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Xenobiotica; the Fate of Foreign Compounds in Biological Systems

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https://www.readbyqxmd.com/read/29334326/predicting-the-dopamine-d2-receptor-occupancy-of-ropinirole-in-rats-using-positron-emission-tomography-and-pharmacokinetic-pharmacodynamic-modeling
#1
Chenrong Huang, Ziteng Wang, Linsheng Liu, Xiaoxue Liu, Ji Dong, Qingqing Xu, Bin Zhang, Liyan Miao
The purpose of this study was to measure dopamine D2/3 receptor occupancy (RO) as a marker of the clinical efficacy of ropinirole in rats via positron emission tomography (PET) using 18F-fallypride as the radiotracer and to explore the relationship between dopamine RO and the plasma concentration of ropinirole via pharmacokinetic-pharmacodynamic modeling. Plasma was collected from 16 rats treated with one of four doses of ropinirole. For the time-dependent study, the data of 16 rats in the 15 mg/kg dose group at four time points were averaged, and another 24 rats were divided into three dose groups (5 mg/kg, 30 mg/kg and 60 mg/kg) for the dose-dependent study; the animals were assessed via 18F-fallypride PET scans...
January 15, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29325475/investigation-of-the-mechanisms-of-genkwa-flos-hepatotoxicity-by-a-cell-metabolomics-strategy-combined-with-serum-pharmacology-in-hl-7702-liver-cells
#2
Zhipeng Wang, Yuanyuan Zhang, Quanli Liu, Linjia Sun, Mingming Lv, Peipei Yu, Xiaohui Chen
1. To investigate Genkwa Flos hepatotoxicity, a cell metabolomics strategy combined with serum pharmacology was performed on human HL-7702 liver cells in this study. 2. Firstly, cell viability and biochemical indicators were determined and the cell morphology was observed to confirm the cell injury and develop a cell hepatotoxicity model. Then, with the help of cell metabolomics based on UPLC-MS, the Genkwa Flos group samples were completely separated from the blank group samples in the score plots and seven upregulated as well as two down-regulated putative biomarkers in the loading plot were identified and confirmed...
January 11, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29320949/absorption-distribution-metabolism-and-excretion-of-an-isocitrate-dehydrogenase-2-inhibitor-enasidenib-in-rats-and-humans
#3
Zeen Tong, Christian Atsriku, Usha Yerramilli, Xiaomin Wang, Yan Li, Josephine Reyes, Bin Fan, Hua Yang, Matthew Hoffmann, Sekhar Surapaneni
1. The absorption, distribution, metabolism and excretion (ADME) of enasidenib were studied following a single oral dose of [14C]enasidenib to rats (10 mg/kg; 100 μCi/kg) and healthy volunteers (100 mg; 318 nCi). 2. Enasidenib was readily absorbed, extensively metabolized and primarily eliminated via the hepatobiliary pathway. Enasidenib-derived radioactivity was widely distributed in rats. Excretion of radioactivity was approximately 95% to 99% of the dose from rats in 168 hours post-dose and 82.4% from human volunteers in 504 hours post-dose...
January 10, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29320899/in-vitro-analysis-of-itraconazole-cis-diastereoisomers-inhibition-of-nine-cytochrome-p450-enzymes-stereoselective-inhibition-of-cyp3a
#4
Kristyna Krasulova, Zdenek Dvorak, Pavel Anzenbacher
Itraconazole (ITZ), an antifungal azole derivate is a chiral drug that consists of four cis-diastereoisomers ((+)-2R,4S,2'R-ITZ-A; (+)-2R,4S,2'S-ITZ-B; (-)2S,4R,2'S-ITZ-C and (-) 2S,4R,2'R-ITZ-D) which may differ in their pharmacokinetics and pharmacodynamics. As itraconazole is known as a CYP3A4 inhibitor causing severe drug-drug interaction, the inhibitory potencies of its individual optical isomers towards nine drug-metabolising cytochrome P450 (including CYP3A, CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1), were investigated...
January 10, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29310511/cytochrome-p450-2a6-and-other-human-p450-enzymes-in-the-oxidation-of-flavone-and-flavanone
#5
Kensaku Kakimoto, Norie Murayama, Shigeo Takenaka, Haruna Nagayoshi, Young-Ran Lim, Vitchan Kim, Donghak Kim, Hiroshi Yamazaki, Masayuki Komori, F Peter Guengerich, Tsutomu Shimada
1. We previously reported that flavone and flavanone interact spectrally with cytochrome P450 (P450 or CYP) 2A6 and 2A13 and other human P450s and inhibit catalytic activities of these P450 enzymes. In this study, we studied abilities of CYP1A1, 1A2, 1B1, 2A6, 2A13, 2C9, and 3A4 to oxidize flavone and flavanone. 2. Human P450s oxidized flavone to 6- and 5-hydroxylated flavones, seven uncharacterized mono-hydroxylated flavones, and five di-hydroxylated flavones. CYP2A6 was most active in forming 6-hydroxy- and 5-hydroxyflavones and several mono- and di-hydroxylated products...
January 9, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29300135/non-clinical-pharmacokinetic-profiles-of-rovatirelin-an-orally-available-thyrotropin-releasing-hormone-analogue
#6
Kaoru Kobayashi, Yoshikazu Abe, Hiroshi Harada, Emiko Oota, Takuro Endo, Hiroo Takeda
The non-clinical pharmacokinetic profiles of rovatirelin, a novel thyrotropin releasing hormone (TRH) analogue, were investigated in vivo and in vitro. Rovatirelin orally administered to rats and dogs was rapidly absorbed and bioavailability was estimated to be 7.3% and 41.3%, respectively. The extent of plasma protein binding of rovatirelin in rats, dogs, and humans was low in all species (∼15%). The permeability of rovatirelin from blood to brain (permeability-surface area) ranged from 1.04 ± 0.14 to 1...
January 4, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29299977/utility-of-food-pellets-containing-1-aminobenzotriazole-for-longer-term-in-vivo-inhibition-of-cytochrome-p450-in-mice
#7
Rowan Stringer, Valerie Cordier, Catherine Afatsawo, Philip Arabin, Sandrine Desrayaud, Laurent Hoffmann, Daniel Lehmann, Philip John Lowe, Francis Risser, Julia Thiel, Toni Widmer, Peter Wipfli, Marc Bigaud
1. The utility of 1-aminobenzotriazole (ABT), incorporated in food, has been investigated as an approach for longer term inhibition of cytochrome P450 (P450) enzymes in mice. 2. In rats ABT inhibits gastric emptying, to investigate this potential limitation in mice we examined the effect of ABT administration on the oral absorption of NVS-CRF38. Two hour prior oral treatment with 50 mg/kg ABT inhibited the oral absorption of NVS-CRF38, Tmax was 4 hours for ABT treated mice compared to 0.5 hours in the control group...
January 4, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29297772/assessment-of-drug-drug-interaction-potential-and-pbpk-modeling-of-cc-223-a-potent-inhibitor-of-the-mammalian-target-of-rapamycin-kinase
#8
Zeen Tong, Rangaraj Narayanan, Christian Atsriku, Jim Nissel, Yan Li, Hong Liu, Xiaomin Wang, Sekhar Surapaneni
1. CC-223 was studied in vitro for metabolism and drug-drug interactions (DDI), and in clinic for interaction with ketoconazole. 2. In vitro, human metabolites of CC-223 included O-desmethyl CC-223 (M1), keto (M2), N-oxide (M3), and imine (M13), with M1 being the most prominent metabolite. 3. CC-223 was metabolized by CYP2C9 and CYP3A, while metabolism of M1 was mediated by CYP2C8 and CYP3A. Ketoconazole increased CC-223 and M1 exposure by 60-70% in healthy volunteers. 4. CC-223 (IC50 ≥ 27 µM) and M1 (IC50 ≥ 46 µM) were inhibitors of CYP2C9 and CYP2C19 in human liver microsomes...
January 3, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29297729/direct-and-quantitative-evaluation-of-the-major-human-cyp-contribution-fmcyp-to-drug-clearance-using-the-in-vitro-silensomes%C3%A2-model
#9
Yannick Parmentier, Corinne Pothier, Nicky Hewitt, Ludwig Vincent, Fabrice Caradec, Jia Liu, Feifei Lin, Marie-Michèle Trancart, Fabrice Guillet, Belkacem Bouaita, Christophe Chesne, Bernard Walther
1. We have applied the concept of using MBIs to produce CYP-Silensomes to quantify the contribution of the major CYPs to drug metabolism (fmCYP). 2. The target CYPs were extensively and selectivity inhibited by the selected MBIs, while non-target CYPs were inhibited by less than 20% of the homologous control activities. Only CYP2D6-Silensomes exhibited a CYP2B6 inhibition that could be easily and efficiently encountered by subtracting the fmCYP2B6 measured using CYP2B6-Silensomes to adjust the fmCYP2D6. 3. To validate the use of a panel of 6 CYP-Silensomes, we showed that the fmCYP values of mono- and multi-CYP metabolised drugs were well predicted, with 70% within ± 15% accuracy...
January 3, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29278046/pregnancy-affects-the-pharmacokinetics-of-sildenafil-and-its-metabolite-in-the-rabbit
#10
Francesca M Russo, Paola Mian, Elke Hj Krekels, Kristel Van Calsteren, Dick Tibboel, Jan Deprest, Karel Allegaert
There is growing interest in the use of sildenafil during pregnancy for various maternal and fetal conditions. This study aims to investigate the effect of pregnancy on the maternal pharmacokinetics (PK) of sildenafil and its main metabolite desmethylsildenafil in rabbits. Using NONMEM, population PK-modelling was performed based on plasma samples from 31 rabbits of whom 15 were pregnant and 16 were not. All received a single subcutaneous sildenafil dose of 10mg/kg. One sample was obtained per rabbit at either 30, 60, 120, 360, 720 or 1320 minutes after sildenafil administration...
December 26, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29251532/metabolism-and-pharmacokinetics-studies-of-allyl-methyl-disulfide-in-rats
#11
Yan Liu, Ang Li, Xiaoyan Jiang, Xiaosong Zhu, Xiuli Feng, Xiao Sun, Zhongxi Zhao
1. Allyl methyl disulfide (AMDS) is one of the main compounds in garlic whereas its metabolism has not been studied yet. 2. In this work, we first identified the metabolites of AMDS in rat erythrocytes and rats using GC-MS. The transformation mechanism study among different metabolites was then conducted. The apparent kinetics of AMDS in rat erythrocytes and pharmacokinetics of AMDS by oral administration in rats were also studied. 3. The metabolic pathway study showed that AMDS were mainly metabolized in rats to allyl methyl sulfoxide (AMSO) and allyl methyl sulfone (AMSO2) through mechanisms of reduction, methylation and oxidation...
December 18, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29251086/pharmacokinetics-and-distribution-of-schisandrol-a-and-its-major-metabolites-in-rats
#12
Xu Liu, Lixin Cong, Chunmei Wang, He Li, Chengyi Zhang, Xingang Guan, Peng Liu, Yu Xie, Jianguang Chen, Jinghui Sun
1. Schizandrol A is an active component in schisandra, also the representative component for the identification of schisandra. 2. A rapid resolution liquid chromatography coupled with quadruple-time-of-flight mass spectrometry (RRLC-QTOF/MS) was developed to investigate the pharmacokinetics of schizandrol A after itsintragastric administration (50 mg/kg) in rats. 3. Schizandrol A was rapidly absorbed (Tmax=2.07 h), with a longer duration (t1/2=9.48 h) and larger apparent volume of distribution (Vz/F = 111...
December 18, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29235899/metabolic-profiles-of-corydaline-in-rats-by-ultra-performance-liquid-chromatography-coupled-to-quadrupole-time-of-flight-mass-spectrometry
#13
Liwei Chai, Paul Owusu Donkor, Kun Wang, Yingjie Sun, Mahmood Brobbey Oppong, Kai Wang, Liqin Ding, Feng Qiu
Corydaline, an isoquinoline alkaloid obtained from the rhizomes of Corydalis yanhusuo, exhibits anti-acetylcholinesterase, anti-angiogenic, anti-allergic and gastric emptying activities. In this study, a rapid and reliable ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS) method was developed and employed for the comprehensive study of the metabolites of corydaline in rats. Altogether, 43 metabolites were identified in the plasma (11), bile (9), urine (34) and feces (21) of rats after oral administration of corydaline at a dose of 4...
December 13, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29228872/the-in-vivo-pharmacokinetics-tissue-distribution-and-excretion-investigation-of-mesaconine-in-rats-and-its-in-vitro-intestinal-absorption-study-using-uplc-ms-ms
#14
Xiuxiu Liu, Minghai Tang, Taohong Liu, Chunyan Wang, Qiaoxin Tang, Yaxin Xiao, Ruixin Yang, Ruobing Chao
Mesaconine, an ingredient from Aconitum carmichaelii Debx., has been proven to have cardiac effect. For further development and better pharmacological elucidation, the in vivo process and intestinal absorptive behavior of mesaconine should be investigated comprehensively. An ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for quantitation of mesaconine in rat plasma, tissue homogenates, urine and feces to investigate the in vivo pharmacokinetic profiles, tissue distribution and excretion...
December 12, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29224415/preclinical-evaluation-of-saroglitazar-magnesium-a-dual-ppar-%C3%AE-%C3%AE-agonist-for-treatment-of-dyslipidemia-and-metabolic-disorders
#15
Harilal Patel, Poonam Giri, Prakash Patel, Sanjay Singh, Laxmikant Gupta, Urvesh Patel, Nirav Modi, Kalpesh Shah, Mukul R Jain, Nuggehally R Srinivas, Pankaj Patel
Saroglitazar, a novel peroxisome proliferator-activated receptor agonist (PPAR), regulates lipid and glucose metabolism. The objective of this report is to provide a preclinical evaluation (in vitro/in vivo) of ADME properties of saroglitazar. In vitro studies included determination of permeability, metabolic stability, plasma protein binding, CYP reaction phenotyping and CYP inhibitory liability. In vivo studies included oral bioavailability and pharmacokinetic assessment in mouse, rat and dog. The excretion of saroglitazar was determined in rats...
December 9, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29219669/metabolic-profile-elucidation-of-zhi-zi-da-huang-decoction-in-rat-intestinal-bacteria-using-high-resolution-mass-spectrometry-combined-with-multiple-analytical-perspectives
#16
Miao Wang, Qing Hu, Qingshui Shi, Gongjun Yang, Fang Feng
1. Zhi-Zi-Da-Huang decoction (ZZDHD) has been widely used for the treatment of alcoholic jaundice, alcoholic liver disease and acute hepatitis in China for thousands of years. Conventionally decoctions are administered orally, after which the metabolism caused by the enzymes in intestinal bacteria may influence significantly on the curative effects or toxicity. 2. In this work, the comprehensive metabolic process of ZZDHD in intestinal bacteria was investigated reliably using high resolution HPLC-DAD-ESI-TOF/MS...
December 8, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29206565/absorption-distribution-metabolism-and-excretion-of-mtor-kinase-inhibitor-cc-223-in-rats-dogs-and-humans
#17
Zeen Tong, Christian Atsriku, Usha Yerramilli, Xiaomin Wang, Jim Nissel, Yan Li, Sekhar Surapaneni
The absorption, distribution, metabolism and excretion of CC-223 were studied following a single oral dose of [14C]CC-223 to rats (3 mg/kg; 90 μCi/kg), dogs (1.5 mg/kg; 10 μCi/kg) and healthy volunteers (20 mg; 200 nCi). CC-223-derived radioactivity was widely distributed in rats. Excretion of radioactivity was rapid and nearly complete from rats (87%), dogs (78%), and humans (97%). Feces was the major excretion pathway for rats (67%) and dogs (70%), while urine (57.6%) was the major elimination route for humans...
December 5, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29198170/the-effects-of-aging-on-hepatic-microsomal-scaling-factor-and-hepatocellularity-number-in-the-horse
#18
Khaled A Shibany, Sabine Tötemeyer, Stefanie L Pratt, Stuart W Paine
Scaling factor values for the in vitro-in vivo extrapolation of hepatic metabolic clearance for xenobiotics have not yet been determined in horses. Scaling factors were determined by comparing the total protein and or CYP P450 content in microsomes and cryopreserved hepatocytes against the content in the liver. Microsomal protein per gram of liver (MPPGL) and hepatocellularity number per gram of liver (HPGL) using CYP P450 content method ranged 41 - 73 mg/gram of liver (mean= 57 mg/gram of liver, n = 39) and 146 - 320 × 106 cells/g of liver (mean = 227× 106 cells/g of liver, n = 18), respectively; and 156 - 352 × 106 cells/g of liver (mean = 232× 106 cells/g of liver) using total protein method...
December 2, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29191071/allosteric-activation-of-cytochrome-p450-3a4-by-efavirenz-facilitates-midazolam-binding
#19
Tomohiko Ichikawa, Hirofumi Tsujino, Takahiro Miki, Masaya Kobayashi, Chiaki Matsubara, Sara Miyata, Taku Yamashita, Kohei Takeshita, Yasushige Yonezawa, Tadayuki Uno
1. The purpose of this study is to investigate the heteroactivation mechanism of CYP3A4 by efavirenz, which enhances metabolism of midazolam in vivo, in terms of its binding to CYP3A4 with in vitro spectroscopic methods. 2. Efavirenz exhibited a type II spectral change with binding to CYP3A4 indicating a possible inhibitor. Although dissociation constant (Kd) was approximated as 550 μM, efavirenz enhanced binding affinity of midazolam as a co-existing drug with an estimated iKd value of 5.6 µM which is comparable to a clinical concentration...
December 1, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29182424/bioactivation-of-cyclopropyl-rings-by-p450-an-observation-encountered-during-the-optimisation-of-a-series-of-hepatitis-c-virus-ns5b-inhibitors
#20
Xiaoliang Zhuo, Ying-Zi Wang, Kap-Sun Yeung, Juliang Zhu, Xiaohua Stella Huang, Kyle E Parcella, Kyle J Eastman, John F Kadow, Nicholas A Meanwell, Yue-Zhong Shu, Benjamin M Johnson
1. Due to its unique C-C and C-H bonding properties, conformational preferences and relative hydrophilicity, the cyclopropyl ring has been used as a synthetic building block in drug discovery to modulate potency and drug-like properties. During an effort to discover inhibitors of the hepatitis C virus nonstructural protein 5B with improved potency and genotype-coverage profiles, the use of a pyrimidinylcyclopropylbenzamide moiety linked to a C6-substituted benzofuran or azabenzofuran core scaffold was explored in an effort to balance antiviral potency and metabolic stability...
November 28, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
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