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CYP2C19 high activity

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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
#1
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...
January 16, 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
#2
Jiachang Gong, Lars Hansen, Lisa Iacono
BMS-823778 is a potent and selective inhibitor of 11beta-HSD1, an enzyme that regulates tissue specific intracellular glucocorticoid metabolism and a compelling target for the treatment of metabolic diseases. Metabolism of BMS-823778 was mainly mediated by polymorphic CYP2C19 with minor contribution from CYP3A3/5 and UGT1A4. Clinical PK of BMS-823778 was first investigated in healthy volunteers after single and multiple ascending doses. BMS-823778 was rapidly absorbed after oral dose, and systemic exposure at steady state increased proportionally to the dose...
January 8, 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
#3
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...
December 22, 2017: 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
#4
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
#5
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
#6
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
#7
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
#8
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
#9
Hui Li, Canet J Mark, John D Clarke, Dean Billheimer, Stavra A Xanthakos, Joel E Lavine, Robert P Erickson, Nathan J Cherrington
Variable drug responses(VDRs) are dependent upon individual variation in the activity of drug-metabolizing enzymes including cytochrome P450s(CYPs). As the most common chronic liver disease in children and adults, nonalcoholic steatohepatitis(NASH) has been identified as a source of significant inter-individual variation in hepatic drug metabolism. Compared to 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 CYPs in children and adolescents...
October 6, 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
#10
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...
September 15, 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
#11
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%C3%A2-and-minor-stroke%C3%A2
#12
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
#13
Harsha V Erathi, Rajasekhar Durgaprasad, Vanajakshamma Velam, P V Sarma, Madhavi Rodda, C Kapil, Sreedhar N Kanavath
OBJECTIVES: 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). BACKGROUND: Platelet function testing may be used to optimize antiplatelet therapy in high risk patients, but identification of this subset of patients remains a challenge...
July 27, 2017: Minerva Cardioangiologica
https://www.readbyqxmd.com/read/28626197/evaluation-of-cyp2d6-protein-expression-and-activity-in-the-small-intestine-to-determine-its-metabolic-capability-in-the-japanese-population
#14
Momoko Kawakami, Sachiko Takenoshita-Nakaya, Yuko Takeba, Yuki Nishimura, Masayuki Oda, Minoru Watanabe, Yuki Ohta, Shinjiro Kobayashi, Takehito Ohtsubo, Shinichi Kobayashi, Naoki Uchida, Naoki Matsumoto
CYP2D6 plays an important role in the metabolism of many drugs such as opioids and antidepressants. Polymorphisms of the CYP2D6 gene are widely observed in the Japanese population, and can affect the first-pass metabolism of orally administered drugs. Several CYP enzymes have been identified in the small intestine of Caucasians, but intestinal CYP enzymes have not been reported in the Japanese population, except for CYP3A4 and CYP2C19. In this study, we evaluated the CYP2D6 metabolic capacity by measurement of CYP2D6 mRNA and protein levels and activity in the small intestine of Japanese individuals...
June 14, 2017: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/28494448/effects-of-cyp2c19-variants-on-fluoxetine-metabolism-in-vitro
#15
Ping Fang, Jia-Yang He, Ai-Xia Han, Tian Lan, Da-Peng Dai, Jian-Ping Cai, Guo-Xin Hu
AIMS: CYP2C19 is an important member of the cytochrome P450 enzyme superfamily. We recently identified 31 CYP2C19 alleles in the Han Chinese population. The aim of this study was to assess the catalytic activities of these allelic isoforms and their effects on the metabolism of fluoxetine in vitro. METHODS: The wild-type and 30 CYP2C19 variants were expressed in insect cells and each variant was characterized using fluoxetine as the substrate. Reactions were performed at 37°C with 20-1,000 µmol/L substrate for 30 min...
2017: Pharmacology
https://www.readbyqxmd.com/read/28489395/identification-of-potent-and-selective-cyp1a1-inhibitors-via-combined-ligand-and-structure-based-virtual-screening-and-their-in-vitro-validation-in-sacchrosomes-and-live-human-cells
#16
Prashant Joshi, Glen J P McCann, Vinay R Sonawane, Ram A Vishwakarma, Bhabatosh Chaudhuri, Sandip B Bharate
Target structure-guided virtual screening (VS) is a versatile, powerful, and inexpensive alternative to experimental high-throughput screening (HTS). To discover potent CYP1A1 enzyme inhibitors for cancer chemoprevention, a commercial library of 50 000 small molecules was utilized for VS guided by both ligand and structure-based strategies. For experimental validation, 300 ligands were proposed based on combined analysis of fitness scores from ligand based e-pharmacophore screening and docking score, prime MMGB/SA binding affinity and interaction pattern analysis from structure-based VS...
June 26, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28470111/serum-clomipramine-and-desmethylclomipramine-levels-in-a-cyp2c19-and-cyp2d6-intermediate-metabolizer
#17
Jacob T Brown, Mark Schneiderhan, Seenae Eum, Jeffrey R Bishop
Pharmacogenetics within psychiatry has the potential to aid in the dose and selection of medications. A substantial number of psychiatric medications are metabolized through either of the highly polymorphic drug-metabolizing enzymes CYP2D6 and CYP2C19. Of these, clomipramine is subject to metabolism by both CYP2C19 and CYP2D6, leaving individuals with deficiencies of these drug-metabolizing enzymes at risk of higher concentrations of the parent molecule. Herein, we present the case of a 29-year-old male with diagnoses of depression and obsessive compulsive disorder who had trialed and failed a dozen psychiatric medications, many of which are subject to metabolism by CYP2D6 and/or CYP2C19, and had most recently been taking clomipramine for approximately 2...
May 4, 2017: Pharmacogenomics
https://www.readbyqxmd.com/read/28440827/molecular-dynamics-investigations-of-membrane-bound-cyp2c19-polymorphisms-reveal-distinct-mechanisms-for-peripheral-variants-by-long-range-effects-on-the-enzymatic-activity
#18
Ying-Lu Cui, Rong-Ling Wu
Increasing sophistication in methods used to account for human polymorphisms in susceptibility to drug metabolism has been one of the success stories in the prevention of adverse drug reactions. Genetic polymorphisms in drug-metabolizing enzymes can affect enzyme activity and cause differences in treatment response or drug toxicity. CYP2C19 is one of the most highly polymorphic CYP enzymes and acts on 10-15% of drugs in current clinical use. Despite the number of experimental analyses carried out for this system, the detailed structural basis for altered catalytic properties of polymorphic CYP2C19 variants remains unexplained at the atomic level...
April 25, 2017: Molecular BioSystems
https://www.readbyqxmd.com/read/28376352/metabolic-profiling-of-five-flavonoids-from-dragon-s-blood-in-human-liver-microsomes-using-high-performance-liquid-chromatography-coupled-with-high-resolution-mass-spectrometry
#19
Yujuan Li, Yushi Zhang, Rui Wang, Lizhong Wei, Yulin Deng, Wei Ren
Although much is known about the pharmacological activities of Dragon's Blood (DB, a traditional Chinese herb), its metabolism in human liver microsomes (HLMs) and the cytochrome P450 (CYP) enzymes has not been studied. This study aims to identify the metabolic profile of five flavonoids (loureirin A, loureirin B, loureirin C, 7,4'-dihydroxyflavone and 5,7,4'-trihydroxyflavanone) from DB in HLMs as well as the CYP enzymes that are involved in the metabolism of them. High-resolution mass spectrometry was used to characterize the structures of their metabolites and 10 cDNA-expressed CYP enzymes (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP3A5) were used to verify which isozymes mediate in the metabolism of the metabolites...
May 1, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/28329746/genotyping-platelet-activation-and-cardiovascular-outcome-in-patients-after-percutaneous-coronary-intervention-two-pieces-of-the-puzzle-of-clopidogrel-resistance
#20
Gerasimos Siasos, Evangelos Oikonomou, Manolis Vavuranakis, Eleni Kokkou, Konstantinos Mourouzis, Sotiris Tsalamandris, Marina Zaromitidou, Stamatios Kioufis, Vasiliki Tsigkou, Spyridon Deftereos, Christodoulos Stefanadis, Dimitris Tousoulis
OBJECTIVES: Individual platelet responses to antiplatelet therapy depend on genetic, cellular, and clinical factors. CYP2C19 and P2Y12 receptor polymorphisms are implicated in platelet responses to antiplatelet treatment. We aimed to evaluate the impact of CYP2C19 and C34T P2Y12 genotyping on platelet reactivity and cardiovascular outcome in patients after percutaneous coronary intervention (PCI) on clopidogrel treatment. METHODS: We enrolled 408 patients with stable coronary artery disease (CAD) receiving aspirin and clopidogrel (75 mg/day) 1 month after PCI...
2017: Cardiology
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