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CYP2C19 high activity

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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
#1
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...
November 27, 2016: 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
#2
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
#3
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
#4
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
#5
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
#6
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
#7
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...
October 12, 2016: Analytical and Bioanalytical Chemistry
https://www.readbyqxmd.com/read/27732553/rapid-screening-for-targeted-genetic-variants-via-high-resolution-melting-curve-analysis
#8
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...
October 12, 2016: 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
#9
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...
August 30, 2016: Biochemical Genetics
https://www.readbyqxmd.com/read/27557470/identifying-clinically-relevant-sources-of-variability-the-clopidogrel-challenge
#10
S Samant, X L Jiang, L A Peletier, A R Shuldiner, R B Horenstein, J P Lewis, L J Lesko, S Schmidt
High interindividual variability in clinical outcomes following clopidogrel's standard dosing regimen continues to be a challenge even two decades after its approval. CYP2C19 polymorphisms, obesity, older age, diabetes, and drug-drug interactions have been identified as risk factors for adverse events and treatment failure. We conducted a mechanism-based pharmacokinetic/pharmacodynamic analysis, where we integrated knowledge on in vitro enzyme kinetic, physiological, genetic, and demographic information to characterize changes in platelet reactivity from baseline following clopidogrel antiplatelet therapy...
August 24, 2016: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/27440862/methylation-of-the-constitutive-androstane-receptor-is-involved-in-the-suppression-of-cyp2c19-in-hepatitis-b-virus-associated-hepatocellular-carcinoma
#11
Xiaojing Tang, Lele Ge, Zhongjian Chen, Sisi Kong, Wenhui Liu, Yingchun Xu, Su Zeng, Shuqing Chen
Hepatocellular carcinoma (HCC), one of the most dangerous malignancies with an increasing incidence and a high mortality rate, represents a major international health problem. HCC progression is known to involve genome-wide alteration of epigenetic modifications, leading to aberrant gene expression patterns. The activity of CYP2C19, an important member of the cytochrome P450 superfamily, was reported to be compromised in HCC, but the underlying mechanism remains unclear. To understand whether epigenetic modification in HCC is associated with a change in CYP2C19 activity, we evaluated the expression levels of CYP2C19 and its transcription factors by quantitative real-time polymerase chain reaction using mRNA extracted from both primary hepatocytes and paired tumor versus nontumor liver tissues of patients infected with hepatitis B virus (HBV)...
October 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/27304207/cyp2c19-and-cyp2d6-genotypes-in-pacific-peoples
#12
REVIEW
Nuala A Helsby
The study of pharmacogenetic variants in populations which reside in Oceania has been focused mainly on CYP2C19 and CYP2D6. Statements about the high prevalence of CYP2C19 no function genotype in 'Pacific Islanders' can be found in the literature. This review article summarizes the published information about these pharmacogenes in this geographical region and highlights the differences observed between Melanesian and Polynesian populations. It is not appropriate to combine the prevalence data of pharmacogenetic variants, particularly CYP2C19, across this region...
November 2016: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27302079/molecular-dynamics-investigations-of-regioselectivity-of-anionic-aromatic-substrates-by-a-family-of-enzymes-a-case-study-of-diclofenac-binding-in-cyp2c-isoforms
#13
Ying-Lu Cui, Fang Xu, Rongling Wu
The CYP2C subfamily is of particular importance in the metabolism of drugs, food toxins, and procarcinogens. Like other P450 subfamilies, 2C enzymes share a high sequence identity, but significantly contribute in different ways to hepatic capacity to metabolize drugs. They often metabolize the same substrate to more than one product with different catalytic sites. Because it is challenging to characterize experimentally, much still remains unknown about the reason for why the substrate regioselectivity of these closely related subfamily members is different...
June 29, 2016: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/27296047/the-wild-egyptian-artichoke-as-a-promising-functional-food-for-the-treatment-of-hepatitis-c-virus-as-revealed-via-uplc-ms-and-clinical-trials
#14
Mahmoud Fahmi Elsebai, Khaled Abass, Jukka Hakkola, Ahmed Rezk Atawia, Mohamed A Farag
Infection by hepatitis C virus (HCV) and its subsequent complications are a major cause of mortality worldwide. The water extract of the wild Egyptian artichoke (WEA) (Cynara cardunculus L. var. sylvestris (Lam.) Fiori) leaves is a freely available herbal product that is used for treatment of HCV-infection complications such as jaundice and ascites. The purpose of this study was to evaluate whether WEA exhibits activity against HCV, identify bioactive chemicals in its extract and to tentatively examine the potential inhibitory interactions of WEA with human drug-metabolizing enzymes...
July 13, 2016: Food & Function
https://www.readbyqxmd.com/read/27236738/high-on-treatment-platelet-reactivity-in-peripheral-arterial-disease-a-pilot-study-to-find-the-optimal-test-and-cut-off-values
#15
T C Leunissen, S M O Peeters Weem, R T Urbanus, H M den Ruijter, F L Moll, F W Asselbergs, G J de Borst
OBJECTIVE: Restenosis and stent thrombosis after endovascular intervention in patients with peripheral arterial disease (PAD) can potentially be tackled by more intensive antiplatelet therapy, such as dual antiplatelet therapy (DAPT) consisting of aspirin and P2Y12 inhibitor. Despite clopidogrel treatment, some patients still display high platelet reactivity (HCPR). Tailored antiplatelet therapy, based on platelet reactivity testing, might overcome HCPR. However, more data are warranted regarding the proportion of patients with HCPR in the PAD population, different platelet reactivity tests, their correlation, and the optimal timing for these tests as a stepping stone for a future trial investigating the potential benefit of tailored antiplatelet therapy in PAD patients...
August 2016: European Journal of Vascular and Endovascular Surgery
https://www.readbyqxmd.com/read/27212172/can-helicobacter-pylori-be-eradicated-with-high-dose-proton-pump-inhibitor-in-extensive-metabolizers-with-the-cyp2c19-genotypic-polymorphism
#16
A Ormeci, Z Emrence, B Baran, O M Soyer, S Gokturk, S Evirgen, F Akyuz, C Karaca, F Besisik, S Kaymakoglu, D Ustek, K Demir
Proton pump inhibitors (PPI) metabolism and pharmacokinetics are regulated by cytochrome P450 enzymes in the liver. Cytochrome P450 2C19 (CYP2C19) polymorphism plays an import role in the metabolism of PPIs. The three possible genotypes for CYP2C19 each has a distinct effect on the pharmacodynamics of PPIs. Homozygote extensive metabolizers (HomEM) are the most frequent genotype and have two wild-types (non-mutant) (*1/*1) alleles. HomEM is associated with increased enzyme activity, which increases the rate of PPI metabolism...
May 2016: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/27196064/the-metabolism-of-clopidogrel-cyp2c19-is-a-minor-pathway
#17
REVIEW
Neville F Ford
The major metabolic pathway of clopidogrel is conversion to carboxylic acid by an esterase (CES1), forming clopidogrelic acid (SR26334) that is inactive. There is agreement on the structure of the active metabolite; however, there are differing views about the mechanism of its formation. Sanofi studied the conversion of clopidogrel to the active metabolite using human liver microsomes. It was concluded that 2-oxo-clopidogrel was formed via CYP3A oxidation. From a subsequent in vitro study by Sankyo of the metabolism of clopidogrel using recombinant DNA CYPs, it was concluded that CYP2C19 was the major oxidative pathway...
December 2016: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27161631/the-investigational-drug-vt-1129-is-a-highly-potent-inhibitor-of-cryptococcus-species-cyp51-but-only-weakly-inhibits-the-human-enzyme
#18
Andrew G S Warrilow, Josie E Parker, Claire L Price, W David Nes, Edward P Garvey, William J Hoekstra, Robert J Schotzinger, Diane E Kelly, Steven L Kelly
Cryptococcosis is a life-threatening disease often associated with HIV infection. Three Cryptococcus species CYP51 enzymes were purified and catalyzed the 14α-demethylation of lanosterol, eburicol, and obtusifoliol. The investigational agent VT-1129 bound tightly to all three CYP51 proteins (dissociation constant [Kd] range, 14 to 25 nM) with affinities similar to those of fluconazole, voriconazole, itraconazole, clotrimazole, and ketoconazole (Kd range, 4 to 52 nM), whereas VT-1129 bound weakly to human CYP51 (Kd, 4...
August 2016: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/27106177/pharmacokinetic-drug-interactions-with-tobacco-cannabinoids-and-smoking-cessation-products
#19
Gail D Anderson, Lingtak-Neander Chan
Tobacco smoke contains a large number of compounds in the form of metals, volatile gases and insoluble particles, as well as nicotine, a highly addictive alkaloid. Marijuana is the most widely used illicit drug of abuse in the world, with a significant increase in the USA due to the increasing number of states that allow medical and recreational use. Of the over 70 phytocannabinoids in marijuana, Δ(9)-tetrahydrocannabinol (Δ(9)THC), cannabidiol (CBD) and cannibinol are the three main constituents. Both marijuana and tobacco smoking induce cytochrome P450 (CYP) 1A2 through activation of the aromatic hydrocarbon receptor, and the induction effect between the two products is additive...
April 22, 2016: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/27066364/relationship-between-cytochrome-p450-polymorphisms-and-prescribed-medication-in-elderly-haemodialysis-patients
#20
Krystina Parker, Willy Aasebø, Tore Haslemo, Knut Stavem
BACKGROUND: Elderly patients on haemodialysis have a high prevalence of polypharmacy and are at risk of drug-related complications. More than 80 % of all prescribed drugs are metabolized by the cytochrome P450 (CYP) enzyme system. The aims of this study were to describe the prevalence of polymorphism in three CYP isoenzymes and the relationship between CYP polymorphism and prescribed drugs. METHODS: Fifty-one elderly haemodialysis patients aged ≥65 years were included...
2016: SpringerPlus
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