Xenobiotica最新文献_第6页

In vitro and in vivo studies on the metabolism and pharmacokinetics of the selective gut microbial β-glucuronidase targeting compound Inh 1. 关于选择性肠道微生物 β-葡萄糖醛酸酶靶向化合物 Inh 1 的代谢和药代动力学的体外和体内研究。

IF 1.3 4区医学

Xenobiotica Pub Date : 2024-06-01 Epub Date: 2024-06-12 DOI: 10.1080/00498254.2024.2357765

Anna Kerins, Phil Butler, Rob Riley, Marta Koszyczarek, Caroline Smith, Faye Cruickshank, Vamsi Madgula, Nilkanth Naik, Matthew R Redinbo, Ian D Wilson

{"title":"In vitro and in vivo studies on the metabolism and pharmacokinetics of the selective gut microbial β-glucuronidase targeting compound Inh 1.","authors":"Anna Kerins, Phil Butler, Rob Riley, Marta Koszyczarek, Caroline Smith, Faye Cruickshank, Vamsi Madgula, Nilkanth Naik, Matthew R Redinbo, Ian D Wilson","doi":"10.1080/00498254.2024.2357765","DOIUrl":"10.1080/00498254.2024.2357765","url":null,"abstract":"In vitro studies using rat, mouse, and human microsomes and hepatocytes on the bacterial β-glucuronidase inhibitor 1-((6,8-dimethyl-2-oxo-1,2-dihydroquinolin-3-yl)methyl)-3-(4-ethoxyphenyl)-1-(2-hydroxyethyl)thiourea) (Inh 1) revealed extensive metabolism in all species.The intrinsic clearances of Inh 1 in human, mouse, and rat hepatic microsomes were 30.9, 67.8, and 201 µL/min/mg, respectively. For intact hepatocytes intrinsic clearances of 21.6, 96.0, and 129 µL/min/106 cells were seen for human, mouse and rat, respectively.The metabolism of Inh 1 involved an uncommon desulphurisation reaction in addition to oxidation, deethylation, and conjugation reactions at multiple sites. Six metabolites were detected in microsomal incubations in human and rat, and seven for the mouse. With hepatocytes, 18 metabolites were characterised, 9 for human, and 11 for mouse and rat.Following IV administration to mice (3 mg/kg), plasma concentrations of Inh 1 exhibited a monophasic decline with a terminal elimination half-life of 0.91 h and low systemic clearance (11.8% of liver blood flow). After PO dosing to mice (3 mg/kg), peak observed Inh 1 concentrations of 495 ng/mL were measured 0.5 h post dose, declining to under 10 ng/mL at 8 h post dose. The absolute oral bioavailability of Inh 1 in the mouse was ca. 26%.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"304-315"},"PeriodicalIF":1.3,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141097039","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

Assessment of P-glycoprotein function using canine intestinal organoid-derived epithelial interfaces. 利用犬肠道类器官衍生上皮细胞界面评估糖蛋白功能

IF 1.3 4区医学

Xenobiotica Pub Date : 2024-06-01 Epub Date: 2024-06-24 DOI: 10.1080/00498254.2024.2358395

Itsuma Nagao, Meg Nakazawa, Yurika Tachibana, Minae Kawasaki, Yoko M Ambrosini

{"title":"Assessment of P-glycoprotein function using canine intestinal organoid-derived epithelial interfaces.","authors":"Itsuma Nagao, Meg Nakazawa, Yurika Tachibana, Minae Kawasaki, Yoko M Ambrosini","doi":"10.1080/00498254.2024.2358395","DOIUrl":"10.1080/00498254.2024.2358395","url":null,"abstract":"P-glycoprotein (P-gp), a multidrug efflux pump encoded by the ABCB1 (formerly MDR1) gene, plays a crucial role in limiting drug absorption and eliminating toxic compounds in both humans and dogs. However, species-specific differences in P-gp substrates necessitate the development of canine-specific evaluation systems. Canine intestinal organoids derived monolayers offer a promising platform for studying drug transport, yet P-gp-mediated transport in these models remains unexplored.We generated canine colonoid-derived 2D monolayers to investigate ABCB1 gene expression and P-gp function. We employed widely recognised P-gp substrates, Rhodamine 123 and Doxorubicin, in conjunction with the P-gp inhibitor PSC833 at Days 5 and 10 of culture.A significant increase in gene expression of P-gp encoded by the ABCB1 was noted on Day 10 compared to Day 5 of culture. Despite this disparity in gene expression, the transport activity of P-gp, as assessed by the efflux of Rhodamine 123 and Doxorubicin with PSC833 inhibition, did not exhibit significant differences between these two time points. However, the inhibition of P-gp function by PSC833 confirms the presence of functional P-gp in our model.Canine intestinal organoid-derived monolayers provide a valuable tool for investigating P-gp-mediated drug transport. These findings highlight the potential for predicting drug bioavailability and adverse reactions in veterinary medicine, aligning with principles of ethical and sustainable research.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"342-349"},"PeriodicalIF":1.3,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11325560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141180889","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

In vitro safety evaluation of (6-methoxy-9-oxo-9H-xanthen-2-yl)methyl (E)-3-(2,4-dimethoxyphenyl)acrylate (K-116) - the novel potential UV filter designed by means of a double chromophore strategy. l (6-甲氧基-9-氧代-9H-氧杂蒽-2-基)甲基(E)-3-(2,4-二甲氧基苯基)丙烯酸酯（K-116）的体外安全性评估--这是一种通过双发色团策略设计的新型潜在紫外线过滤器。

IF 1.3 4区医学

Xenobiotica Pub Date : 2024-06-01 Epub Date: 2024-06-24 DOI: 10.1080/00498254.2024.2363332

Justyna Popiół, Agnieszka Gunia-Krzyżak, Karolina Słoczyńska, Kamil Piska, Natalia Kocot, Dorota Żelaszczyk, Anna Krupa, Katarzyna Wójcik-Pszczoła, Henryk Marona, Elżbieta Pękala

{"title":"In vitro safety evaluation of (6-methoxy-9-oxo-9H-xanthen-2-yl)methyl (E)-3-(2,4-dimethoxyphenyl)acrylate (K-116) - the novel potential UV filter designed by means of a double chromophore strategy.","authors":"Justyna Popiół, Agnieszka Gunia-Krzyżak, Karolina Słoczyńska, Kamil Piska, Natalia Kocot, Dorota Żelaszczyk, Anna Krupa, Katarzyna Wójcik-Pszczoła, Henryk Marona, Elżbieta Pękala","doi":"10.1080/00498254.2024.2363332","DOIUrl":"10.1080/00498254.2024.2363332","url":null,"abstract":"The use of topical photoprotection is necessary to reduce adverse effects caused by excessive exposure to ultraviolet radiation. Despite the high standards set for UV filters, many of them may contribute to the occurrence of adverse effects. The newly synthesised compound K-116, the (E)-cinnamoyl xanthone derivative, could be an alternative. We conducted extended in vitro safety evaluation of compound K-116. The research included assessment of irritation potential on skin tissue, evaluation of penetration through the epidermis, and assessment of phototoxicity, and mutagenicity. Additionally, the eco-safety of compound K-116 was evaluated, including an examination of its degradation pathway in the Cunninghamella echinulata model, as well as in silico simulation of the toxicity of both the parent compound and its degradation products. The research showed that compound K-116 tested in future application conditions is deprived of skin irritant potential additionally it does not penetrate through the epidermis. Results showed that K-116 concentrate is not phototoxic and not mutagenic. The eco-safety studies showed that it undergoes biodegradation in 27% in Cunninghamella echinulata model. The parent compound and formed metabolite are less toxic than reference UV filters (octinoxate and octocrylene).","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"266-278"},"PeriodicalIF":1.3,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141184795","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

An in silico investigation of the toxicological effects and biological activities of 3-phenoxybenzoic acid and its metabolite products. 对 3-苯氧基苯甲酸及其代谢产物的毒理效应和生物活性进行的硅学研究。

IF 1.3 4区医学

Xenobiotica Pub Date : 2024-06-01 Epub Date: 2024-06-24 DOI: 10.1080/00498254.2024.2361457

Hai Duc Nguyen, Thuy Linh Hoang, Giang Huong Vu

{"title":"An in silico investigation of the toxicological effects and biological activities of 3-phenoxybenzoic acid and its metabolite products.","authors":"Hai Duc Nguyen, Thuy Linh Hoang, Giang Huong Vu","doi":"10.1080/00498254.2024.2361457","DOIUrl":"10.1080/00498254.2024.2361457","url":null,"abstract":"We aimed to elucidate the toxic effects and biological activities of 3-phenoxybenzoic acid (3PBA) and its metabolite products.Numerous in silico methods were used to identify the toxic effects and biological activities of 3PBA, including PASS online, molecular docking, ADMETlab 2.0, ADMESWISS, MetaTox, and molecular dynamic simulation.Ten metabolite products were identified via Phase II reactions (O-glucuronidation, O-sulfation, and methylation).All of the investigated compounds were followed by Lipinski's rule, indicating that they were stimulants or inducers of hazardous processes.Because of their high gastrointestinal absorption and ability to reach the blood-brain barrier, the studied compounds' physicochemical and pharmacokinetic properties matched existing evidence of harmful effects, including haematemesis, reproductive dysfunction, allergic dermatitis, toxic respiration, and neurotoxicity.The studied compounds have been linked to the apoptotic pathway, the reproductivity system, neuroendocrine disruptors, phospholipid-translocating ATPase inhibitors, and JAK2 expression.An O-glucuronidation metabolite product demonstrated higher binding affinity and interaction with CYP2C9, CYP3A4, caspase 3, and caspase 8 than 3PBA and other metabolite products, whereas metabolite products from methylation were predominant and more toxic.Our in silico findings partly meet the 3Rs principle by minimizing animal testing before more study is needed to identify the detrimental effects of 3PBA on other organs (liver, kidneys).Future research directions may involve experimental validation of in silico predictions, elucidation of molecular mechanisms, and exploration of therapeutic interventions.These findings contribute to our understanding of the toxicological profile of 3PBA and its metabolites, which has implications for risk assessment and regulatory decisions.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"322-341"},"PeriodicalIF":1.3,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141248776","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 pharmacokinetics and tissue distribution of deoxypodophyllotoxin and its metabolites in tumour-bearing mice. 研究肿瘤小鼠体内脱氧鬼臼毒素及其代谢物的药代动力学和组织分布。

IF 1.3 4区医学

Xenobiotica Pub Date : 2024-06-01 Epub Date: 2024-07-01 DOI: 10.1080/00498254.2024.2370049

Fei Liu, Aibin Zheng, Min Li, Yang Chen, Xiaodong Liu

{"title":"Study on pharmacokinetics and tissue distribution of deoxypodophyllotoxin and its metabolites in tumour-bearing mice.","authors":"Fei Liu, Aibin Zheng, Min Li, Yang Chen, Xiaodong Liu","doi":"10.1080/00498254.2024.2370049","DOIUrl":"10.1080/00498254.2024.2370049","url":null,"abstract":"To study the pharmacokinetics of deoxypodophyllotoxin and its metabolites in non-small cell lung cancer (NSCLC) bearing mice.Using the established LC-MS/MS method for simultaneous determination of deoxypodophyllotoxin and its three main metabolites (M1, M2 and M7) in biological samples, the concentrations of deoxypodophyllotoxin and its metabolites in plasma, tumour and major tissues of tumour-bearing mice were investigated after 6.25 and 25 mg/kg intravenous administration of deoxypodophyllotoxin.The exposure results of drug concentration showed that after intravenous injection of 6.25 and 25 mg/kg of DPT into tumour-bearing mice, the AUC ratio of DPT in tumour tissue to DPT in plasma was 4.23 and 3.80, respectively. While, the AUC ratio of metabolite M2 in tumour tissue to M2 in plasma was 0.82 and 0.76, respectively.Deoxypodophyllotoxin had higher affinity with tumour tissues than plasma, while its metabolite M2 had less affinity with tumour tissues than deoxypodophyllotoxin, but the exposure level of M2 in plasma was higher than that of deoxypodophyllotoxin. Deoxypodophyllotoxin was widely distributed in tumour-bearing mice. After intravenous injection of 25 mg/kg deoxypodophyllotoxin, the concentration of deoxypodophyllotoxin in other tissues except liver and muscle was relatively high, especially in lung, fat and reproductive organs.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"316-321"},"PeriodicalIF":1.3,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141447114","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 of the 4th European biotransformation workshop. 第四届欧洲生物转化研讨会会议报告。

IF 1.3 4区医学

Xenobiotica Pub Date : 2024-05-01 Epub Date: 2024-01-17 DOI: 10.1080/00498254.2024.2302547

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

引用次数: 0

mRNA expression levels of cytochrome P450 CYP1A2, CYP3A4, and CYP3A5 in the epidermis: a focus on individual differences among Japanese individuals. 表皮中细胞色素 P450 CYP1A2、CYP3A4 和 CYP3A5 的 mRNA 表达水平：关注日本人的个体差异。

IF 1.3 4区医学

Xenobiotica Pub Date : 2024-05-01 Epub Date: 2024-04-24 DOI: 10.1080/00498254.2024.2344664

Hiroko Makihara, Mika Maezawa, Kazusa Kaiga, Toshihiko Satake, Mayu Muto, Yui Tsunoda, Tsutomu Shimada, Tomoko Akase

{"title":"mRNA expression levels of cytochrome P450 CYP1A2, CYP3A4, and CYP3A5 in the epidermis: a focus on individual differences among Japanese individuals.","authors":"Hiroko Makihara, Mika Maezawa, Kazusa Kaiga, Toshihiko Satake, Mayu Muto, Yui Tsunoda, Tsutomu Shimada, Tomoko Akase","doi":"10.1080/00498254.2024.2344664","DOIUrl":"10.1080/00498254.2024.2344664","url":null,"abstract":"Various cytochrome P450 enzymes (CYPs) that contribute to drug metabolism are expressed in the skin. However, variation among individuals in CYP expression profiles is not well-understood.To investigate CYPs related to the metabolism of transdermal preparations in Japan, multiple skin tissue specimens of individuals of Japanese descent were prepared, and the mRNA expression levels of CYP1A2, CYP3A4, and CYP3A5 were measured. Associations between the expression patterns of these CYPs and body mass index (BMI) were also investigated.There were considerable individual differences in epidermal CYP1A2 mRNA expression levels, and CYP1A2 showed a weak positive correlation with CYP3A4 mRNA expression levels. In contrast to previous results for other organs, epidermal CYP3A4 mRNA expression levels showed a weak positive correlation with BMI.CYP3A4 in the epidermis may have been locally enhanced as a defence mechanism against xenobiotics in response to impaired barrier function. These differences in mRNA expression in the skin may affect the transdermal absorption of drugs, such as lidocaine and fentanyl, which are metabolised by multiple overlapping CYPs.Our study provides new insights into drug metabolism in the skin. These results are valuable for predicting drug effects and transdermal drug transfer rates in Japanese patients.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"226-232"},"PeriodicalIF":1.3,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140864986","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

Assessment of cytochrome P450 induction in canine intestinal organoid models. 评估犬肠道类器官模型中的细胞色素 P450 诱导。

IF 1.8 4区医学

Xenobiotica Pub Date : 2024-05-01 Epub Date: 2024-03-13 DOI: 10.1080/00498254.2024.2326973

Itsuma Nagao, Meg Nakazawa, Takashi Goyama, Michael H Court, Yoko M Ambrosini

{"title":"Assessment of cytochrome P450 induction in canine intestinal organoid models.","authors":"Itsuma Nagao, Meg Nakazawa, Takashi Goyama, Michael H Court, Yoko M Ambrosini","doi":"10.1080/00498254.2024.2326973","DOIUrl":"10.1080/00498254.2024.2326973","url":null,"abstract":"Understanding cytochrome P450 (CYP) enzymes in the canine intestine is vital for predicting drug metabolism and developing safer oral medications. This study evaluates canine colonoids as a model to assess the expression and induction of essential intestinal CYP enzymes.Canine colonoids were cultured in expansion medium (EM) with Wnt-3A and in differentiation medium (DM) without Wnt-3A. We assessed the mRNA expression of CYP2B11, CYP2C21, CYP3A12, and CYP3A98 using qPCR and examined the effects of rifampicin and phenobarbital as inducers.Our findings show that DM significantly increased the mRNA expression of CYP3A98 and CYP2B11, but not CYP3A12, compared to EM. CYP2C21, not typically expressed in the intestine, remained unexpressed in colonoids. Rifampicin induced CYP3A98, aligning with pregnane x receptor (PXR) regulation, while phenobarbital did not, suggesting no constitutive androstane receptor (CAR) involvement. CYP2B11 did not respond to either inducer, suggesting alternative regulatory pathways in canine colonoids.This study is a pioneering effort to establish conditions for studying P450 expression in canine colonoids, confirming significant CYP3A98 expression in the canine intestine. It demonstrated colonoids can induce CYP activity post drug treatments. Further research is needed to enhance species-specific drug metabolism understanding and validate this model for broader applications.","PeriodicalId":23812,"journal":{"name":"Xenobiotica","volume":" ","pages":"217-225"},"PeriodicalIF":1.8,"publicationDate":"2024-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11178462/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140029127","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

Preparation, characterisation, pharmacokinetics and distribution of esculin microspheres administered via intravitreal injection into rabbit brain 通过玻璃体内注射给药兔脑的艾司西林微球的制备、特性、药代动力学和分布

IF 1.8 4区医学

Xenobiotica Pub Date : 2024-04-19 DOI: 10.1080/00498254.2024.2341402

Danqing Wu, Rui Luo, Yangnan Chen, Zhiyun Zheng, Shuangying Gui, Ning He

引用次数: 0

Developmental stage and infection status may affect drug distribution in the prostate of rats 发育阶段和感染状况可能影响药物在大鼠前列腺中的分布

IF 1.8 4区医学

Xenobiotica Pub Date : 2024-04-18 DOI: 10.1080/00498254.2024.2343892

Ziyang Xu, Lianzhan Sun, Chang Yin, Handa Wang, Xue Wang, Yunyun Yang, Zhuo Wang

引用次数: 0