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Xenobiotica; the Fate of Foreign Compounds in Biological Systems

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https://www.readbyqxmd.com/read/28092216/metabolism-of-metofluthrin-in-rats-i-identification-of-metabolites
#1
Jun Abe, Hirohisa Nagahori, Hirokazu Tarui, Yoshitaka Tomigahara, Naohiko Isobe
Metofluthrin (2,3,5,6-tetrafluoro-4-(methoxymethyl)benzyl (Z/E)-(1R)-trans-2,2-dimethyl-3-(1-propenyl)-cyclopropanecarboxylate) is a novel pyrethroid insecticide, which has E/Z isomers at prop-1-enyl group. Rats were orally dosed with each [(14)C]-labeled E/Z isomer, and the excreta were collected for isolation and identification of metabolites. Analysis of the excreta by LC/MS and NMR revealed formation of 33 and 23 (total 42) metabolites from rats dosed with Z-isomer and E-isomer, respectively. Major metabolic reactions were cleavage of ester linkage, O-demethylation, hydroxylation, epoxidation or reduction of double bond, glutathione conjugation and its further metabolism, hydroxylation of epoxide, and formation of lactone ring...
January 16, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28084139/a-high-frequency-missense-sult1b1-allelic-variant-l145v-selectively-expressed-in-african-descendants-exhibits-altered-kinetic-properties
#2
Zachary E Tibbs, Amber L Guidry, Josie L Falany, Susan A Kadlubar, Charles N Falany
1. Human cytosolic sulfotransferase 1B1 (SULT1B1) sulfates small phenolic compounds and bioactivates polycyclic aromatic hydrocarbons. To date, no SULT1B1 allelic variants have been well-characterized. 2. While cloning SULT1B1 from human endometrial specimens, an allelic variant resulting in valine instead of leucine at the 145th amino acid position (L145V) was detected. NCBI reported this alteration as the highest frequency SULT1B1 allelic variant. 3. L145V frequency comprised 9% of 37 mixed-population human patients and was specific to African Americans with an allelic frequency of 25%...
January 13, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28081667/contributions-of-caspase-8-and-9-to-liver-injury-from-cyp2e1-produced-metabolites-of-halogenated-hydrocarbons
#3
Yoshio Ijiri, Ryuji Kato, Maiko Sadamatsu, Mina Takano, Yuki Yasuda, Fumiaki Tanaka, Chiyo Oishi, Hideki Imano, Yoshikatsu Okada, Kazuhiko Tanaka, Tetsuya Hayashi
1. Drug-induced liver injury is difficult to predict at the pre-clinical stage. This study aimed to clarify the roles of caspase-8 and -9 in CYP2E1 metabolite-induced liver injury in both rats and cell cultures in vitro treated with carbon tetrachloride (CCl4), halothane or sevoflurane. The human hepatocarcinoma functional liver cell line was maintained in 3-dimensional culture alone or in co-culture with human acute monocytic leukemia cells. 2. In vivo, laboratory indices of liver dysfunction and histology were normal after administration of sevoflurane...
January 12, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28051355/pharmacokinetic-interaction-of-aconitine-liquiritin-and-6-gingerol-in-a-traditional-chinese-herbal-formula-sini-decoction
#4
Sen Sun, Qingshan Chen, Jiyun Ge, Xiang Liu, Xinxia Wang, Qi Zhan, Hai Zhang, Guoqing Zhang
This study aimed to investigate the pharmacokinetic interaction of the three ingredients in a traditional Chinese herbal formulation, Sini Decoction, and provide evidence for its compatibility mechanism. Firstly, the effect of liquiritin and 6-gingerol on the pharmacokinetic parameters of aconitine were investigated in rats by using a sensitive and reliable LC-MS/MS method. Then the Caco-2 cell monolayer model and Rhodamine-123 uptake assay were used to investigate the effect of liquiritin and 6-gingerol on the absorption of aconitine and the activity of P-gp...
January 4, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28051340/altered-tolbutamide-pharmacokinetics-by-a-decrease-in-hepatic-expression-of-cyp2c6-11-in-rats-pretreated-with-5-fluorouracil
#5
Shuhei Fukuno, Katsuhito Nagai, Keita Kasahara, Yuki Mizobata, Sachiko Omotani, Yasutoshi Hatsuda, Michiaki Myotoku, Hiroki Konishi
We investigated the change in the pharmacokinetic profile of tolbutamide (TB), a substrate for CYP2C6/11, 4 days after single administration of 5-fluorouracil (5-FU), and the hepatic gene expression and activity of CYP2C6/11 were also examined in 5-FU-pretreated rats. Regarding the pharmacokinetic parameters of the 5-FU group, the area under the curve (AUC) was significantly increased, and correspondingly, the elimination rate constant at the terminal phase (ke) was significantly decreased without significant change in the volume of distribution at the steady state (Vdss)...
January 4, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28043194/differential-regulation-of-intestinal-efflux-transporters-by-pregnancy-in-mice
#6
Jamie E Moscovitz, Gabriel Yarmush, Guadalupe Herrera-Garcia, Grace L Guo, Lauren M Aleksunes
1. In the intestines, the nuclear receptors farnesoid X receptor (Fxr) and pregnane X receptor (Pxr) regulate the transcription of metabolizing enzymes and transporters that dictate the absorption of nutrients and xenobiotics. 2. Here, we sought to determine whether Fxr and Pxr signaling pathways are disrupted in response to high-circulating concentrations of steroid hormones late in pregnancy leading to altered transporter expression. To test this, ileum were collected from virgin and pregnant C57BL/6 mice on gestation days 14, 17 and 19...
January 3, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27937048/effects-of-cytochrome-p450-3a4-and-non-genetic-factors-on-initial-voriconazole-serum-trough-concentrations-in-hematological-patients-with-different-cytochrome-p450-2c19-genotypes
#7
Beibei Shao, Yongcheng Ma, Qiaoyan Li, Yimeng Wang, Zunmin Zhu, Hongwei Zhao, Jun Sun, Lingfang Dong, Yingli Zhu, Ningmin Zhao, Yuhua Qin
1. Polymorphisms of cytochrome P450 2C19 (CYP2C19) is an important factor contributing to variability of voriconazole pharmacokinetics. Polymorphisms of CYP3A4, CYP3A5, CYP2C9 and non-genetic factors such as age, gender, body mass index (BMI), transaminase levels, concomitant medications might also affect voriconazole initial steady serum trough concentration (VICmin) in haematological patients, but the effects were not clear. 2. Eighteen single-nucleotide polymorphisms in CYP2C19, CYP3A4, CYP3A5, CYP2C9 were genotyped...
January 3, 2017: 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
#8
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 12,230 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 feces)...
January 3, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28042744/influence-of-acute-and-chronic-kidney-failure-in-rats-on-the-disposition-and-pharmacokinetics-of-zyan1-a-novel-prolyl-hydroxylase-inhibitor-for-the-treatment-of-chronic-kidney-disease-induced-anemia
#9
Harilal Patel, Amit Arvind Joharapurkar, Vrajesh Bhaskarbhai Pandya, Vishal Jagjivanbhai Patel, Samadhan Govind Kshirsagar, Prakash Patel, Bhavesh Gevriya, Mukul R Jain, Nuggehally R Srinivas, Pankaj Ramanbhai Patel, Ranjit C Desai
1. ZYAN1 is a prolyl hydroxylase inhibitor in clinical development for treatment of anaemia associated with chronic kidney disease (CKD). We evaluated the effect of acute and chronic kidney impairment on the pharmacokinetics of ZYAN1 in rat models. 2. Cisplatin (2.5, 5 and 7.5 mg/kg) was used to induce acute kidney injury (AKI), and five-sixth and total nephrectomy was used to induce chronic kidney injury (CKI) in male Wistar rats. All groups received a single 15 mg/kg oral dose of ZYAN1. Blood/urine samples were analysed for ZYAN1 to assess peak concentration (Cmax), area under the concentration-time curve (AUCinf), total body clearance (CL/F), and elimination half-life (T1/2)...
December 31, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28010169/consequences-of-daily-corticosteroid-dosing-with-or-without-pre-treatment-with-quinidine-on-the-in-vivo-cytochrome-p450-2d-cyp2d-enzyme-in-rats-effect-on-o-demethylation-activity-of-dextromethorphan-and-expression-levels-of-cyp2d1-mrna
#10
Poonam Giri, Prashant Delvadia, Laxmikant Gupta, Nirmal Patel, Priyal Trivedi, Krishna Lad, Hiren M Patel, Nuggehally R Srinivas
1. Present investigation was carried out in rats to study influence of corticosteroids after repeated dosing with/without pre-treatment with CYP2D inhibitor quinidine on the CYP2D1 mRNA levels and CYP2D enzyme activity using dextromethorphan as probe substrate. 2. CYP2D1 mRNA was measured in liver homogenate using quantitative Real-Time Polymerase Chain Reaction [qRT-PCR] and enzymatic reaction was studied ex vivo in liver S-9 fractions of rats treated with oral 10 mg/kg dexamethasone or prednisolone for five days or pre-treated with quinidine and followed by treatment with oral 10 mg/kg corticosteroids for five days...
December 23, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28010166/reappraisal-and-perspectives-of-clinical-drug-drug-interaction-potential-of-%C3%AE-glucosidase-inhibitors-such-as-acarbose-voglibose-and-miglitol-in-the-treatment-of-type-2-diabetes-mellitus
#11
Ranjeet Prasad Dash, R Jayachandra Babu, Nuggehally R Srinivas
1. Amidst the new strategies being developed for the management of Type 2 diabetes mellitus (T2DM) with both established and newer therapies, alpha glucosidase inhibitors (AGIs) has found a place in several treatment protocols. 2. The objectives of the review were: a) to compile and evaluate the various clinical pharmacokinetic drug interaction data for AGIs such as acarbose, miglitol and voglibose; b) provide perspectives on the drug interaction data since it encompasses coadministered drugs in several key areas of comorbidity with T2DM...
December 23, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28005438/interactions-of-crizotinib-and-gefitinib-with-organic-anion-transporting-polypeptides-oatp-1b1-oatp1b3-and-oatp2b1-gefitinib-shows-contradictory-interaction-with-oatp1b3
#12
Toshihiro Sato, Hajime Ito, Ayaka Hirata, Takaaki Abe, Nariyasu Mano, Hiroaki Yamaguchi
1. The drug-drug interaction (DDI) mediated by organic anion-transporting polypeptide (OATP)1B1, OATP1B3, and OATP2B1 has a major impact on the hepatic clearance of drugs. The effects of tyrosine kinase inhibitors (TKIs) on OATPs have not been well studied. In the present study, we evaluated the contribution of OATPs to the hepatic uptake of crizotinib and gefitinib and the interaction of those TKIs with OATPs to estimate DDIs. 2. To clarify whether crizotinib and gefitinib were substrates for OATPs, we performed uptake studies...
December 22, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28001472/two-sulfonate-metabolites-of-physalin-a-in-rats
#13
Hongxia Liu, Kai Wang, Guiyang Xia, Kun Wang, Liwei Chai, Paul Owusu Donkor, Liqin Ding, Feng Qiu
1. Physalin A is a bioactive withanolide isolated from the natural plant Physalis alkekengi var. franchetii (Solanaceae), a common traditional Chinese herbal medicine. This study aims to investigate the metabolites of physalin A in vivo. 2. Two metabolites (M1 and M2) were characterized as sulfonate metabolites in the feces obtained from rats treated with physalin A orally at a dose of 15 mg/kg/day for 3 days, by application of a UPLC-Q/TOF-MS method. Furthermore, formation of the two sulfonate metabolites was verified by chemical synthesis and NMR including (1)H NMR, (13)C NMR, and two-dimensional NMR...
December 21, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28001462/comparative-pharmacokinetics-between-madecassoside-and-asiaticoside-presented-in-a-standardised-extract-of-centella-asiatica-eca-233-and-their-respective-pure-compound-given-separately-in-rats
#14
Patcharaporn Hengjumrut, Tosapol Anukunwithaya, Mayuree H Tantisira, Boonyong Tantisira, Phisit Khemawoot
1. ECa 233, the standardised extract of Centella asiatica, contains not less than 80% triterpenoid glycosides, in a madecassoside:asiaticoside ratio of 1.5 (± 0.5): 1. 2. The pharmacokinetic comparison of madecassoside and asiaticoside was performed in rats following intravenous and oral administration of ECa 233, or an equivalent dose of the individual compounds. Blood, tissues, urine and faeces were collected after dosing to determine drug and metabolite levels using liquid chromatography-tandem mass spectrometry...
December 21, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27977936/potent-inhibition-of-human-organic-cation-transporter-2-hoct2-by-%C3%AE-carboline-alkaloids
#15
David J Wagner, Haichuan Duan, Alenka Jaklic, Richard W Lee, Joanne Wang
1. Beta-carbolines are indole alkaloids with a wide range of pharmacological and toxicological activities. Beta-carbolines are structurally related to the neurotoxin 1-methyl-4-phenylpyridinium (MPP+), a known substrate of organic cation transporters (OCTs). The goal of this study is to determine the interaction of β-carbolines with human OCT1, 2, and 3 (SLC22A1-3). 2. Dose-dependent inhibition studies were performed for five commercially available β-carbolines using a fluorescent substrate assay in HEK293 cells stably expressing hOCT1-3...
December 15, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/27937053/association-of-pear1-rs12041331-polymorphism-and-pharmacodynamics-of-ticagrelor-in-healthy-chinese-volunteers
#16
Mupeng Li, Yaodong Hu, Zhipeng Wen, Huilan Li, Xiaolei Hu, Yanjiao Zhang, Zanling Zhang, Jian Xiao, Jie Tang, Xiaoping Chen
Genetic polymorphisms in platelet endothelial aggregation receptor 1 (PEAR1) were associated with responsiveness to aspirin and P2Y12 receptor antagonists. This study aimed to investigate whether PEAR1 polymorphism is associated with ticagrelor pharmacodynamics in healthy Chinese subjects. The in vitro inhibition of platelet aggregation (IPA) was evaluated before and after ticagrelor incubated with platelet rich plasma from 196 healthy Chinese male subjects. Eight polymorphisms at PEAR1 locus were genotyped...
December 12, 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
#17
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 0.1-3 mg/kg, the total body clearance and the volume of distribution were 3.53-6.69 mL/min/kg and 1.47-2.49 L/kg, respectively, in rats, and 2.79-3.69 mL/min/kg and 1.34-1.54 L/kg, respectively, in monkeys. The absolute oral bioavailability was 61...
December 12, 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
#18
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 (TG) in healthy human subjects and fasting TG 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...
December 12, 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
#19
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...
December 7, 2016: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
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
#20
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
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