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https://www.readbyqxmd.com/read/29775322/prediction-of-human-cytochrome-p450-inhibition-using-a-multi-task-deep-autoencoder-neural-network
#1
Xiang Li, Youjun Xu, Luhua Lai, Jianfeng Pei
Adverse side effects of drug-drug interactions induced by human cytochrome P450 (CYP450) inhibition is an important consideration in drug discovery. It is highly desirable to develop computational models that can predict the inhibitive effect of a compound against a specific CYP450 isoform. In this study, we developed a multi-task model for concurrent inhibition prediction of five major CYP450 isoforms, namely 1A2, 2C9, 2C19, 2D6, and 3A4. The model was built by training multi-task autoencoder deep neural network (DNN) on a large dataset containing more than 13000 compounds, extracted from PubChem BioAssay Database...
May 18, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29768713/clinical-drug-drug-interaction-potential-of-bfe1224-prodrug-of-antifungal-ravuconazole-using-two-types-of-cocktails-in-healthy-subjects
#2
Yasuyuki Ishii, Yuko Ito, Shunji Matsuki, Kasumi Sanpei, Osamu Ogawa, Kenji Takeda, Edgar L Schuck, Naoto Uemura
BFE1224, prodrug of ravuconazole, is a novel, once-daily, oral, triazole antifungal drug, and currently in development for the treatment of onychomycosis. The clinical drug-drug interaction (DDI) potential of BFE1224 with cytochrome P450 (CYP) and transporter was assessed by using two types of cocktails in healthy subjects in separate clinical studies. The CYP and transporter cocktails consisted of caffeine/tolbutamide/omeprazole/dextromethorphan/midazolam used in study 1 and digoxin/rosuvastatin used in study 2...
May 16, 2018: Clinical and Translational Science
https://www.readbyqxmd.com/read/29741901/stereoselective-metabolism-of-omeprazole-by-cytochrome-p-450-2c19-and-3a4-mechanistic-insights-from-dft-study
#3
Kalyanashis Jana, Tusar Bandyopadhyay, Bishwajit Ganguly
The efficacy of S-omeprazole as proton pump inhibitor compared to its enantiomer R-omeprazole is studied using density functional theoretical calculations. The pharmacokinetic studies suggest that the efficacy of S-omeprazole presumably depends on metabolic pathway and excretion from the human body. The DFT calculations at SMDWater -B3LYP-D3/6-311+G(d,p)/LANL2DZ//B3LYP/6-31G(d)/LANL2DZ with triradicaloid model active species, [Por•+ FeIV (SH)O], of the CYP2C19 enzyme with high spin quartet and low spin doublet states demonstrate C-H bond activation mechanism through a two-state rebound process for hydroxylation of R-omeprazole and S-omeprazole...
May 9, 2018: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/29707143/the-secondary-prevention-of-stroke-according-to-cytochrome-p450-2c19-genotype-in-patients-with-acute-large-artery-atherosclerosis-stroke
#4
Xingyang Yi, Jing Lin, Ju Zhou, Yanfeng Wang, Ruyue Huang, Chun Wang
Purpose: To investigated the effectiveness of antiplatelet agents for the secondary prevention of stroke according to CYP2C19 genotype in patients with ischemic stroke (IS). Methods: Between August 2009 and December 2011, 570 acute IS patients with acute large-artery atherosclerosis were randomly assigned to receive either combined clopidogrel and aspirin for the first 30 day, and clopidogrel thereafter (clopidogrel group, n=284) or aspirin monotherapy (aspirin group, n=286)...
April 3, 2018: Oncotarget
https://www.readbyqxmd.com/read/29695615/metabolism-of-a-5ht6-antagonist-2-methyl-1-phenylsulfonyl-4-piperazin-1-yl-1h-benzo-d-imidazole-sam-760-impact-of-sulfonamide-metabolism-on-diminution-of-a-ketoconazole-mediated-clinical-drug-drug-interaction
#5
Aarti Sawant-Basak, R Scott Obach, Angela C Doran, Peter Lockwood, Klaas Schildknegt, Hongying Gao, Jessica Mancuso, Susanna Tse, Tom Comery
SAM-760, (2-methyl-1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-benzo[d]imidazole), a 5HT6 antagonist, was investigated in humans for the treatment of Alzheimer's dementia. In liver microsomes and recombinant CYP450 isozymes, SAM-760 was predominantly metabolized by CYP3A (~85%). Based on these observations and an expectation of 5-fold magnitude of interaction with moderate to strong CYP3A inhibitors, a clinical DDI study was performed. In presence of ketoconazole, mean Cmax and AUC0-inf of SAM-760 showed only a modest increase by 30% and 38%, respectively...
April 25, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29676195/in-vitro-inhibitory-effects-of-sophocarpine-on-human-liver-cytochrome-p450-enzymes
#6
Jingwei Zhang, Chuansheng Li, Jingfa Zhang, Fan Zhang
1. Sophocarpine is a biologically active component isolated from the foxtail-like sophora herb and seed that is often orally administered for the treatment of cancer and chronic bronchial asthma. However, whether sophocarpine affects the activity of human liver cytochrome P450 (CYP) enzymes remains unclear. 2. In this study, the inhibitory effects of sophocarpine on the eight human liver CYP isoforms (CYP1A2, 3A4, 2A6, 2E1, 2D6, 2C9, 2C19, and 2C8) were investigated in vitro using human liver microsomes (HLMs)...
April 20, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29659506/in-vitro-inhibitory-effects-of-synthetic-cannabinoid-eam-2201-on-cytochrome-p450-and-udp-glucuronosyltransferase-enzyme-activities-in-human-liver-microsomes
#7
Tae Yeon Kong, Soon-Sang Kwon, Jae Chul Cheong, Hee Seung Kim, Jin Young Kim, Hye Suk Lee
EAM-2201, a synthetic cannabinoid, is a potent agonist of the cannabinoid receptors that is widely abused as an illicit recreational drug in combination with other drugs. To evaluate the potential of EAM-2201 as a perpetrator of drug–drug interactions, the inhibitory effects of EAM-2201 on major drug-metabolizing enzymes, cytochrome P450s (CYPs) and uridine 5′-diphospho-glucuronosyltransferases (UGTs) were evaluated in pooled human liver microsomes using liquid chromatography–tandem mass spectrometry (LC-MS/MS)...
April 16, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29628024/the-association-between-cyp2c9-2c19-polymorphisms-and-phenytoin-maintenance-doses-in-asian-epileptic-patients-a-systematic-review-and-meta-analysis
#8
Kai Liao, Yong Liu, Chun-Zhi Ai, Xi Yu, Wei Li
OBJECTIVE: Therapeutic response to phenytoin (PHT), a first-line antiepileptic drug (AED), is highly variable, in part likely due to genetic factors. Genetic polymorphisms in cytochrome P450 (CYP) 2C9 and CYP2C19 are expected to affect the metabolism of PHT and consequently affect its maintenance doses. We aimed to clarify the effects of genetic polymorphisms in both enzymes on daily PHT maintenance dosage in Asian epileptic patients by meta-analysis. MATERIALS AND METHODS: A systematic literature search was conducted in PubMed and EMBASE for relevant studies published prior to April 14, 2017...
April 9, 2018: International Journal of Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29626440/in-vivo-and-in-vitro-diclofenac-5-hydroxylation-mediated-primarily-by-cytochrome-p450-3a-enzymes-in-common-marmoset-livers-genotyped-for-p450-2c19-variants
#9
Kazuyuki Nakanishi, Shotaro Uehara, Takashi Kusama, Takashi Inoue, Kanami Shimura, Yusuke Kamiya, Norie Murayama, Makiko Shimizu, Yasuhiro Uno, Erika Sasaki, Hiroshi Yamazaki
Common marmosets (Callithrix jacchus) are potentially useful nonhuman primate models for preclinical studies. An anti-inflammatory drug, diclofenac is reportedly metabolized mainly by human cytochrome P450 (P450) 2C9 to 4'-hydroxydiclofenac and minorly by P450 3A4 to 5-hydroxydiclofenac that leads to reactive intermediates. In this study, in vivo pharmacokinetics in six marmosets and in vitro metabolism in nine marmoset liver microsomes were analyzed using diclofenac to evaluate marmosets as preclinical drug metabolism models...
April 4, 2018: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29618712/cytochrome-p450-dependent-drug-oxidation-activities-in-commercially-available-hepatocytes-derived-from-human-induced-pluripotent-stem-cells-cultured-for-3-weeks
#10
Norie Murayama, Hiroshi Yamazaki
Hepatocyte-like cells differentiated from human induced pluripotent stem (iPS) cells are of great interest for applications in pharmacological research. For drug metabolism testing, commercially available hepatocytes derived from human iPS cells are generally recommended to be used 1 week after seeding on plates. In this study, however, after 3-4 weeks of culture according to the manufacturer's instructions, human cytochrome P450 (P450) 2C9- and 2C19-dependent diclofenac 4'-hydroxylation and omeprazole 5-hydroxylation activities of the iPS-derived hepatocytes had significantly increased above the activities at 1 week and had reached levels similar to those in HepaRG cells, a human hepatocyte-like cell line...
2018: Journal of Toxicological Sciences
https://www.readbyqxmd.com/read/29616291/the-role-of-hepatic-cytochrome-p450s-in-the-cytotoxicity-of-dronedarone
#11
Si Chen, Qiangen Wu, Baitang Ning, Matthew Bryant, Lei Guo
Dronedarone is used to treat patients with cardiac arrhythmias and has been reported to be associated with liver injury. Our previous mechanistic work demonstrated that DNA damage-induced apoptosis contributes to the cytotoxicity of dronedarone. In this study, we examined further the underlying mechanisms and found that after a 24-h treatment of HepG2 cells, dronedarone caused cytotoxicity, G1-phase cell cycle arrest, suppression of topoisomerase II, and DNA damage in a concentration-dependent manner. We also investigated the role of cytochrome P450s (CYPs)-mediated metabolism in the dronedarone-induced toxicity using our previously established HepG2 cell lines expressing individually 14 human CYPs (1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5, and 3A7)...
April 3, 2018: Archives of Toxicology
https://www.readbyqxmd.com/read/29572664/identification-of-cytochrome-p450-mediated-drug-drug-interactions-at-risk-in-cases-of-gene-polymorphisms-by-using-a-quantitative-prediction-model
#12
Nicolas Fermier, Laurent Bourguignon, Sylvain Goutelle, Nathalie Bleyzac, Michel Tod
BACKGROUND AND OBJECTIVE: The magnitude of drug-drug interactions mediated by cytochrome P450 (CYP) may depend on the genotype of polymorphic cytochromes. The objective of this study was to identify drug-drug interactions with greater magnitude in CYP variant groups than in extensive metabolizers. METHODS: The in-vivo mechanistic static model was used to predict the area under the curve ratio of drug-drug interactions. Five cytochromes (CYP3A4/5, 2D6, 2C9, 2C19, 1A2) and five groups of genotypes for each polymorphic cytochrome (CYP2D6, 2C9, 2C19) were considered...
March 23, 2018: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/29571132/ugt-mediated-metabolism-plays-a-dominant-role-in-the-pharmacokinetic-behavior-and-the-disposition-of-morusin-in-vivo-and-in-vitro
#13
Chuqi Hou, Wenqin Liu, Zhi Liang, Weichao Han, Jinqing Li, Ling Ye, Menghua Liu, Zheng Cai, Jie Zhao, Yi Chen, Shuwen Liu, Lan Tang
Morusin is a prenylated flavone isolated from mulberry, the branch and root bark of various Morus species, which possesses diverse pharmacological activities. However, it lacks extensive studies about its absorption and disposition. This study investigated the pharmacokinetic behavior of morusin in rat, and its first-pass metabolism in situ. The metabolic pathway of morusin was further investigated by 12 human recombinant UDP-glucuronosyltransferases (UGTs), 9 CYP450s, as well as liver and intestinal microsomes...
March 12, 2018: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/29570504/effects-of-cytochrome-p450-cyp-2c19-genotypes-on-steady-state-plasma-concentrations-of-escitalopram-and-its-desmethyl-metabolite-in-japanese-patients-with-depression
#14
Shoko Tsuchimine, Shinichiro Ochi, Misuzu Tajiri, Yutaro Suzuki, Norio Sugawara, Yoshimasa Inoue, Norio Yasui-Furukori
BACKGROUND: Plasma concentrations of the S-enantiomer of citalopram were different between extensive and poor CYP2C19 metabolizers in healthy subjects and depressed patients. However, most studies applied dose-corrected concentrations. Thus, we studied the effects of polymorphisms of the CYP2C19 gene on raw plasma drug concentrations in Japanese patients with depression. METHODS: Subjects in this study consisted of 412 depressed patients receiving 5, 10, 15, or 20 mg of escitalopram once a day...
March 22, 2018: Therapeutic Drug Monitoring
https://www.readbyqxmd.com/read/29567399/the-safety-tolerability-and-pharmacokinetics-of-bi-409306-a-novel-and-potent-pde9-inhibitor-overview-of-three-phase-i-randomised-trials-in-healthy-volunteers
#15
Viktoria Moschetti, Maria Kim, Michael Sand, Glen Wunderlich, Grit Andersen, Ulrich Feifel, In-Jin Jang, Wolfgang Timmer, Holger Rosenbrock, Katja Boland
Safety, tolerability and pharmacokinetics of BI 409306, a potent and selective phosphodiesterase 9A inhibitor, were assessed in healthy subjects in three Phase I, within-dose group, double-blind trials. Trial 1 randomised young and elderly subjects to receive BI 409306 25, 50, 100 mg, placebo once daily (OD) or BI 409306 50 mg twice daily (young) for 14 days. Trial 2 randomised young poor metabolisers (PM) of cytochrome P450 isoform 2C19 (CYP2C19) and elderly subjects to receive BI 409306 25, 50 mg or placebo OD for 14 days...
March 19, 2018: European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology
https://www.readbyqxmd.com/read/29540584/randomized-dose-ranging-safety-trial-of-cannabidiol-in-dravet-syndrome
#16
Orrin Devinsky, Anup D Patel, Elizabeth A Thiele, Matthew H Wong, Richard Appleton, Cynthia L Harden, Sam Greenwood, Gilmour Morrison, Kenneth Sommerville
OBJECTIVE: To evaluate the safety and preliminary pharmacokinetics of a pharmaceutical formulation of purified cannabidiol (CBD) in children with Dravet syndrome. METHODS: Patients aged 4-10 years were randomized 4:1 to CBD (5, 10, or 20 mg/kg/d) or placebo taken twice daily. The double-blind trial comprised 4-week baseline, 3-week treatment (including titration), 10-day taper, and 4-week follow-up periods. Completers could continue in an open-label extension. Multiple pharmacokinetic blood samples were taken on the first day of dosing and at end of treatment for measurement of CBD, its metabolites 6-OH-CBD, 7-OH-CBD, and 7-COOH-CBD, and antiepileptic drugs (AEDs; clobazam and metabolite N -desmethylclobazam [N-CLB], valproate, levetiracetam, topiramate, and stiripentol)...
March 14, 2018: Neurology
https://www.readbyqxmd.com/read/29524040/site-directed-mutagenesis-of-cytochrome-p450-2d6-and-2c19-enzymes-expression-and-spectral-characterization-of-naturally-occurring-allelic-variants
#17
Amelia Nathania Dong, Yan Pan, Uma Devi Palanisamy, Beow Chin Yiap, Nafees Ahemad, Chin Eng Ong
Genetic polymorphism of the cytochrome P450 (CYP) genes particularly affects CYP2D6 and CYP2C19 to a functionally relevant extent, and it is therefore crucial to elucidate the enzyme kinetic and molecular basis for altered catalytic activity of these allelic variants. This study explored the expression and function of the reported alleles CYP2D6*2, CYP2D6*10, CYP2D6*17, CYP2C19*23, CYP2C19*24, and CYP2C19*25 with respect to gene polymorphisms. Site-directed mutagenesis (SDM) was carried out to generate these six alleles...
March 10, 2018: Applied Biochemistry and Biotechnology
https://www.readbyqxmd.com/read/29498658/enzyme-kinetics-and-molecular-docking-studies-on-cytochrome-2b6-2c19-2e1-and-3a4-activities-by-sauchinone
#18
Eun Chae Gong, Satya Chea, Anand Balupuri, Nam Sook Kang, Young-Won Chin, Young Hee Choi
Sauchinone, an active lignan isolated from the aerial parts of Saururus chinensis (Saururaceae), exhibits anti-inflammatory, anti-obesity, anti-hyperglycemic, and anti-hepatic steatosis effects. As herb-drug interaction (HDI) through cytochrome P450s (CYPs)-mediated metabolism limits clinical application of herbs and drugs in combination, this study sought to explore the enzyme kinetics of sauchinone towards CYP inhibition in in vitro human liver microsomes (HLMs) and in vivo mice studies and computational molecular docking analysis...
March 2, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29483383/a-multicenter-randomized-double-blind-and-placebo-controlled-study-of-the-effects-of-tongxinluo-capsules-in-acute-coronary-syndrome-patients-with-high-on-treatment-platelet-reactivity
#19
Lei Zhang, Yi Li, Bai-Song Yang, Lu Li, Xiao-Zeng Wang, Mei-Ling Ge, Quan-Min Jing, Ying-Yan Ma, Geng Wang, Hai-Wei Liu, Xin Zhao, Bin Wang, Kai Xu, Ya-Ling Han
Background: High platelet reactivity (HPR) during clopidogrel treatment predicts postpercutaneous coronary intervention (PCI) ischemic events strongly and independently. Tongxinluo capsules (TCs) are a traditional Chinese medicine formulation used as antiplatelet treatment. However, its efficacy against HPR is not known. The aim of the present study was to evaluate the effects of TCs in acute coronary syndrome (ACS) patients with HPR. Methods: This multicenter, randomized, double-blind, placebo-controlled study prospectively analyzed 136 ACS patients with HPR who underwent PCI...
March 5, 2018: Chinese Medical Journal
https://www.readbyqxmd.com/read/29469947/evaluation-of-the-metabolic-capability-of-primary-human-hepatocytes-in-three-dimensional-cultures-on-microstructural-plates
#20
Satoshi Koyama, Hiroshi Arakawa, Manabu Itoh, Norio Masuda, Kentaro Yano, Hajime Kojima, Takuo Ogihara
The NanoCulture Plate (NCP) is a novel microstructural plate designed as a base for the three-dimensional culture of cells/tissues. This study examined whether or not the metabolic capability of human primary hepatocytes is well maintained during culture on NCPs. The hepatocytes formed aggregates after seeding and their ATP content was well maintained during culture for 21 days. Expression of CYP1A2, 2B6, 2C9, 2C19, 2D6, 2E1 and 3A4 mRNAs was detected throughout the 21-day culture period. Addition of CYP substrate drugs (midazolam, diclofenac, lamotrigine and acetaminophen) resulted in the formation of multiple metabolites with a corresponding decrease in the amounts of the unchanged compounds...
April 2018: Biopharmaceutics & Drug Disposition
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