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Xenobiotica; the Fate of Foreign Compounds in Biological Systems

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https://www.readbyqxmd.com/read/27921450/oral-pharmacokinetic-interaction-of-ester-rich-fruit-juices-and-pharmaceutical-excipients-with-tenofovir-disoproxil-fumarate-in-male-wistar-rats
#1
Joseph Shailender, Punna Rao Ravi, Paramita Saha, Srividya Myneni
The aim of this study was to evaluate the role of intestinal esterases on the absorption process of tenofovir disoproxil fumarate (TDF). The esterase inhibition capacity of fruit juices (FJs) rich in ester linkages and pharmaceutical excipients (having ester) was performed in vitro by incubating TDF with each FJ and excipient in the intestinal washings. The ex vivo everted gut sac model was also used to evaluate the absorption enhancement capacity of these FJs and excipients. Single dose oral pharmacokinetic studies were performed by concomitant administration of TDF with each of the selected FJs and excipients...
December 6, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27919190/investigation-of-the-influence-of-glycyrrhizin-on-the-pharmacokinetics-of-celastrol-in-rats-using-lc-ms-and-its-potential-mechanism
#2
Guangkui Yan, Hanhua Zhang, Wei Wang, Yuan Li, Chenghuang Mao, Mingqiao Fang, Xianhong Yi, Jingdong Zhang
1. The aim of this study was to investigate the effects of glycyrrhizin on the pharmacokinetics of celastrol in rats. 2. Twelve male Sprague-Dawley rats were randomly assigned to two groups: control group and test group. Test group was pretreated with glycyrrhizin at a dose of 100 mg/kg/day for 10 days, and then the two groups were orally administered with celastrol at a dose of 1 mg/kg. The concentration of celastrol was determined using a sensitive and reliable LC-MS method. 3. The results showed that glycyrrhizin could significantly decrease the plasma concentration (from 64...
December 5, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27618478/long-circulation-nanostructured-lipid-carriers-for-gambogenic-acid-formulation-design-characterization-and-pharmacokinetic
#3
Tongyuan Lin, Xia Huang, Yanyan Wang, Tingting Zhu, Qing Luo, Xiaoxiao Wang, Kai Zhou, Hao Cheng, Daiyin Peng, Weidong Chen
1. GNA-PEG-NLC and GNA-NLC were prepared by emulsification and low-temperature solidification methods. The optimized GNA-PEG-NLC and GNA-NLC were not only found to have small mean size (146.33 ± 2.11 and 144.07 ± 1.44) nm, high Zeta potential (-25.10 ± 1.35 and -28.03 ± 0.29) mV, but also great entrapment efficiency (79.07 ± 1.11 and 84.65 ± 0.98%). TEM proved that particles were nearly spherical with smooth surface shape. Furthermore, in vitro release revealed a burst release initially, followed by a sustained profiles up to 48 h, and the cumulative drug release of GNA-PEG-NLC and GNA-NLC was 65...
December 5, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27910730/retrospective-use-of-pbpk-modelling-to-understand-a-clinical-drug-drug-interaction-between-dextromethorphan-and-gsk1034702
#4
Michael J Hobbs, Jackie Bloomer, Gordon Dear
: 1. PURPOSE: In a clinical trial, a strong drug-drug interaction (DDI) was observed between dextromethorphan (DM, the object or victim drug) and GSK1034702 (the precipitant or perpetrator drug), following single and repeat doses. This study determined the inhibition parameters of GSK1034702 in vitro and applied PBPK modelling approaches to simulate the clinical observations and provide mechanistic hypotheses to understand the DDI. 2. METHODS: In vitro assays were conducted to determine the inhibition parameters of human CYP2D6 by GSK1034702...
December 2, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27910729/identification-of-cytochrome-p450s-involved-in-the-metabolism-of-6-benzyl-1-benzyloxymethyl-5-iodouracil-w-1-using-human-recombinant-enzymes-and-rat-liver-microsomes-in-vitro
#5
Ying-Yuan Lu, Hai-Xu Cheng, Xin Wang, Xiao-Wei Wang, Jun-Yi Liu, Pu Li, Ya-Qing Lou, Jun Li, Chuang Lu, Guo-Liang Zhang
1. The aim of this study was to identify the hepatic metabolic enzymes, which involved in the biotransformation of 6-benzyl-1-benzyloxymethyl-5-iodouracil (W-1), a novel non-nucleoside reverse transcriptase inhibitor (NNRTIs) in rat and human in vitro. 2. The parent drug of W-1 was incubated with RLMs or recombinant CYPs (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP3A5, respectively) in the presence or absence of NADPH regenerating system. The metabolites of W-1 were analyzed with liquid chromatography-ion trap-time of flight-mass spectrometry (LC-IT-TOF-MS)...
December 2, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27841077/preclinical-evaluation-of-the-potential-for-cytochrome-p450-inhibition-and-induction-of-the-selective-alk-inhibitor-alectinib
#6
Nobuo Sekiguchi, Shunsuke Nagao, Kenji Takanashi, Motohiro Kato, Akihisa Kaneko, Keiichi Morita, Hidetoshi Shindoh, Masaki Ishigai
1. A novel selective anaplastic lymphoma kinase (ALK) inhibitor, alectinib, has shown remarkable efficacy and safety in patients with ALK-positive non-small-cell lung cancer (NSCLC). The purpose of this study was to evaluate in vitro the potential to inhibit and induce cytochrome P450 (CYP) isoforms for alectinib and its major metabolite M4. 2. Alectinib and M4 did not show the meaningful direct inhibition of six major CYP isoforms (CYP1A2, 2B6, 2C9, 2C19, 2D6 and 3A4) in human liver microsomes (HLM). Alectinib, but not M4, competitively inhibited CYP2C8, by which few marketed drugs are exclusively metabolized, with an inhibition constant of 1...
December 1, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27841072/functional-expression-and-comparative-characterization-of-four-feline-p450-cytochromes-using-fluorescent-substrates
#7
Gaku Okamatsu, Kei Kawakami, Tetsuya Komatsu, Takio Kitazawa, Yasuhiro Uno, Hiroki Teraoka
1. Cytochrome P450s (CYP) are a major group of metabolizing enzymes for xenobiotics in humans and other mammals. The properties of CYP isoforms in the domestic cat, an obligate carnivore, are largely unknown at present. In this study, we studied relative expression in tissues and enzymatic properties of nine significant feline CYP isoforms. 2. CYP2E2 transcript was most abundant in the feline liver, followed by CYP2A13 and 2E1. Transcripts of CYP3A131, 1A2 and 1A1 were also present in the liver, while CYP2D6 and 3A132 were only slightly expressed...
November 30, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27892765/comparison-of-predictability-for-human-pharmacokinetics-parameters-among-monkeys-rats-and-chimeric-mice-with-humanised-liver
#8
Maki Miyamoto, Shinji Iwasaki, Ikumi Chisaki, Sayaka Nakagawa, Nobuyuki Amano, Hideki Hirabayashi
The aim of the present study was to evaluate the usefulness of chimeric mice with humanised liver (PXB mice) for the prediction of clearance (CLt) and volume of distribution at steady state (Vdss), in comparison with monkeys, which have been reported as a reliable model for human pharmacokinetics (PK) prediction, and with rats, as a conventional PK model. CLt and Vdss values in PXB mice, monkeys, and rats were determined following intravenous administration of 30 compounds known to be mainly eliminated in humans via the hepatic metabolism by various drug-metabolising enzymes...
November 28, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27866463/pharmacokinetics-distribution-and-disposition-of-esaxerenone-a-novel-highly-potent-and-selective-non-steroidal-mineralocorticoid-receptor-antagonist-in-rats-and-monkeys
#9
Makiko Yamada, Makoto Takei, Eiko Suzuki, Hideo Takakusa, Masakatsu Kotsuma, Takuo Washio, Nobuyuki Murayama, Shin-Ichi Inoue, Takashi Izumi
1. Esaxerenone (CS-3150) is a novel non-steroidal mineralocorticoid receptor antagonist. The pharmacokinetics, tissue distribution, excretion, and metabolism of esaxerenone were evaluated in rats and monkeys. 2. Following intravenous dosing of esaxerenone at 0.1 to 3 mg/kg, the total body clearance and the volume of distribution were 3.53 to 6.69 mL/min/kg and 1.47 to 2.49 L/kg, respectively in rats, and 2.79 to 3.69 mL/min/kg and 1.34 to 1.54 L/kg, respectively in monkeys. The absolute oral bioavailability was 61...
November 21, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27866461/metabolism-excretion-and-pharmacokinetics-of-14-c-glasdegib-pf-04449913-in-healthy-volunteers-following-oral-administration
#10
Justine L Lam, Alfin Vaz, Brian Hee, Yali Liang, Xin Yang, M Naveed Shaik
1. The metabolism, excretion and pharmacokinetics of glasdegib (PF-04449913) were investigated following administration of a single oral dose of 100 mg/100 µCi [(14)C]glasdegib to six healthy male volunteers (NCT02110342). 2. The peak concentrations of glasdegib (890.3 ng/mL) and total radioactivity (1043 ngEq/mL) occurred in plasma at 0.75 hours post-dose. The AUCinf were 8469 ng.h/mL and 12230 ngEq.h/mL respectively, for glasdegib and total radioactivity. 3. Mean recovery of [(14)C]glasdegib-related radioactivity in excreta was 91% of the administered dose (49% in urine and 42% in faeces)...
November 21, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27855567/pradigastat-disposition-in-humans-in-vivo-and-in-vitro-investigations
#11
Alana Upthagrove, Jin Chen, Charles D Meyers, Kenneth Kulmatycki, Angela Bretz, Lai Wang, Lana Peng, Safet Palamar, Melissa Lin, Tapan Majumdar, Phi Tran, Heidi J Einolf
1. Pradigastat is a potent and specific diacylglycerol acyltransferase-1 (DGAT1) inhibitor effective in lowering postprandial triglycerides in healthy human subjects and fasting triglycerides in familial chylomicronemia syndrome (FCS) patients. 2. Here we present the results of human oral absorption, metabolism and excretion (AME), intravenous pharmacokinetic (PK), and in vitro studies which together provide an overall understanding of the disposition of pradigastat in humans. 3. In human in vitro systems, pradigastat is metabolized slowly to a stable acyl glucuronide (M18...
November 18, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27855531/abcc2-1249g%C3%A2-%C3%A2-a-polymorphism-implicates-altered-transport-activity-for-sorafenib
#12
Danyun Wei, Hong Zhang, Rui Peng, Cuiyuan Huang, Ruidan Bai
1. Multidrug resistance-associated protein 2 (MRP2), encoded by the ABCC2 gene, is an efflux transporter of several endogenous substrates and xenobiotics. Here we investigated whether the 1249G > A (rs2273697) polymorphism in ABCC2 affects the ability of MRP2 to pump the multi-tumor drug sorafenib out of cells. 2. Human embryonic kidney 293 (HEK 293) cell lines transfected with ABCC2-1249G and ABCC2-1249A were used to assess the sensitivity and accumulation to sorafenib. The isolated MRP2 were applied to estimate the ATPase activity...
November 18, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27852146/metabolic-profiles-of-pomalidomide-in-human-plasma-simulated-with-pharmacokinetic-data-in-control-and-humanized-liver-mice
#13
Makiko Shimizu, Hiroshi Suemizu, Marina Mitsui, Norio Shibata, F Peter Guengerich, Hiroshi Yamazaki
1. Pomalidomide has been shown to be potentially teratogenic in thalidomide-sensitive animal species such as rabbits. Screening for thalidomide analogs devoid of teratogenicity/toxicity - attributable to metabolites formed by cytochrome P450 enzymes - but having immunomodulatory properties is a strategic pathway towards development of new anticancer drugs. 2. In this study, plasma concentrations of pomalidomide, its primary 5-hydroxylated metabolite, and its glucuronide conjugate(s) were investigated in control and humanized-liver mice...
November 16, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27670974/effect-of-piperine-on-cyp2e1-enzyme-activity-of-chlorzoxazone-in-healthy-volunteers
#14
Satish Kumar Bedada, Praveen Kumar Boga
1. The purpose of the present study was to investigate the effect of piperine (PIP) on CYP2E1 enzyme activity and pharmacokinetics of chlorzoxazone (CHZ) in healthy volunteers. 2. An open-label, two period, sequential study was conducted in 12 healthy volunteers. A single dose of PIP 20 mg was administered daily for 10 days during treatment phase. A single dose of CHZ 250 mg was administered during control and after treatment phases under fasting conditions. The blood samples were collected at predetermined time intervals after CHZ dosing and analyzed by HPLC...
November 16, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27571049/screening-of-drug-metabolizing-enzymes-for-fusidic-acid-and-its-interactions-with-isoform-selective-substrates-in-vitro
#15
D Chen, X-X Lin, Q Zhao, J Xiao, S-F Peng, M-F Xiao, D-S Ouyang, Z-R Tan, Y-C Wang, J-B Peng, W Zhang, Y Chen
1. Fusidic acid (FA) is widely used for the treatment of infections of sensitive osteomyelitis or skin and soft tissue caused by bacteria. However, the role of cytochrome P450s (CYPs) in the metabolism of FA is unclear. In the present study, we screened the main CYPs for the metabolism of FA and studied its interactions with isoform-selective substrates in vitro. 2. The main CYP450s were screened according to the inhibitory effect of specific inhibitors on the metabolism of FA in human liver microsomes (HLMs) or recombinant CYP isoforms...
November 15, 2016: 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
#16
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 therapy. As a water-soluble compound, (131)I-Sennoside A ((131)I-SA) might be excreted mainly through the kidneys with 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...
November 10, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27827094/effect-of-ferulic-acid-on-the-brain-pharmacokinetics-of-tetramethylpyrazine-in-conscious-rats
#17
Yinai Wu, Fengyun Liao, Weiguo Liao, Jianye Yu, Xingyun Deng, Huazhu Zheng, YingJiao Meng, Lisheng Wang
1. In traditional Chinese medicine, Angelica sinensis is often co-prescribed with Ligusticum chuanxiong Hort for the treatment of ischemic cerebrovascular diseases. Tetramethylpyrazine (TMP) is one of the most important active ingredients isolated from Ligusticum chuanxiong Hort; Ferulic acid (FA) is the main water-soluble component of Angelica sinensis. 2. The purpose of this study was to investigate the possible effect of FA on the brain pharmacokinetics of TMP in conscious Sprague-Dawley rats. The pharmacokinetic parameters of TMP were investigated in brain microdialysates after oral and intravenous administration of TMP (4mg/kg) to rats in the absence and presence of FA (5mg/kg)...
November 9, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27817253/multidrug-and-toxin-extrusion-protein-1-mediated-interaction-of-metformin-and-scutellariae-radix-in-rats
#18
Sreymom Yim, Byoung Hoon You, Hee-Sung Chae, Young-Won Chin, Hojun Kim, Han Seok Choi, Young Hee Choi
The metformin and Scutellariae Radix extract (SB) combination has been previously reported to enhance anti-diabetic activity. Considering that organic cation transporters (OCTs) and multi-drug and toxin extrusion proteins (MATEs) in the liver and kidney are determinant factors on hepatic distribution and renal clearance of metformin, the effects of SB on OCT or MATE-mediated systemic exposure of metformin as well as on glucose tolerance and hypoglycemia were examined. Although SB inhibited metformin uptake through human transporters OCT1 and MATE1 in vitro, the systemic exposures of metformin in vivo rats were not altered after metformin treatment with and without SB due to unchanged renal excretion of metformin...
November 7, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27819189/inhibitory-effects-of-curculigoside-on-human-liver-cytochrome-p450-enzymes
#19
Jixiao Lang, Wei Li, Jingming Zhao, Kaiyou Wang, Dexi Chen
1. Curculigoside possesses numerous pharmacological activities, and however, little data available for the effects of curculigoside on the activity of human liver cytochrome P450 (CYP) enzymes. 2. This study investigates the inhibitory effects of curculigoside on the main human liver CYP isoforms. In this study, the inhibitory effects of curculigoside on the eight human liver CYP isoforms 1A2, 2A6, 2E1, 2D6, 2C9, 2C19, 2C8, and 3A4 were investigated in human liver microsomes. 3. The results indicated that curculigoside could inhibit the activity of CYP1A2, CYP2C8, and CYP3A4, with IC50 values of 15...
November 5, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27771980/the-biological-fate-of-decabromodiphenyl-ethane-following-oral-dermal-or-intravenous-administration
#20
Gabriel A Knudsen, J Michael Sanders, Michael F Hughes, Ethan P Hull, Linda S Birnbaum
1. It was important to investigate the disposition of decabromodiphenyl ethane (DBDPE) based on concerns over its structural similarities to decabromodiphenyl ethane (decaBDE), high potential for environmental persistence & bioaccumulation, and high production volume. 2. In the present study, female Sprague Dawley rats were administered a single dose of [(14)C]-DBDPE by oral, topical, or IV routes. Another set of rats were administered 10 daily oral doses of [(14)C]-DBDPE. Male B6C3F1/Tac mice were administered a single oral dose...
October 24, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
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