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CYP2C19 high activity

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https://www.readbyqxmd.com/read/28494448/effects-of-cyp2c19-variants-on-fluoxetine-metabolism-in-vitro
#1
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...
May 12, 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
#2
Prashant Joshi, Glen J P McCann, Vinay 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). In order to discover potent CYP1A1 enzyme inhibitors for cancer chemoprevention, a commercially 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...
May 10, 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
#3
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
#4
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
#5
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...
March 27, 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
#6
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
https://www.readbyqxmd.com/read/28247238/clinical-pharmacokinetic-monitoring-of-leflunomide-in-renal-transplant-recipients-with-bk-virus-reactivation-a-review-of-the-literature
#7
REVIEW
Joan C Y Ng, Marianna Leung, Alissa J Wright, Mary H H Ensom
Leflunomide is an immunosuppressive drug with in vitro and initial observational evidence of antiviral activity against BK virus (BKV), a pathogen that causes opportunistic infection upon reactivation in renal transplant recipients. Leflunomide is considered an ancillary option to immunosuppression reduction in the management of BKV reactivation. Plasma or blood concentrations of teriflunomide, the active metabolite of leflunomide, are commonly monitored because of high leflunomide doses being used, known inter-individual variability in pharmacokinetics, and hepatotoxicity risk...
February 28, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28135763/the-cyp2c19-2-and-cyp2c19-17-polymorphisms-play-a-vital-role-in-clopidogrel-responsiveness-after-percutaneous-coronary-intervention-a-pharmacogenomics-study
#8
Faruk Saydam, İrfan Değirmenci, Alparslan Birdane, Mahmut Özdemir, Taner Ulus, Cansu Özbayer, Ertuğrul Çolak, Necmi Ata, Hasan Veysi Güneş
Clopidogrel inhibits platelet activation and aggregation by blocking the P2Y12 receptor. Dual antiplatelet therapy with clopidogrel and aspirin is recommended treatment by current guidelines for patients undergoing percutaneous interventions. Recurrent ischaemic cardiac events after this treatment showed lack of clopidogrel responsiveness. We aimed to investigate the most noticeable variants in the genes involved in clopidogrel pharmacokinetics and pharmacodynamics. 347 Turkish patients who underwent percutaneous coronary interventions with stent implantation were included in our study...
January 30, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/28111763/cytochrome-p450-reaction-phenotyping-and-inhibition-and-induction-studies-of-pinostrobin-in-human-liver-microsomes-and-hepatocytes
#9
Shengnan Tan, Zhimin Dong, Jiashuo Zhang, Thomas Efferth, Yujie Fu, Xin Hua
Pinostrobin (PI, 5-hydroxy-7-methoxyflavanone) is a natural flavonoid known for its rich pharmacological activities. The objective of this study was to identify the human liver cytochrome P450 (CYP450) isoenzymes involved in the metabolism of PI. A single hydoxylated metabolite was obtained from PI after an incubation with pooled human liver microsomes (HLMs). The relative contributions of different CYP450s were evaluated using CYP450-selective inhibitors in HLMs and recombinant human CYP450 enzymes, and the results revealed the major involvement of CYP1A2, CYP2C9 and CYP2E1 in PI metabolism...
November 7, 2016: Biomedical Chromatography: BMC
https://www.readbyqxmd.com/read/28056947/triptolide-induces-hepatotoxicity-via-inhibition-of-cyp450s-in-rat-liver-microsomes
#10
Yan Lu, Tong Xie, Yajie Zhang, Fuqiong Zhou, Jie Ruan, Weina Zhu, Huaxu Zhu, Zhe Feng, Xueping Zhou
BACKGROUND: Triptolide (TP), an active constituent of Tripterygium wilfordii, possesses numerous pharmacological activities. However, its effects on cytochrome P450 enzymes (CYP450s) in rats remain unexplored. METHODS: In this study, the effects of triptolide on the six main CYP450 isoforms (1A2, 2C9, 2C19, 2D6, 2E1, and 3A) were investigated both in vivo and in vitro. We monitored the body weight, survival proportions, liver index, changes in pathology, and biochemical index upon TP administration, in vivo...
January 5, 2017: BMC Complementary and Alternative Medicine
https://www.readbyqxmd.com/read/28007398/development-of-gc-ms-based-cytochrome-p450-assay-for-the-investigation-of-multi-herb-interaction
#11
Hyun-A Oh, Hyunbeom Lee, Donghak Kim, Byung Hwa Jung
As drug interactions with cytochrome P450 enzymes become increasingly important in the field of drug discovery, a high-throughput screening method for analysing the effects of a drug is needed. We have developed a simple and rapid simultaneous analytical method using a cocktail approach for measuring the activities of seven cytochrome P450 enzymes (CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4). Human liver microsomes were used as a source for the seven cytochrome P450 enzymes, and a gas chromatography-mass spectrometry (GC-MS) was used for analysing their activities...
February 15, 2017: Analytical Biochemistry
https://www.readbyqxmd.com/read/27915193/metabolic-fate-and-detectability-of-the-new-psychoactive-substances-2-4-bromo-2-5-dimethoxyphenyl-n-2-methoxyphenyl-methyl-ethanamine-25b-nbome-and-2-4-chloro-2-5-dimethoxyphenyl-n-2-methoxyphenyl-methyl-ethanamine-25c-nbome-in-human-and-rat-urine-by-gc-ms
#12
Achim T Caspar, Simon D Brandt, Andreas E Stoever, Markus R Meyer, Hans H Maurer
25B-NBOMe and 25C-NBOMe are potent 5-HT2A receptor agonists that have been associated with inducing hallucinogenic effects in drug users and severe intoxications. This paper describes the identification of their metabolites in rat and human urine by liquid chromatography (LC)-high resolution (HR)-MS/MS, the comparison of metabolite formation in vitro and in vivo and in different species, the general involvement of human cytochrome-P450 (CYP) isoenzymes on their metabolism steps, and their detectability by standard urine screening approaches (SUSAs) using GC-MS, LC-MS(n), or LC-HR-MS/MS...
February 5, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/27901175/adme-studies-and-preliminary-safety-pharmacology-of-ldt5-a-lead-compound-for-the-treatment-of-benign-prostatic-hyperplasia
#13
F Noël, J B Nascimento-Viana, L A S Romeiro, R O Silva, L F N Lemes, A S Oliveira, T B S Giorno, P D Fernandes, C L M Silva
This study aimed to estimate the absorption, distribution, metabolism and excretion (ADME) properties and safety of LDT5, a lead compound for oral treatment of benign prostatic hyperplasia that has previously been characterized as a multi-target antagonist of α1A-, α1D-adrenoceptors and 5-HT1A receptors. The preclinical characterization of this compound comprised the evaluation of its in vitro properties, including plasma, microsomal and hepatocytes stability, cytochrome P450 metabolism and inhibition, plasma protein binding, and permeability using MDCK-MDR1 cells...
2016: Brazilian Journal of Medical and Biological Research, Revista Brasileira de Pesquisas Médicas e Biológicas
https://www.readbyqxmd.com/read/27896399/cytochrome-p450-mediated-metabolism-of-triclosan-attenuates-its-cytotoxicity-in-hepatic-cells
#14
Yuanfeng Wu, Priyanka Chitranshi, Lucie Loukotková, Gonçalo Gamboa da Costa, Frederick A Beland, Jie Zhang, Jia-Long Fang
Triclosan is a widely used broad-spectrum anti-bacterial agent. The objectives of this study were to identify which cytochrome P450 (CYP) isoforms metabolize triclosan and to examine the effects of CYP-mediated metabolism on triclosan-induced cytotoxicity. A panel of HepG2-derived cell lines was established, each of which overexpressed a single CYP isoform, including CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A7, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP3A4, CYP3A5, CYP3A7, CYP4A11, and CYP4B1...
November 28, 2016: Archives of Toxicology
https://www.readbyqxmd.com/read/27867264/traditional-herbal-formulas-to-as-treatments-for-musculoskeletal-disorders-their-inhibitory-effects-on-the-activities-of-human-microsomal-cytochrome-p450s-and-udp-glucuronosyltransferases
#15
Seong Eun Jin, Chang-Seob Seo, Hyeun-Kyoo Shin, Hyekyung Ha
OBJECTIVE: The aim of this study was to assess the influence of traditional herbal formulas, including Bangpungtongseong-san (BPTSS; Fangfengtongsheng-san, Bofu-tsusho-san), Ojeok-san (OJS; Wuji-san, Goshaku-san), and Oyaksungi-san (OYSGS; Wuyaoshungi-san, Uyakujyunki-san), on the activities of the human cytochrome P450s (CYP450s) and UDP-glucuronosyltransferases (UGTs), which are drug-metabolizing enzymes. MATERIALS AND METHODS: The activities of the major human CYP450 isozymes (CYP1A2, CYP3A4, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP2E1) and UGTs (UGT1A1, UGT1A4, and UGT2B7) were investigated using in vitro fluorescence-based and luminescence-based enzyme assays, respectively...
October 2016: Pharmacognosy Magazine
https://www.readbyqxmd.com/read/27849442/to-genotype-or-phenotype-for-personalized-medicine-cyp450-drug-metabolizing-enzyme-genotype-phenotype-concordance-and-discordance-in-the-ecuadorian-population
#16
Fernando De Andrés, Santiago Terán, Francisco Hernández, Enrique Terán, Adrián LLerena
Genetic variations within the cytochrome P450 (CYP450) superfamily of drug metabolizing enzymes confer substantial person-to-person and between-population differences in pharmacokinetics, and by extension, highly variable clinical effects of medicines. In this context, "personalized medicine," "precision medicine," and "stratified medicine" are related concepts attributed to what is essentially targeted therapeutics and companion diagnostics, aimed at improving safety and effectiveness of health interventions...
December 2016: Omics: a Journal of Integrative Biology
https://www.readbyqxmd.com/read/27803446/genetic-polymorphisms-and-in-vitro-functional-characterization-of-cyp2c8-cyp2c9-and-cyp2c19-allelic-variants
#17
REVIEW
Masahiro Hiratsuka
Genetic variations in CYP 2C (CYP2C) subfamily, CYP2C8, CYP2C9, and CYP2C19 contribute to interindividual variability in the metabolism of clinically used drugs. Changes in the drug metabolizing activity of CYP2C members may cause unexpected and serious adverse drug reactions and inadequate therapeutic effects. Therefore, CYP2C gene polymorphism is used as a genome biomarker for predicting responsiveness to administered drugs. The most direct method for understanding the extent of the effects of CYP2C gene polymorphism on drug pharmacokinetics is by evaluating the blood and urine concentrations of the drug in subjects...
2016: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/27734142/a-liquid%C3%A2-chromatography-tandem-mass-spectrometry-analysis-of-nine-cytochrome-p450-probe-drugs-and-their-corresponding-metabolites-in-human-serum-and-urine
#18
Elena Puris, Markku Pasanen, Mikko Gynther, Merja R Häkkinen, Jussi Pihlajamäki, Tapani Keränen, Paavo Honkakoski, Hannu Raunio, Aleksanteri Petsalo
Cocktail phenotyping using specific probe drugs for cytochrome P450 (CYP) enzymes provides information on the real-time activity of multiple CYPs. We investigated different sample preparation techniques and validated a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with simple protein precipitation for the analysis of nine CYP probe drugs and their metabolites in human serum and urine. Specific CYP probe drugs (melatonin, CYP1A2; nicotine, CYP2A6; bupropion, CYP2B6; repaglinide, CYP2C8; losartan, CYP2C9; omeprazole, CYP2C19 and CYP3A4; dextromethorphan, CYP2D6; chlorzoxazone, CYP2E; midazolam, CYP3A4) and their main metabolites, with the exception of 3'-hydroxyrepaglinide, were quantified in human serum and urine using the developed LC-MS/MS method...
January 2017: Analytical and Bioanalytical Chemistry
https://www.readbyqxmd.com/read/27732553/rapid-screening-for-targeted-genetic-variants-via-high-resolution-melting-curve-analysis
#19
Allison B Chambliss, Molly Resnick, Athena K Petrides, William A Clarke, Mark A Marzinke
BACKGROUND: Current methods for the detection of single nucleotide polymorphisms (SNPs) associated with aberrant drug-metabolizing enzyme function are hindered by long turnaround times and specialized techniques and instrumentation. In this study, we describe the development and validation of a high-resolution melting (HRM) curve assay for the rapid screening of variant genotypes for targeted genetic polymorphisms in the cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP3A5. METHODS: Sequence-specific primers were custom-designed to flank nine SNPs within the genetic regions of aforementioned drug metabolizing enzymes...
March 1, 2017: Clinical Chemistry and Laboratory Medicine: CCLM
https://www.readbyqxmd.com/read/27578295/in-vitro-functional-characterisation-of-cytochrome-p450-cyp-2c19-allelic-variants-cyp2c19-23-and-cyp2c19-24
#20
Pui Shen Lau, Kenny Voon Gah Leong, Chin Eng Ong, Amelia Nathania Hui Min Dong, Yan Pan
Cytochrome P450 (CYP) 2C19 is essential for the metabolism of clinically used drugs including omeprazole, proguanil, and S-mephenytoin. This hepatic enzyme exhibits genetic polymorphism with inter-individual variability in catalytic activity. This study aimed to characterise the functional consequences of CYP2C19*23 (271 G>C, 991 A>G) and CYP2C19*24 (991 A>G, 1004 G>A) in vitro. Mutations in CYP2C19 cDNA were introduced by site-directed mutagenesis, and the CYP2C19 wild type (WT) as well as variants proteins were subsequently expressed using Escherichia coli cells...
February 2017: Biochemical Genetics
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