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Xenobiotica; the Fate of Foreign Compounds in Biological Systems

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https://www.readbyqxmd.com/read/28548030/everolimus-inhibited-multiple-isoforms-of-udp-glucuronosyltransferases-ugts
#1
Zuo Du, Guang Wang, Yun-Feng Cao, Cui-Min Hu, Kun Yang, Yong-Zhe Liu, Chun-Ze Zhang, Wei-Hua Zhang, Zhi-Tu Zhu, Hong-Zhi Sun, Xiao-Yu Sun, Mo Hong, Zhong-Ze Fang
1. Everolimus is an inhibitor of mammalian target of rapamycin (mTOR) and has been clinically utilized to prevent the rejection of organ transplants. This study aims to determine the inhibition of everolimus on the activity of phase II drug-metabolizing enzymes UDP-glucuronosyltransferases (UGTs). 2. The results showed that 100 uM of everolimus exerted more than 80% inhibition towards UGT1A1, -1A3, and -2B7. UGT1A3 and UGT2B7 were selected to elucidate the inhibition mechanism, and in silico docking showed that hydrogen bonds and hydrophobic interactions mainly contributed to the strong binding of everolimus towards the activity cavity of UGT1A3 and UGT2B7...
May 26, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28532263/establishment-and-assessment-of-a-novel-in-vitro-bio-pk-pd-system-in-predicting-the-in-vivo-pharmacokinetics-and-pharmacodynamics-of-cyclophosphamide
#2
Shanshan Tong, Hong Sun, Caifu Xue, Hanmei Chen, Jing Liu, Huiying Yang, Ning Zhou, Xiaoqiang Xiang, Weimin Cai
1. A novel bio-pharmacokinetic/pharmacodynamic (PK/PD) system was established and assessed in predicting the PK parameters and PD effects of the model drug cyclophosphamide (CP) considering the interrelationships between drug metabolism, pharmacological effects and dynamic blood circulation processes in vitro. 2. The system contains a peristaltic pump, a reaction chamber with rat liver microsomes (RLMs) encapsulated in pluronic F127-acrylamide-bisacrylamide (FAB) hydrogels, an effector cell chamber and a recirculating pipeline...
May 23, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28532270/predominant-contributions-of-carboxylesterase-1-and-2-in-hydrolysis-of-anordrin-in-humans
#3
Jinfang Jiang, Xiaoyan Chen, Dafang Zhong
1. Anordrin (2α, 17α-diethynyl-A-nor-5α-androstane-2β, 17β-diol diproprionate) is post-coital contraceptive drug that is on the market in China for more than 30 years. This study aims to elucidate enzymes involved in anordrin hydrolysis, and to evaluate the significant role of carboxylesterases in anordrin hydrolysis in humans. 2. Human liver and intestinal microsomes, recombinant human carboxylesterase were selected as enzyme sources. In human liver microsomes, intrinsic clearance was 684 ± 83 μL/min/mg protein, which was considerably higher than the value of intestine microsomes (94...
May 22, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28489504/validation-of-the-cell-line-ls180-as-a-model-for-study-of-the-gastrointestinal-toxicity-of-mycophenolic-acid
#4
Svenja Heischmann, Uwe Christians
1. Gastrointestinal (GI) intolerability is a concern for drugs such as mycophenolic acid (MPA) and drug metabolism may play a role. Few in vitro models exist that allow for the pre-clinical evaluation of a potential role of drug metabolism in intestinal drug toxicity. Thus, we sought to develop an in vitro model based on the human colon adenocarcinoma cell line LS180 to investigate MPA's negative effects on intestinal cells. 2. Stability of expression of key enzymes of MPA metabolism (UGT1A7, UGT1A9, UGT1A10, UGT2B7, CYP3A4, and CYP3A5), transporters (OATP1B1, OATP1B3, OATP2B1, MRP1, MRP2, and MDR1) and the nuclear receptor PXR over 12 passages in combination with guanosine supplementation to counter MPA's anti-proliferative effects (determined by western blot analysis and proliferation assays, respectively), was established...
May 10, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28489480/ponesimod-a-selective-sphingosine-1-phosphate-s1p1-receptor-modulator-for-autoimmune-diseases-review-of-clinical-pharmacokinetics-and-drug-disposition
#5
Ranjeet Prasad Dash, Rana Rais, Nuggehally R Srinivas
1. Ponesimod, a selective sphingosine 1-phosphate (S1P1) receptor modulator, is undergoing clinical development for the treatment of autoimmune diseases (multiple sclerosis/psoriasis). 2. Published literature data describing pharmacokinetic disposition of ponesimod were collected, reviewed and tabulated. 3. Across various clinical phase I studies, ponesimod displayed consistent pharmacokinetics - relatively faster absorption peak time (approximately 2.5 h), elimination half-life of approximately 30 h, and modest accumulation (2 to 2...
May 10, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28489470/reaction-products-of-hexamethylene-diisocyanate-vapors-with-self-molecules-in-the-airways-of-rabbits-exposed-via-tracheostomy
#6
Adam V Wisnewski, Jean Kanyo, Jennifer Asher, James A Goodrich, Grace Barnett, Lyn Patrylak, Jian Liu, Carrie A Redlich, Ala F Nassar
Hexamethylene diisocyanate (HDI) is a widely used aliphatic diisocyanate and a well-recognized cause of occupational asthma. "Self" molecules (peptides/proteins) in the lower airways, susceptible to chemical reactivity with HDI, have been hypothesized to play a role in asthma pathogenesis and/or chemical metabolism, but remain poorly characterized. This study employed unique approaches to identify and characterize "self" targets of HDI reactivity in the lower airways. Anesthetized rabbits free breathed through a tracheostomy tube connected to chambers containing either, O2, or O2 plus ∼200 ppb HDI vapors...
May 10, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28485193/preclinical-absorption-distribution-metabolism-excretion-and-pharmacokinetics-of-a-novel-selective-inhibitor-of-breast-cancer-resistance-protein-bcrp
#7
Mingxiang Liao, Bei-Ching Chuang, Qing Zhu, Yuexian Li, Emily Guan, Shaoxia Yu, Johnny Yang, Prakash Shimoga, Cindy Q Xia
1. Breast cancer resistance protein (BCRP) plays an important role in drug absorption, distribution, and excretion. It is challenging to evaluate BCRP functions in preclinical models because commonly used BCRP inhibitors are nonspecific or unstable in animal plasma. 2. In the present work, in vitro absorption, distribution, metabolism and elimination (ADME) assays and pharmacokinetic (PK) experiments in Bcrp knockout (KO) (Abcg2-/-) and wild-type (WT) FVB mice and Wistar rats were conducted to characterize the preclinical properties of a novel selective BCRP inhibitor (ML753286, a Ko143 analog)...
May 9, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28481715/efflux-proteins-at-the-blood-brain-barrier-review-and-bioinformatics-analysis
#8
Massoud Saidijam, Fatemeh Karimi Dermani, Sareh Sohrabi, Simon G Patching
1. Efflux proteins at the blood-brain barrier provide a mechanism for export of waste products of normal metabolism from the brain and help to maintain brain homeostasis. They also prevent entry into the brain of a wide range of potentially harmful compounds such as drugs and xenobiotics. 2. Conversely, efflux proteins also hinder delivery of therapeutic drugs to the brain and central nervous system used to treat brain tumours and neurological disorders. For bypassing efflux proteins, a comprehensive understanding of their structures, functions and molecular mechanisms is necessary, along with new strategies and technologies for delivery of drugs across the blood-brain barrier...
May 8, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28415902/metabolism-studies-on-hydroxygenkwanin-and-genkwanin-in-human-liver-microsomes-by-uhplc-q-tof-ms
#9
Lin Yuan, Caijuan Liang, Xinpeng Diao, Xiaoye Cheng, Man Liao, Lantong Zhang
Hydroxygenkwanin (HYGN) and genkwanin (GN) are major constituents of Genkwa Flos for the treatment of edema, ascites, cough, asthma and cancer. This is a report about the investigation of the metabolic fate of HYGN and GN in human liver microsomes and the recombinant UDP-glucuronosyltransferase (UGT) enzymes by using ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS). An on-line data acquisition method multiple mass defect filter (MMDF) combined with dynamic background subtraction (DBS) was developed to trace all probable metabolites...
May 5, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28471331/study-on-the-pharmacokinetics-of-deoxyschizandrin-and-schizandrin-in-combination-with-epigallocatechin-gallate-a-component-of-green-tea-in-rats
#10
Yan Liu, Dong Zhang, Yingli Wang, Wenjuan Zhang, Xiaohong Liu
1. Green tea is commonly used worldwide due to its potential positive health benefits. We have examined the effects of epigallocatechin gallate (EGCG), the most abundant catechin in green tea, on the pharmacokinetics of deoxyschizandrin (DSD) and schizandrin (SD), which are the representative lignans in popular traditional Chinese medicines Fructus schisandrae, in rats. 2. The effects on the transport in Caco-2 cells and metabolism in human liver microsomes of DSD and SD by EGCG were determined to analyze their interactions thoroughly...
May 4, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28443803/a-strategy-for-early-risk-predictions-of-clinical-drug-drug-interactions-involving-the-gastroplus-tm-ddi-module-for-time-dependent-cyp-inhibitors
#11
Anna-Karin Sohlenius-Sternbeck, Gabrielle Meyerson, Ann-Louise Hagbjörk, Sanja Juric, Ylva Terelius
1. A set of reference compounds for time-dependent inhibition (TDI) of cytochrome P450 with available literature data for kinact and KI was used to predict clinical implications using the GastroPlus(TM) software. Comparisons were made to in vivo literature interaction data. 2. The predicted AUC ratios (AUC+inhibitor/AUCcontrol) could be compared with the observed ratios from literature for all compounds with detailed information about in vivo administration, pharmacokinetics and in vivo interactions (N = 21)...
April 26, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28443723/glucuronidation-of-icaritin-by-human-liver-microsomes-human-intestine-microsomes-and-expressed-udp-glucuronosyltransferase-enzymes-identification-of-ugt1a3-1a9-and-2b7-as-the-main-contributing-enzymes
#12
Li Wang, Xiaodan Hong, Zhihong Yao, Yi Dai, Guoping Zhao, Zifei Qin, Baojian Wu, Frank J Gonzalez, Xinsheng Yao
1. Icaritin is a natural flavonoid with anti-osteoporosis activity. This study aimed to characterize icaritin glucuronidation by pooled human liver microsomes (HLM) and pooled human intestine microsomes (HIM), and to determine the contribution of individual UDP-glucuronosyltrans-ferase (UGT) enzyme to icaritin glucuronidation. 2. Glucuronidation rates were determined by incubating icaritin with uridine diphosphate glucuronic acid (UDPGA)-supplemented microsomes. Kinetic parameters were derived by appropriate model fitting...
April 26, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28436712/disposition-and-metabolism-of-14-c-galunisertib-a-tgf-%C3%AE-ri-kinase-alk5-inhibitor-following-oral-administration-in-healthy-subjects-and-mechanistic-prediction-of-the-effect-of-itraconazole-on-galunisertib-pharmacokinetics
#13
Kenneth C Cassidy, Ivelina Gueorguieva, Colin Miles, Jessica Rehmel, Ping Yi, William J Ehlhardt
The disposition and metabolism of galunisertib (LY2157299 monohydrate, a TGF-βRI Kinase/ALK5 Inhibitor) was characterized following a single oral dose of 150 mg of [(14)C]-galunisertib (100 µCi) to six healthy human subjects. The galunisertib plasma half-life was 8.6 h, while the (14)C half-life was 10.0 h. Galunisertib was abundant in circulation (40.3% of the (14)C AUC0-24h), with 7 additional metabolites detected in plasma. Two metabolites LSN3199597 (M5, mono-oxidation), and M4 (glucuronide of M3) were the most abundant circulating metabolites (10...
April 24, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28436281/terfenadine-t-butyl-hydroxylation-catalyzed-by-human-and-marmoset-cytochrome-p450-3a-and-4f-enzymes-in-livers-and-small-intestines
#14
Shotaro Uehara, Yukako Yuki, Yasuhiro Uno, Takashi Inoue, Erika Sasaki, Hiroshi Yamazaki
1. Roles of human cytochrome P450 (P450) 3A4 in oxidation of an antihistaminic drug terfenadine have been previously investigated in association with terfenadine-ketoconazole interaction. Several antihistamine drugs have been recently identified as substrates for multiple P450 enzymes. In this study, overall roles of P450 3A4, 2J2, and 4F12 enzymes in terfenadine t-butyl hydroxylation were investigated in small intestines and livers from humans, marmosets, and/or cynomolgus monkeys. 2. Human liver microsomes and liver and small intestine microsomes from marmosets and cynomolgus monkeys effectively mediated terfenadine t-butyl hydroxylation...
April 22, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28385095/in-vitro-inhibitory-effects-of-pristimerin-on-human-liver-cytochrome-p450-enzymes
#15
Xiaoyi Hao, Jianlei Yuan, Yansen Xu, Zhao Wang, Jianzhang Hou, Tao Hu
1. Pristimerin (PTM) is a biological component isolated from Chinese herbal plant Celastrus and Maytenus spp and it possesses numerous pharmacological activities. However, whether PTM affects the activity of human liver cytochrome P450 (CYP) enzymes remains unclear. 2. In this study, the inhibitory effects of PTM on the eight human liver CYP isoforms (i.e., 1A2, 3A4, 2A6, 2E1, 2D6, 2C9, 2C19, and 2C8) were investigated in vitro using human liver microsomes (HLMs). 3. The results showed that PTM inhibited the activity of CYP1A2, 3A4, and 2C9, with IC50 values of 21...
April 7, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28375049/delayed-o-methylation-of-l-dopa-in-mb-comt-deficient-mice-after-oral-administration-of-l-dopa-and-carbidopa
#16
Anne Tammimäki, Anu Aonurm-Helm, Pekka T Männistö
1. Catechol-O-methyltransferase (COMT) is involved in the O-methylation of L-DOPA, dopamine and other catechols. The enzyme is expressed in two isoforms: soluble (S-COMT), which resides in the cytoplasm, and membrane-bound (MB-COMT), which is anchored to intracellular membranes. 2. To obtain specific information on the functions of COMT isoforms, we studied how a complete MB-COMT deficiency affects the total COMT activity in the body, peripheral L-DOPA levels and metabolism after L-DOPA (10 mg kg(-1)) plus carbidopa (30 mg kg(-1)) administration by gastric tube in wild type and MB-COMT deficient mice...
April 4, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28375032/pharmacodynamic-properties-and-bioequivalence-of-dalteparin-sodium-subcutaneous-injection-in-healthy-chinese-male-subjects
#17
Lijin Yu, Xin Guo, Sujie Jia, Yuanyuan Xiang, Zhigang Ding, Ren Guo
1. Dalteparin sodium (DS) is a low molecular weight heparin that is widely used in the treatment of thromboembolism. The purpose of this study was to compare the pharmacodynamic properties and bioequivalence of the two formulations of DS with subcutaneous injection in healthy Chinese male subjects. 2. In this randomized, open-label, two-period crossover study, a total of 24 male subjects were recruited to receive single subcutaneous doses of test and reference dalteparin sodium injection in 2 different sequences (12 subjects each) with a 7-day washout period...
April 4, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28287856/enzymatic-kinetics-regarding-reversible-metabolism-of-cs-0777-a-sphingosine-1-phosphate-receptor-modulator-via-phosphorylation-and-dephosphorylation-in-humans
#18
Shin-Ichi Inaba, Maki Yamaguchi-Goto, Kaoru Tanaka-Takanaka, Kiyoaki Yonesu, Hidetaka Sakurai, Kazuishi Kubota, Takashi Izumi
1. CS-0777, a candidate compound for autoimmune diseases, becomes phosphorylated active metabolite, M1, by fructosamine 3-kinase (FN3K), FN3K-related protein (FN3K-RP); and M1 is reverted back to CS-0777 by alkaline phosphatase (ALP) in the body. We performed enzyme kinetic analysis of phosphorylation of CS-0777 by FN3K, FN3K-RP, human erythrocytes and human platelets; and dephosphorylation of M1 by various ALP isozymes and human liver, kidney, lung and small intestine microsomes. 2. The Michaelis constants of human FN3K, FN3K-RP and erythrocytes for CS-0777 phosphorylation were in the range from 498 μM to 1060 μM...
April 3, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28359180/influence-of-grapefruit-juice-on-pharmacokinetics-of-triptolide-in-rats
#19
Yuzhen Jia, Jie Liu, Jisen Xu
1. Triptolide, a major pharmacological component isolated from Tripterygium wilfordii Hook F (TWHF), is a substrate of both CYP3A4 and P-glycoprotein (P-gp). 2. This study investigates the effects of GFJ on the pharmacokinetics of triptolide in rats. 3. The pharmacokinetics of orally administered triptolide with or without GFJ pretreatment were investigated. A mechanistic study was also undertaken using the Caco-2 cell transwell model and rat liver microsomes incubation systems to support the in vivo pharmacokinetic data...
March 31, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28322061/potential-biomarkers-for-monitoring-the-toxicity-of-long-term-exposure-to-atrazine-in-rat-by-metabonomic-analysis
#20
Xiao-Feng Zhang, Chong-Hua Zhang, Jing Zheng, Long-Xue Li, Tian-Qi Geng, Yang Zhang
1. Herbicide atrazine (ATR) poses harmful effects on human health. The purpose of this study is to study potential biomarkers used for monitoring the toxic effects after chronic exposure to ATR by studying urine metabolites. 2. Rats were assigned into clinical chemistry and metabonomics arms, and each arm was divided into low-dose, high-dose and control groups. ATR was administered to rats along with their feed. At the end of 16, 20 and 24 weeks, clinical parameters and histopathologic changes was assessed to monitor the toxic effects...
March 21, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
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