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Xenobiotica; the Fate of Foreign Compounds in Biological Systems

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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
#1
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
#2
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
#3
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
#4
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/28415902/metabolism-studies-on-hydroxygenkwanin-and-genkwanin-in-human-liver-microsomes-by-uhplc-q-tof-ms
#5
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 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...
April 18, 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
#6
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
#7
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
#8
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
#9
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
#10
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
#11
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
https://www.readbyqxmd.com/read/28316274/co-treatment-with-indole-3-carbinol-and-resveratrol-modify-porcine-cyp1a-and-cyp3a-activities-and-expression
#12
Galia Zamaratskaia, Rebekka Thøgersen, Marjeta Čandek-Potokar, Martin Krøyer Rasmussen
1. Humans and animals are commonly exposed to indole-3-carbinol (I3C) and resveratrol (RES) via food or beverages. Moreover, these compounds have been demonstrated to potentially cause food-drug interactions. However, information about their combined effects is limited. Therefore, we investigated the effects of I3C and RES, both as single compounds and in combination, on cytochrome P450 1A and 3A activity and gene expression. 2. Using porcine microsomes, we demonstrated that RES caused non-competitive inhibition of CYP1A activity and un-competitive inhibition of CYP3A activity...
March 19, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28298174/the-involvement-of-multidrug-and-toxin-extrusion-protein-1-in-the-distribution-and-excretion-of-berberine
#13
Ling Xiao, Yaru Xue, Cuifeng Zhang, Le Wang, Yunfei Lin, Guoyu Pan
1. Berberine (BBR), an isoquinoline alkaloid, has demonstrated multiple clinical pharmacological actions. As a substrate of multiple transporters in the liver, BBR is rarely excreted into the bile but can be found in the urine. The purpose of the present study was to investigate the role of multidrug and toxin extrusion protein 1 (MATE1) in the transport of BBR in the liver and kidney. 2. Using human MATE1 (hMATE1)-transfected HEK293 cells, BBR was shown to be a substrate of hMATE1 (Km = 4.28 ± 2.18 μM)...
March 16, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28294690/stereoselective-and-non-stereoselective-pharmacokinetics-of-rabeprazole-an-overview
#14
Ranjeet Prasad Dash, Rana Rais, Nuggehally R Srinivas
1. Proton pump inhibitors have been extensively used for the treatment of ailments due to increased gastric acid secretion such as peptic ulcers, gastroesophageal reflux disease etc. 2. There are several approved drugs in the proton pump inhibitor class with the latest entries representing single enantiomer drugs of the previously approved racemic drugs. 3. Despite having a high degree of structural resemblance, rabeprazole, was shown to possess some unique differentiation from other drugs in the class. One of the key distinguishing features of rabeprazole was related to the lesser involvement of polymorphic metabolism in its pharmacokinetic disposition...
March 15, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28290233/area-under-the-curve-predictions-of-dalbavancin-a-new-lipoglycopeptide-agent-using-the-end-of-intravenous-infusion-concentration-data-point-by-regression-analyses-such-as-linear-log-linear-and-power-models
#15
Ravi Kanth Bhamidipati, Muzeeb Syed, Ramesh Mullangi, Nuggehally Srinivas
1. Dalbavancin, a lipoglycopeptide, is approved for treating gram-positive bacterial infections. Area under plasma concentration versus time curve (AUCinf) of dalbavancin is a key parameter and AUCinf/MIC ratio is a critical pharmacodynamic marker. 2. Using end of intravenous infusion concentration (i.e. Cmax) Cmax versus AUCinf relationship for dalbavancin was established by regression analyses (i.e. linear, log-log, log-linear and power models) using 21 pairs of subject data. 3. The predictions of the AUCinf were performed using published Cmax data by application of regression equations...
March 14, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28287050/the-effect-of-fenofibric-acid-on-the-pharmacokinetics-and-pharmacodynamics-of-warfarin-in-rats
#16
Chaorui Guo, Siqi Xue, Xiufen Zheng, Lu Yang, Di Zhao, Xijing Chen, Ning Li
1. Case reports have shown that coadministration of fenofibric acid (FA) could increase bleeding risks of warfarin, but the mechanisms remained unknown. We therefore investigated the pharmacokinetic and pharmacodynamic interaction between warfarin and FA in rats. 2. Rats received warfarin alone (2 mg/kg) or coadministered with FA (100 mg/kg). FA significantly increased the exposure to warfarin, and decreased that to 7-hydroxywarfarin in rats nearly by two-fold, meanwhile increased Cmax and prolonged t1/2 of warfarin...
March 13, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28287022/metabolic-map-of-osthole-and-its-effect-on-lipids
#17
Qi Zhao, Xin-Mei Li, Hong-Ning Liu, Frank J Gonzalez, Fei Li
1. Osthole, a coumarin compound from plants, is a promising agent for the treatment of metabolic diseases, including hyperglycemia, fatty liver, and cancers. Studies indicate that the peroxisome proliferator-activated receptors (PPAR) α and γ are involved in the pharmacological effects of osthole. The in vitro and in vivo metabolism of osthole, and its biological activity are not completely understood. 2. In this study, UPLC-ESI-QTOFMS-based metabolomics was used to determine the metabolic pathway of osthole and its influence on the levels of endogenous metabolites...
March 13, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28285550/the-inhibition-of-udp-glucuronosyltransferases-ugts-by-tetraiodothyronine-t4-and-triiodothyronine-t3
#18
Da-Wei Chen, Zuo Du, Chun-Ze Zhang, Wei-Hua Zhang, Yun-Feng Cao, Hong-Zhi Sun, Zhi-Tu Zhu, Kun Yang, Yong-Zhe Liu, Ze-Wei Zhao, Zhi-Wei Fu, Wen-Qing Gu, Yang Yu, Zhong-Ze Fang
1. UDP-glucuronosyltransferases (UGTs) are important drug-metabolizing enzymes (DMEs) catalyzing the glucuronidation elimination of various xenobiotics and endogenous substances. Endogenous substances are important regulators for the activity of various UGT isoforms. Triiodothyronine (T3) and thyroxine (T4) are important thyroid hormones essential for normal cellular differentiation and growth. The present study aims to elucidate the inhibition behavior of T3 and T4 on the activity of UGT isoforms. 2. In vitro recombinant UGTs-catalyzed glucuronidation of 4-methylumbelliferone (4-MU) was used to screen the inhibition potential of triiodothyronine (T3) and thyroxine (T4) on the activity of various UGT isoforms...
March 13, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27830982/excretion-and-toxicity-evaluation-of-131-i-sennoside-a-as-a-necrosis-avid-agent
#19
Zhiqi Yin, Lidan Sun, Qiaomei Jin, Shaoli Song, Yuanbo Feng, Hong Liao, Yicheng Ni, Jian Zhang, Wei Liu
1. Sennoside A (SA) is a newly identified necrosis-avid agent that shows capability for imaging diagnosis and tumor necrosis targeted radiotherapy. As a water-soluble compound, (131)I-Sennoside A ((131)I-SA) might be excreted predominately through the kidneys with the possibility of nephrotoxicity. 2. To further verify excretion pathway and examine nephrotoxicity of (131)I-SA, excretion and nephrotoxicity were appraised. The pharmacokinetics, hepatotoxicity and hematotoxicity of (131)I-SA were also evaluated to accelerate its possible clinical translation...
March 13, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28281401/a-novel-in-vitro-allometric-scaling-methodology-for-aldehyde-oxidase-substrates-to-enable-selection-of-appropriate-species-for-traditional-allometry
#20
Rachel D Crouch, J Matthew Hutzler, J Scott Daniels
1. Failure to predict human pharmacokinetics of aldehyde oxidase (AO) substrates using traditional allometry has been attributed to species differences in AO metabolism. 2. To identify appropriate species for predicting human in vivo clearance by single-species scaling (SSS) or multispecies allometry (MA), we scaled in vitro intrinsic clearance (CLint) of five AO substrates obtained from hepatic S9 of mouse, rat, guinea pig, monkey and minipig to human in vitro CLint. 3. When predicting human in vitro CLint, average absolute fold-error was ≤2...
March 10, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
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