoretical basis for investigating the mechanism of oral NK supplementation in greater depth.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"670-680"},"PeriodicalIF":1.8,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136399458","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 metabolite profiling of YR-1702 injection in human plasma, urine and feces by HPLC-Q-TOF-MS/MS. YR-1702注射液在人血浆、尿液和粪便中的代谢产物HPLC-Q-TOF-MS/MS分析。

IF 1.8 4区医学

Xenobiotica Pub Date : 2023-12-01 Epub Date: 2023-11-26 DOI: 10.1080/00498254.2023.2272193

Yuxuan Fan, Yufeng Ni, Minlu Cheng, Wenjing Guo, Huaye Gao, WenHui Hu, Chang Shu, Li Ding

{"title":"The metabolite profiling of YR-1702 injection in human plasma, urine and feces by HPLC-Q-TOF-MS/MS.","authors":"Yuxuan Fan, Yufeng Ni, Minlu Cheng, Wenjing Guo, Huaye Gao, WenHui Hu, Chang Shu, Li Ding","doi":"10.1080/00498254.2023.2272193","DOIUrl":"10.1080/00498254.2023.2272193","url":null,"abstract":"YR-1702, a hybrid μ/κ/δ receptor agonist, is modified from the traditional opioid analgesic dezocine. It had shown both excellent analgesic effect and lower addiction in phase I clinical trial in China, however, the metabolic pathway of YR-1702 in humans remains unelucidated.The goals of this study are to characterise the metabolism of YR-1702 in human liver microsomes (HLMs) and patients with chronic non-cancer pain by high performance liquid chromatography-coupled with quadrupole-time-of-flight mass spectrometry (HPLC-Q-TOF-MS/MS).The results showed that a total of twelve metabolites were identified in HLMs, in which 7, 6 and 5 metabolites were also found in human plasma, urine and feces, respectively. And the major metabolic pathways include mono-hydroxylation, di-hydroxylation, dehydrogenation and glucuronidation. The locations of hydroxylation and dehydrogenation were identified by the signature fragments of the metabolites.The relative contents of the metabolites in human plasma were also evaluated, in which the main metabolite M1 notably accounting for more than 14% of the total drug exposure. This study would contribute to the understanding of the in vivo metabolite profile of YR-1702 injection for future use.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"536-546"},"PeriodicalIF":1.8,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41239103","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

Hyperoside ameliorates cisplatin-induced acute kidney injury by regulating the expression and function of Oat1. 金丝桃苷通过调节Oat1的表达和功能改善顺铂诱导的急性肾损伤。

IF 1.8 4区医学

Xenobiotica Pub Date : 2023-12-01 Epub Date: 2023-11-26 DOI: 10.1080/00498254.2023.2270046

Wenjing Yuan, Shanshan Kou, Ying Ma, Yusi Qian, Xinyu Li, Yuanyuan Chai, Zhenzhou Jiang, Luyong Zhang, Lixin Sun, Xin Huang

{"title":"Hyperoside ameliorates cisplatin-induced acute kidney injury by regulating the expression and function of Oat1.","authors":"Wenjing Yuan, Shanshan Kou, Ying Ma, Yusi Qian, Xinyu Li, Yuanyuan Chai, Zhenzhou Jiang, Luyong Zhang, Lixin Sun, Xin Huang","doi":"10.1080/00498254.2023.2270046","DOIUrl":"10.1080/00498254.2023.2270046","url":null,"abstract":"Cisplatin is a widely used chemotherapeutic agent to treat solid tumours in clinics. However, cisplatin-induced acute kidney injury (AKI) limits its clinical application. This study investigated the effect of hyperoside (a flavonol glycoside compound) on regulating AKI.The model of cisplatin-induced AKI was established, and hyperoside was preadministered to investigate its effect on improving kidney injury.Hyperoside ameliorated renal pathological damage, reduced the accumulation of SCr, BUN, Kim-1 and indoxyl sulphate in vivo, increased the excretion of indoxyl sulphate into the urine, and upregulated the expression of renal organic anion transporter 1 (Oat1). Moreover, evaluation of rat kidney slices demonstrated that hyperoside promoted the uptake of PAH (p-aminohippurate, the Oat1 substrate), which was confirmed by transient over-expression of OAT1 in HEK-293T cells. Additionally, hyperoside upregulated the mRNA expression of Oat1 upstream regulators hepatocyte nuclear factor-1α (HNF-1α) and pregnane X receptor (PXR).These findings indicated hyperoside could protect against cisplatin-induced AKI by promoting indoxyl sulphate excretion through regulating the expression and function of Oat1, suggesting hyperoside may offer a potential tactic for cisplatin-induced AKI treatment.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"559-571"},"PeriodicalIF":1.8,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"54231271","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

Empirical scaling factor for predicting human pharmacokinetic profiles of disproportionate metabolites using the Css-MRTpo method and chimeric mice with humanised livers. 使用Css-MRTpo方法和具有人源化肝脏的嵌合小鼠预测不成比例代谢物的人类药代动力学特征的经验比例因子。

IF 1.8 4区医学

Xenobiotica Pub Date : 2023-12-01 Epub Date: 2023-11-26 DOI: 10.1080/00498254.2023.2280785

Hidetaka Kamimura, Shotaro Uehara, Nao Yoneda, Hiroshi Suemizu

{"title":"Empirical scaling factor for predicting human pharmacokinetic profiles of disproportionate metabolites using the Css-MRTpo method and chimeric mice with humanised livers.","authors":"Hidetaka Kamimura, Shotaro Uehara, Nao Yoneda, Hiroshi Suemizu","doi":"10.1080/00498254.2023.2280785","DOIUrl":"10.1080/00498254.2023.2280785","url":null,"abstract":"Predicting plasma concentration-time profiles of disproportionate metabolites in humans is crucial for evaluating metabolites according to the Safety Testing guidelines. We evaluated Css-MRTpo, an empirical method, using chimeric mice with humanised livers capable of generating human-disproportionate metabolites. Azilsartan and AZ-M2 were administered to humanised chimeric mice, and pharmacokinetic parameters were obtained. Pharmacokinetic data for DS-1971a and DS-M1 in humanised chimeric mice were obtained from the literature. The human plasma concentration-time profiles of these compounds were simulated using the Css-MRTpo method. Azilsartan, DS-1971a, and PF-04937319 produced human disproportionate metabolites, AZ-M2, DS-M1, and PF-M1, respectively. The predicted human pharmacokinetic profiles of PF-04937319 and PF-M1 were obtained from a previous study, and their outcomes were re-evaluated. Our findings revealed that the plasma concentrations of the three metabolites were unexpectedly underpredicted, whereas the three unchanged drugs were reasonably predicted. Further, the introduction of the empirical scaling factor of 3, obtained from six model compounds, improved the predictability of metabolites, suggesting the potential usefulness of the Css-MRTpo method in combination with humanised chimeric mice for predicting the pharmacokinetic profiles of disproportionate metabolites at the early stage of new drug development.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"523-535"},"PeriodicalIF":1.8,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71486667","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