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CYP2C19 high activity

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https://www.readbyqxmd.com/read/29782255/-high-on-treatment-platelet-reactivity-determinants-on-dual-antiplatelet-therapy-in-patients-with-ischemic-heart-disease-before-elective-percutaneous-coronary-intervention
#1
E Z Golukhova, M V Grigoryan, M N Ryabinina, N I Bulaeva
OBJECTIVE: to determine impact of different laboratory and genetic factors on high on-treatment platelet reactivity (HOPR) during dual antiplatelet therapy (DAPT). METHODS: We included in this study 94 patients with stable ischemic heart disease (mean age 59±9.67 years). All patients underwent elective PCI with implantation of drug eluting stents at the background of dual antiplatelet therapy (DAPT) with aspirin and clopidogrel. Platelet reactivity was assessed using light transmission aggregometry with 5 μmol/L ADP (LTA 5ADP) and VerifyNow assay before PCI...
April 2018: Kardiologiia
https://www.readbyqxmd.com/read/29762875/in-vivo-assessment-of-the-effect-of-cyp1a2-inhibition-and-induction-on-pomalidomide-pharmacokinetics-in-healthy-subjects
#2
Yan Li, Liangang Liu, Xiaomin Wang, Chengyue Zhang, Josephine Reyes, Matthew Hoffmann, Maria Palmisano, Simon Zhou
Pomalidomide is an immunomodulatory drug, and the dosage of 4 mg per day taken orally on days 1-21 of repeated 28-day cycles has been approved in the European Union and the United States to treat patients with relapsed/refractory multiple myeloma. In vitro data showed that pomalidomide is a substrate of multiple cytochrome P450 (CYP) isozymes and that its oxidative metabolism is mediated primarily by CYP1A2 and CYP3A4, with minor contributions from CYP2C19 and CYP2D6. The effect of CYP1A2 inhibition by fluvoxamine (a strong CYP1A2 inhibitor) and CYP1A2 induction by smoking on pomalidomide pharmacokinetics in healthy subjects has been assessed in 2 separate phase 1 open-label, single-dose studies...
May 15, 2018: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29749249/hplc-high-resolution-mass-spectrometry-with-polarity-switching-for-increasing-throughput-of-human-in-vitro-cocktail-drug-drug-interaction-assay
#3
Ragu Ramanathan, Anima Ghosal, Lakshmi Ramanathan, Kate Comstock, Helen Shen, Dil Ramanathan
AIM: Evaluation of HPLC-high-resolution mass spectrometry (HPLC-HRMS) full scan with polarity switching for increasing throughput of human in vitro cocktail drug-drug interaction assay. MATERIALS & METHODS: Microsomal incubates were analyzed using a high resolution and high mass accuracy Q-Exactive mass spectrometer to collect integrated qualitative and quantitative (Qual/Quant) data. RESULTS: Within assay, positive-to-negative polarity switching HPLC-HRMS method allowed quantification of eight and two probe compounds in the positive and negative ionization modes, respectively, while monitoring for LOR and its metabolites...
May 11, 2018: Bioanalysis
https://www.readbyqxmd.com/read/29741901/stereoselective-metabolism-of-omeprazole-by-cytochrome-p-450-2c19-and-3a4-mechanistic-insights-from-dft-study
#4
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/29570971/phenotypic-assessment-of-drug-metabolic-pathways-and-p-glycoprotein-in-patients-treated-with-antidepressants-in-an-ambulatory-setting
#5
Célia Lloret-Linares, Marija Bosilkovska, Youssef Daali, Marianne Gex-Fabry, Kyle Heron, Victor Bancila, Giorgio Michalopoulos, Nader Perroud, Hélène Richard-Lepouriel, Jean-Michel Aubry, Jules Desmeules, Marie Besson
OBJECTIVE: Drug-metabolizing enzymes (DMEs), such as cytochrome P450 (CYP) enzymes, and transporters have emerged as major determinants of variability in drug metabolism and response. This study investigated the association between CYP and P-glycoprotein activities and plasma antidepressant concentration in an outpatient clinical setting. Secondary outcomes were antidepressant efficacy and tolerance. We also describe phenotypes in patients treated with antidepressants and evaluate the tolerance of a minimally invasive phenotyping approach...
March 20, 2018: Journal of Clinical Psychiatry
https://www.readbyqxmd.com/read/29491651/studying-the-inhibitory-effect-of-quercetin-and-thymoquinone-on-human-cytochrome-p450-enzyme-activities
#6
Fawzy Elbarbry, Aimy Ung, Khaled Abdelkawy
Background: Quercetin (QR) and thymoquinone (TQ) are herbal remedies that are currently extensively used by the general population to prevent and treat various chronic conditions. Therefore, investigating the potential of pharmacokinetic interactions caused by the concomitant use of these herbal remedies and conventional medicine is warranted to ensure patient safety. Purpose of the Study: This study was conducted to determine the inhibitory effect of QR and TQ, two commonly used remedies, on the activities of selected cytochrome P450 (CYP) enzymes that play an important role in drug metabolism and/or toxicology...
January 2018: Pharmacognosy Magazine
https://www.readbyqxmd.com/read/29363499/metabolic-profiling-of-the-novel-hypoxia-inducible-factor-2-%C3%AE-inhibitor-pt2385-in-vivo-and-in-vitro
#7
Cen Xie, Xiaoxia Gao, Dongxue Sun, Youbo Zhang, Kristopher W Krausz, Xuemei Qin, Frank J Gonzalez
PT2385 is a first-in-class, selective small-molecule inhibitor of hypoxia-inducible factor-2 α (HIF-2 α ) developed for the treatment of advanced clear cell renal cell carcinoma. Preclinical results demonstrated that PT2385 has potent antitumor efficacy in mouse xenograft models of kidney cancer. It also has activity toward metabolic disease in a mouse model. However, no metabolism data are currently publically available. It is of great importance to characterize the metabolism of PT2385 and identify its effect on systemic homeostasis in mice...
April 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29334682/body-mass-index-and-plasma-p-selectin-before-coronary-stenting-predict-high-residual-platelet-reactivity-at-6-months-on-dual-antiplatelet-therapy
#8
Elena Z Golukhova, Marina V Grigoryan, Mariya N Ryabinina, Naida I Bulaeva, Victor L Serebruany
BACKGROUND: High residual platelet reactivity (HRPR) during dual antiplatelet therapy (DAPT) may impact clinical outcomes following percutaneous coronary interventions (PCI). However, whether any biomarkers assessed before PCI at DAPT loading may predict delayed maintenance HRPR is not clear. OBJECTIVE: The aim of this study was to determine whether conventional clinical or laboratory indices at loading before stenting may predict HRPR at 6 months of maintenance DAPT...
2018: Cardiology
https://www.readbyqxmd.com/read/29311135/clinical-pharmacokinetics-and-the-impact-of-genetic-polymorphism-on-a-cyp2c19-substrate-bms-823778-in-healthy-subjects
#9
Jiachang Gong, Lars Hansen, Lisa Iacono
BMS-823778 is a potent and selective inhibitor of 11 β -HSD1, an enzyme that regulates tissue-specific intracellular glucocorticoid metabolism and is a compelling target for the treatment of metabolic diseases. Metabolism of BMS-823778 was mediated mainly by polymorphic CYP2C19, with minor contributions from CYP3A4/5 and UGT1A4. The clinical pharmacokinetics (PK) of BMS-823778 was first investigated in healthy volunteers after single and multiple ascending doses. BMS-823778 was rapidly absorbed after the oral dose, and systemic exposure at steady state increased proportionally to the dose...
March 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29277574/human-cytochrome-p450-kinetic-studies-on-six-n-2-methoxybenzyl-nbome-derived-new-psychoactive-substances-using-the-substrate-depletion-approach
#10
Achim T Caspar, Markus R Meyer, Hans H Maurer
A huge number of new chemical derivatives of known drugs of abuse, so-called new psychoactive substances (NPS), are sold and consumed without prior preclinical and clinical testing. For assessing the elimination behaviors, determination of the kinetic constants Km and Vmax of the cytochrome P450 (CYP) isoforms involved in the hepatic metabolism of NPS could help to predict their contributions to hepatic clearance, drug-drug interactions and polymorphisms. Therefore, the aims of the present study were to determine the Km and Vmax values for CYP isoforms using the substrate depletion approach for the six N-2-methoxybenzyl (NBOMe)-derived NPS 25B-NBOMe, 25C-NBOMe, 25I-NBOMe, 3,4-DMA-NBOMe, 4-EA-NBOMe, and 4-MMA-NBOMe...
March 15, 2018: Toxicology Letters
https://www.readbyqxmd.com/read/29168799/modulation-of-cytochrome-p450-p-glycoprotein-and-pregnane-x-receptor-by-selected-antimalarial-herbs-implication-for-herb-drug-interaction
#11
Pius S Fasinu, Vamshi K Manda, Olivia R Dale, Nosa O Egiebor, Larry A Walker, Shabana I Khan
Seven medicinal plants popularly used for treating malaria in West Africa were selected to assess herb-drug interaction potential through a series of in vitro methods. Fluorescent cytochrome P450 (CYP) assays were conducted using the recombinant CYP enzymes for CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 to assess the effect of the methanolic extracts on the metabolic activity of CYPs. Secondly, the inhibitory effect of the extracts was evaluated on P-glycoproteins (P-gp) using calcein-AM, a fluorescent substrate, in MDCK-II and hMDR1-MDCK-II cells...
November 23, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29118712/comparative-long-term-effect-of-three-anti-p2y12-drugs-after-percutaneous-angioplasty-an-observational-study-based-on-electronic-drug-adherence-monitoring
#12
Valentina Forni Ogna, Isabelle Bassi, Isabelle Menetrey, Olivier Muller, Eric Tousset, Pierre Fontana, Eric Eeckhout, Chin B Eap, Bernard Vrijens, Michel Burnier, Grégoire Wuerzner
Aims: Dual platelet inhibition using anti-P2Y12 drugs and aspirin is the standard of care in patients after percutaneous coronary interventions (PCI). Prasugrel and ticagrelor have been shown to be more potent than clopidogrel with less high on-treatment platelet reactivity. Whether differences in long-term adherence to these drugs can partly explain different antiplatelet efficacy has not been studied so far. The objective was to compare the long-term P2Y12 receptor inhibition and drug adherence to different anti-P2Y12 drugs, and to assess the impact of adherence on the pharmacodynamic effect...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/29098786/functional-characterization-of-cyp2c19-variants-in-nebivolol-4-hydroxlation-in-vitro
#13
Xiao-Yang Zhou, Xiao-Xia Hu, Meng-Fang Li, Hao Wang, Li-Qun Zhang, Guo-Xin Hu, Jian-Ping Cai
Cytochrome P450 2C19 (CYP2C19) allelic variants are thought to play an important part in inter-individual variability in drug metabolism. We evaluated the in vitro hydroxylation of nebivolol by 31 CYP2C19 alleles identified in a Chinese Han population recently. Wild-type CYP2C19*1B and 30 isoforms were highly expressed in insect cells, and the enzymatic activities of CYP2C19 variants towards nebivolol hydroxylation were characterized. Among the 30 CYP2C19 alleles, most of the recombinant CYP2C19 variants exhibited no or significantly low activity compared with CYP2C19*1B...
November 3, 2017: Drug Testing and Analysis
https://www.readbyqxmd.com/read/29065189/establishment-of-a-novel-hepatocyte-model-that-expresses-four-cytochrome-p450-genes-stably-via-mammalian-derived-artificial-chromosome-for-pharmacokinetics-and-toxicity-studies
#14
Daisuke Satoh, Satoru Iwado, Satoshi Abe, Kanako Kazuki, Shinobu Wakuri, Mitsuo Oshimura, Yasuhiro Kazuki
The utility of HepG2 cells to assess drug metabolism and toxicity induced by chemical compounds is hampered by their low cytochrome P450 (CYP) activities. To overcome this limitation, we established HepG2 cell lines expressing major CYP enzymes involved in drug metabolism (CYP2C9, CYP2C19, CYP2D6, and CYP3A4) and CYP oxidoreductase (POR) using the mammalian-derived artificial chromosome vector. Transchromosomic HepG2 (TC-HepG2) cells expressing four CYPs and POR were used to determine time- and concentration-dependent inhibition and toxicity of several compounds by luminescence detection of CYP-specific substrates and cell viability assays...
2017: PloS One
https://www.readbyqxmd.com/read/29033601/urine-metabolic-ratio-of-omeprazole-in-relation-to-cyp2c19-polymorphisms-in-russian-peptic-ulcer-patients
#15
Natalia P Denisenko, Dmitriy A Sychev, Zhanna M Sizova, Valeriy V Smirnov, Kristina A Ryzhikova, Zhannet A Sozaeva, Elena A Grishina
BACKGROUND: CYP2C19 is known to be the main enzyme of biotransformation of proton pump inhibitors (PPIs), whereas the CYP2C19 gene is highly polymorphic. Genotyping and phenotyping together represent more reliable data about patient's CYP2C19 activity. PURPOSE: The aim of the study was to investigate the applicability of urine metabolic ratio of omeprazole for CYP2C19 phenotyping in Russian peptic ulcer patients with different CYP2C19 genotypes. PATIENTS AND METHODS: A total of 59 patients (19 men and 40 women) aged 18-91 years (mean age 53...
2017: Pharmacogenomics and Personalized Medicine
https://www.readbyqxmd.com/read/28986475/pediatric-cytochrome-p450-activity-alterations-in-nonalcoholic-steatohepatitis
#16
Hui Li, Mark J Canet, John D Clarke, Dean Billheimer, Stavra A Xanthakos, Joel E Lavine, Robert P Erickson, Nathan J Cherrington
Variable drug responses depend on individual variation in the activity of drug-metabolizing enzymes, including cytochrome P450 enzymes (CYP). As the most common chronic liver disease in children and adults, nonalcoholic steatohepatitis (NASH) has been identified as a source of significant interindividual variation in hepatic drug metabolism. Compared with adults, children present age-related differences in pharmacokinetics and pharmacodynamics. The purpose of this study was to determine the impact of fatty liver disease severity on the activity of a variety of CYP enzymes in children and adolescents...
December 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28914344/influence-of-genetic-co-factors-on-the-population-pharmacokinetic-model-for-clopidogrel-and-its-active-thiol-metabolite
#17
Dorota Danielak, Marta Karaźniewicz-Łada, Anna Komosa, Paweł Burchardt, Maciej Lesiak, Łukasz Kruszyna, Agnieszka Graczyk-Szuster, Franciszek Główka
PURPOSE: A high interindividual variability is observed in the pharmacokinetics of clopidogrel, a widely used antiplatelet drug. In the present study, a joint parent-metabolite population pharmacokinetic model was developed to adequately describe observed concentrations of clopidogrel and its active thiol metabolite (H4). METHODS: The study included 63 patients undergoing elective coronarography or percutaneous coronary intervention. The population pharmacokinetic model was developed in the NONMEM 7...
December 2017: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28873029/cyp450-genotype-phenotype-concordance-in-mexican-amerindian-indigenous-populations-where-to-from-here-for-global-precision-medicine
#18
Fernando de Andrés, Martha Sosa-Macías, Blanca Patricia Lazalde Ramos, María-Eugenia G Naranjo, Adrián LLerena
Global precision medicine demands characterization of drug metabolism and phenotype variation in diverse populations, including the indigenous societies. A related question is the extent to which CYP450 drug metabolizing enzyme genotype and phenotype data are concordant and whether they can be used interchangeably. These issues are increasingly debated as precision medicine continues to expand as a popular research topic worldwide. We report here the first study in clinically relevant CYP450 drug metabolism phenotypes and genotypes in Mexican Amerindian indigenous subjects...
September 2017: Omics: a Journal of Integrative Biology
https://www.readbyqxmd.com/read/28766499/association-between-platelet-function-and-recurrent-ischemic-vascular-events-after-tia-and-minor-stroke
#19
Jinbiao Zhang, Jiangshan Zhang, Hairong Sun, Tan Ming, Xinwu Liu, Yannan Cong, Fang Li, Zhenguang Li
Platelet activation and aggregation play an important role in the pathological and physiological processes of recurrent ischemic vascular events in stroke patients. The purpose of this study is to determine the association between platelet function measured in the acute period and recurrent ischemic vascular events in patients with transient ischemic attack (TIA) or minor stroke. A total of 417 patients who were within the 24-hour period of clopidogrel-aspirin therapy after onset of a minor stroke or high-risk transient ischemic attack according to the Clopidogrel in High-risk patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial were included in this study...
October 2017: International Journal of Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28752728/evaluation-of-on-clopidogrel-platelet-reactivity-overtime-syntax-score-genetic-polymorphisms-and-their-relationship-to-one-year-clinical-outcomes-in-stemi-patients-undergoing-pci
#20
Harsha V Erathi, Rajasekhar Durgaprasad, Vanjakshamma Velam, Sarma Pvgk, Madhavi Rodda, Kapil C, Sreedhar N Kanavath
BACKGROUND: The aim of this paper was to investigate the variability of On-clopidogrel platelet reactivity overtime, the association between HTPR, gene polymorphism and Syntax Score (SS) for risk prediction of MACE in patients with ST-Elevation Myocardial Infarction (STEMI) undergoing percutaneous coronary intervention (PCI). Platelet function testing may be used to optimize antiplatelet therapy in high-risk patients, but identification of this subset of patients remains a challenge...
February 2018: Minerva Cardioangiologica
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