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https://www.readbyqxmd.com/read/28229374/effect-of-short-term-fasting-on-systemic-cytochrome-p450-mediated-drug-metabolism-in-healthy-subjects-a-randomized-controlled-crossover-study-using-a-cocktail-approach
#1
Laureen A Lammers, Roos Achterbergh, Ron H N van Schaik, Johannes A Romijn, Ron A A Mathôt
BACKGROUND AND OBJECTIVE: Short-term fasting can alter drug exposure but it is unknown whether this is an effect of altered oral bioavailability and/or systemic clearance. Therefore, the aim of our study was to assess the effect of short-term fasting on oral bioavailability and systemic clearance of different drugs. METHODS: In a randomized, controlled, crossover trial, 12 healthy subjects received a single administration of a cytochrome P450 (CYP) probe cocktail, consisting of caffeine (CYP1A2), metoprolol (CYP2D6), midazolam (CYP3A4), omeprazole (CYP2C19) and warfarin (CYP2C9), on four occasions: an oral (1) and intravenous (2) administration after an overnight fast (control) and an oral (3) and intravenous (4) administration after 36 h of fasting...
February 22, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28228413/determination-of-human-hepatic-cyp2c8-and-cyp1a2-age-dependent-expression-to-support-human-health-risk-assessment-for-early-ages
#2
Gina Song, Xueying Sun, Ronald N Hines, D Gail McCarver, Brian G Lake, Thomas G Osimitz, Moire R Creek, Harvey J Clewell, Miyoung Yoon
Predicting age-specific metabolism is important for evaluating age-related drug and chemical sensitivity. Multiple cytochrome P450s (CYP) and carboxylesterase (CES) enzymes are responsible for human pyrethroid metabolism. Complete ontogeny data for each enzyme is needed to support in vitro to in vivo extrapolation (IVIVE). This study was designed to determine age-dependent human hepatic CYP2C8 expression, for which only limited ontogeny data are available, and to further define CYP1A2 ontogeny. CYP2C8 and 1A2 protein levels were measured by quantitative Western blotting using liver microsomal samples prepared from 222 subjects with ages ranging from 8 weeks gestation to 18 years after birth...
February 22, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28224948/predictors-of-warfarin-dose-requirements-in-south-african-patients-attending-an-anticoagulation-clinic
#3
Elise Schapkaitz, Johanna Sithole
INTRODUCTION: Warfarin is the most common oral anticoagulant for the treatment and prevention of thromboembolic disease. However, it has a wide interpatient variability in dose requirements due to various genetic and clinical factors. MATERIALS AND METHODS: This study investigated the effect of clinical and genetic factors on the variability of warfarin dose requirements in 147 South African patients (81 white and 66 black). The study was performed at a University Hospital Anticoagulation Clinic managed by nursing sisters at the Charlotte Maxeke Johannesburg Academic Hospital...
March 2017: Journal of Vascular Nursing: Official Publication of the Society for Peripheral Vascular Nursing
https://www.readbyqxmd.com/read/28222316/discovery-and-characterization-of-novel-cyp1b1-inhibitors-based-on-heterocyclic-chalcones-overcoming-cisplatin-resistance-in-cyp1b1-overexpressing-lines
#4
Neill J Horley, Kenneth J M Beresford, Tarun Chawla, Glen J P McCann, Ketan C Ruparelia, Linda Gatchie, Vinay R Sonawane, Ibidapo S Williams, Hoon L Tan, Prashant Joshi, Sonali S Bharate, Vikas Kumar, Sandip B Bharate, Bhabatosh Chaudhuri
The structure of alpha-napthoflavone (ANF), a potent inhibitor of CYP1A1 and CYP1B1, mimics the structure of chalcones. Two potent CYP1B1 inhibitors 7k (DMU2105) and 6j (DMU2139) have been identified from two series of synthetic pyridylchalcones. They inhibit human CYP1B1 enzyme bound to yeast-derived microsomes (Sacchrosomes™) with IC50 values of 10 and 9 nM, respectively, and show a very high level of selectivity towards CYP1B1 with respect to the IC50 values obtained with CYP1A1, CYP1A2, CYP3A4, CYP2D6, CYP2C9 and CYP2C19 Sacchrosomes™...
February 9, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28199000/overexpression-of-pregnane-x-and-glucocorticoid-receptors-and-the-regulation-of-cytochrome-p450-in-human-epileptic-brain-endothelial-cells
#5
Chaitali Ghosh, Mohammed Hossain, Jesal Solanki, Imad M Najm, Nicola Marchi, Damir Janigro
OBJECTIVE: Recent evidence suggests a metabolic contribution of cytochrome P450 enzymes (CYPs) to the drug-resistant phenotype in human epilepsy. However, the upstream molecular regulators of CYP in the epileptic brain remain understudied. We therefore investigated the expression and function of pregnane xenobiotic (PXR) and glucocorticoid (GR) nuclear receptors in endothelial cells established from post-epilepsy surgery brain samples. METHODS: PXR/GR localization was evaluated by immunohistochemistry in specimens from subjects who underwent temporal lobe resections to relieve drug-resistant seizures...
February 15, 2017: Epilepsia
https://www.readbyqxmd.com/read/28198005/clinical-pharmacogenetics-implementation-consortium-cpic-guideline-for-pharmacogenetics-guided-warfarin-dosing-2017-update
#6
Julie A Johnson, Kelly E Caudle, Li Gong, Michelle Whirl-Carrillo, C Michael Stein, Stuart A Scott, Ming Ta Michael Lee, Brian F Gage, Stephen E Kimmel, Minoli A Perera, Jeffrey L Anderson, Munir Pirmohamed, Teri E Klein, Nita A Limdi, Larisa H Cavallari, Mia Wadelius
This document is an update to the 2011 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C9 and VKORC1 genotypes and warfarin dosing. Evidence from the published literature is presented for CYP2C9, VKORC1, CYP4F2, and rs12777823 genotype-guided warfarin dosing to achieve a target international normalized ratio of 2-3 when clinical genotype results are available. In addition, this updated guideline incorporates recommendations for adult and pediatric patients that are specific to continental ancestry...
February 15, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28190634/discovery-and-characterization-of-cyclopentyl-ethyl-benzoic-acid-inhibitors-of-microsomal-prostaglandin-e-synthase-1
#7
Katherine M Partridge, Stephen Antonysamy, Shobha N Bhattachar, Srinivasan Chandrasekhar, Matthew J Fisher, Adrian Fretland, Karen Gooding, Anita Harvey, Norman E Hughes, Steven L Kuklish, John G Luz, Peter R Manninen, James E McGee, Daniel R Mudra, Antonio Navarro, Bryan H Norman, Steven J Quimby, Matthew A Schiffler, Ashley V Sloan, Alan M Warshawsky, Jennifer M Weller, Jeremy S York, Xiao-Peng Yu
We describe a novel class of acidic mPGES-1 inhibitors with nanomolar enzymatic and human whole blood (HWB) potency. Rational design in conjunction with structure-based design led initially to the identification of anthranilic acid 5, an mPGES-1 inhibitor with micromolar HWB potency. Structural modifications of 5 improved HWB potency by over 1000×, reduced CYP2C9 single point inhibition, and improved rat clearance, which led to the selection of [(cyclopentyl)ethyl]benzoic acid compound 16 for clinical studies...
November 7, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28179614/genotyping-of-six-clopidogrel-metabolizing-enzyme-polymorphisms-has-a-minor-role-in-the-assessment-of-platelet-reactivity-in-patients-with-acute-coronary-syndrome
#8
María Henar García-Lagunar, Luciano Consuegra-Sánchez, Pablo Conesa-Zamora, Javier Ruiz-Cosano, Federico Soria-Arcos, Luis García de Guadiana, Pedro Cano Vivar, Juan Antonio Castillo-Moreno, Antonio Melgarejo-Moreno
OBJECTIVE: To evaluate the contribution of six polymorphisms to the platelet reactivity in patients with acute coronary syndrome (ACS) treated with clopidogrel. METHODS: Cross-sectional study of 278 consecutive patients with ACS. Detailed clinical information for each patient was collected and genotypes (CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2C19*17, CYP3A4*1B, and PON1-Q192R) were evaluated with TaqMan® and KASPar® assays. Platelet reactivity was measured with VerifyNow®...
February 1, 2017: Anatolian Journal of Cardiology
https://www.readbyqxmd.com/read/28179134/inhibition-of-cytochrome-p450-enzymes-by-saturated-and-unsaturated-fatty-acids-in-human-liver-microsomes-characterization-of-enzyme-kinetics-in-the-presence-of-bovine-serum-albumin-0-1-and-1-0-w-v-and-in-vitro-in-vivo-extrapolation-of-hepatic-clearance
#9
Raghava Choudary Palacharla, Venkatesham Uthukam, Arunkumar Manoharan, Ranjith Kumar Ponnamaneni, Nagasurya Prakash Padala, Rajesh Kumar Boggavarapu, Gopinadh Bhyrapuneni, Devender Reddy Ajjala, Ramakrishna Nirogi
The objective of the study was to determine the effect of fatty acids on CYP enzymes and the effect of BSA on intrinsic clearance of probe substrates. The inhibitory effect of thirteen fatty acids including saturated, mono-unsaturated and polyunsaturated fatty acids on CYP enzymes, kinetic parameters and intrinsic clearance values of nine CYP marker probe substrate reactions in the absence and presence of BSA (0.1 and 1.0% w/v) were characterized in human liver microsomes. The results demonstrate that most of the unsaturated fatty acids showed marked inhibition towards CYP2C8 mediated amodiaquine N-deethylation followed by inhibition of CYP2C9 and CYP2B6 mediated activities...
February 4, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28178648/polymorphisms-of-esr1-ugt1a1-hcn1-map3k1-and-cyp2b6-are-associated-with-the-prognosis-of-hormone-receptor-positive-early-breast-cancer
#10
Sung-Hsin Kuo, Shi-Yi Yang, San-Lin You, Huang-Chun Lien, Ching-Hung Lin, Po-Han Lin, Chiun-Sheng Huang
In this study, we investigated whether single nucleotide polymorphisms (SNPs) identified by genome-wide association study (GWAS) (MAP3K1, FGFR2, TNRC9, HCN1, and 5p12), and SNPs involved in the metabolism of estrogen (CYP19, COMT, ESR1, and UGT1A1), tamoxifen (CYP2C9, CYP2C19, CYP3A5, and CYP2D6), and chemotherapeutic agents (ABCB1, ALDH3A1, and CYP2B6) are associated with the prognoses of 414 hormone receptor (HR)-positive early breast cancers with negative or 1 to 3 nodal metastases. At a median follow-up period of 10...
February 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28173639/bosentan-and-rifampin-interactions-modulate-influx-transporter-and-cytochrome-p450-expression-and-activities-in-primary-human-hepatocytes
#11
Kyoung-Moon Han, Sun-Young Ahn, Hyewon Seo, Jaesuk Yun, Hye Jin Cha, Ji-Soon Shin, Young-Hoon Kim, Hyungsoo Kim, Hye-Kyung Park, Yong-Moon Lee
The incidence of polypharmacy-which can result in drug-drug interactions-has increased in recent years. Drug-metabolizing enzymes and drug transporters are important polypharmacy modulators. In this study, the effects of bosentan and rifampin on the expression and activities of organic anion-transporting peptide (OATP) and cytochrome P450 (CYP450) 2C9 and CYP3A4 were investigated in vitro. HEK293 cells and primary human hepatocytes overexpressing the target genes were treated with bosentan and various concentrations of rifampin, which decreased the uptake activities of OATP transporters in a dose-dependent manner...
February 6, 2017: Biomolecules & Therapeutics
https://www.readbyqxmd.com/read/28164519/angiotensin-converting-enzyme-inhibitors-influence-on-antiplatelet-therapy-of-clopidogrel-in-acs
#12
Shuo Yang, Chanjuan Cui, Jie Zhang, Rui Qiao
BACKGROUND: Clopidogrel is a prodrug, the minority of which is converted to an active metabolite by hepatic cytochrome P450 (CYP2C19), however, most of it is metabolized to inactive substance by hepatic carboxylesterase1 (CES1). Meanwhile angiotensin-converting enzyme inhibitors (ACEIs) are mostly metabolized by CES1. We aimed to assess the impact of ACEIs on platelet inhibition by clopidogrel. METHODS: We genotyped variants CES1, CYP2C19*2 and *3 in 502 patients with acute coronary syndrome (ACS) receiving clopidogrel therapy, and analyzed the effects of ACEIs on responsiveness to clopidogrel by the vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay and ADP-stimulated impedance whole blood platelet aggregation assay...
October 1, 2016: Clinical Laboratory
https://www.readbyqxmd.com/read/28159531/a-validated-lc-ms-ms-method-for-the-estimation-of-glimepiride-and-pitavastatin-in-rat-plasma-application-to-drug-interaction-studies
#13
Shruti Surendran, David Paul, Ratna Sushmita, Lavanya Krishna, Nirbhay Kumar Tiwari, Sanjeev Giri, Nanjappan Satheeshkumar
Glimepiride (GLI) is prescribed for the management of type-2 diabetes where as pitavastatin (PIT) for the treatment of diabetes associated dyslipidemia. Both the drugs are metabolized by CYP2C9 and have the potential of altering the enzyme through either inhibition or induction. In this respect, we present a simple, fast and validated bioanalytical LC-MS/MS method for the simultaneous estimation of GLI and PIT from rat plasma. Waters XTerra RP HPLC column (4.6×100mm, 5μm) with mobile phase consisting of acetonitrile and 10mM ammonium acetate (pH-6...
January 9, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/28157069/delayed-de-induction-of-cyp2c9-compared-to-cyp3a-after-discontinuation-of-rifampicin-report-of-two-cases%C3%A2
#14
Soichi Shibata, Harumi Takahashi, Akiyasu Baba, Kei Takeshita, Koichiro Atsuda, Hajime Matsubara, Hirotoshi Echizen
OBJECTIVE: Timely dose reduction of concomitant medications is important after withdrawal of rifampicin, a CYP inducer. However, little is known about the differences in the time course of deinduction for various CYP isoforms. To clarify the time courses of deinduction of CYP2C9 and -CYP3A activities after rifampicin withdrawal, we monitored these enzyme activities in 2 patients over time after discontinuing rifampicin. MATERIALS AND METHODS: Two patients (aged 70 and 80 years) received warfarin and rifampicin for anticoagulation and antituberculosis therapy, respectively...
February 3, 2017: International Journal of Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28135601/interaction-of-quercetin-and-its-metabolites-with-warfarin-displacement-of-warfarin-from-serum-albumin-and-inhibition-of-cyp2c9-enzyme
#15
Miklós Poór, Gabriella Boda, Paul W Needs, Paul A Kroon, Beáta Lemli, Tímea Bencsik
Flavonoids are ubiquitous molecules in nature with manifold pharmacological effects. Flavonoids interact with several proteins, and thus potentially interfere with the pharmacokinetics of various drugs. Though much is known about the protein binding characteristics of flavonoid aglycones, the behaviour of their metabolites, which are extensively formed in the human body has received little attention. In this study, the interactions of the flavonoid aglycone quercetin and its main metabolites with the albumin binding of the oral anticoagulant warfarin were investigated by fluorescence spectroscopy and ultrafiltration...
January 27, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28135054/integrated-analysis-of-genetic-variation-and-gene-expression-reveals-novel-variant-for-increased-warfarin-dose-requirement-in-african-americans
#16
Wenndy Hernandez, Eric R Gamazon, Keston Aquino-Michaels, Erin Smithberger, Travis J O'Brien, Arthur F Harralson, Matthew Tuck, April Barbour, Larisa H Cavallari, Minoli A Perera
BACKGROUND: Warfarin is commonly used to control and prevent thromboembolic disorders. However, due to warfarin's complex dose-requirement relationship, safe and effective use is challenging. Pharmacogenomics-guided warfarin dosing algorithms that include the well-established VKORC1 and CYP2C9 polymorphisms explain only a small proportion of inter-individual variability in African Americans (AAs). OBJECTIVES: We aimed to assess whether transcriptomic analyses could be used to identify regulatory variants associated with warfarin dose response in AAs...
January 30, 2017: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/28131653/identification-of-novel-glutathione-adducts-of-benzbromarone-in-human-liver-microsomes
#17
Naoki Cho, Kaoru Kobayashi, Mina Yoshida, Noriyuki Kogure, Hiromitsu Takayama, Kan Chiba
Benzbromarone (BBR) is a potent uricosuric drug that can cause serious liver injury. Our recent study suggested that 1'-hydroxy BBR, one of major metabolites of BBR, is metabolized to a cytotoxic metabolite that could be detoxified by glutathione (GSH). The aim of this study was to clarify whether GSH adducts are formed from 1'-hydroxy BBR in human liver microsomes (HLM). Incubation of 1'-hydroxy BBR with GSH in HLM did not result in the formation of GSH adducts, but 1',6-dihydroxy BBR was formed. In addition, incubation of 1',6-dihydroxy BBR with GSH in HLM resulted in the formation of three novel GSH adducts (M1, M2 and M3)...
October 27, 2016: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28129313/clinical-outcomes-of-concomitant-use-of-warfarin-and-selective-serotonin-reuptake-inhibitors-a-multidatabase-observational-cohort-study
#18
Yaa-Hui Dong, Katsiaryna Bykov, Niteesh K Choudhry, Macarius M Donneyong, Krista F Huybrechts, Raisa Levin, Sebastian Schneeweiss, Joshua J Gagne
BACKGROUND: Patients treated with warfarin are often coprescribed selective serotonin reuptake inhibitors (SSRIs) for coexisting depression. Some SSRIs are potent CYP2C9 inhibitors that may increase warfarin plasma concentrations and the risk of bleeding. We aimed to examine the effect of the putative CYP2C9-mediated warfarin-SSRI interaction on clinical outcomes. METHODS: We conducted an observational cohort study among warfarin initiators who had a subsequent SSRI prescription in 5 US claims databases...
January 26, 2017: Journal of Clinical Psychopharmacology
https://www.readbyqxmd.com/read/28127194/three-dimensional-perfused-human-in-vitro-model-of-non-alcoholic-fatty-liver-disease
#19
Tomasz Kostrzewski, Terri Cornforth, Sophie A Snow, Larissa Ouro-Gnao, Cliff Rowe, Emma M Large, David J Hughes
AIM: To develop a human in vitro model of non-alcoholic fatty liver disease (NAFLD), utilising primary hepatocytes cultured in a three-dimensional (3D) perfused platform. METHODS: Fat and lean culture media were developed to directly investigate the effects of fat loading on primary hepatocytes cultured in a 3D perfused culture system. Oil Red O staining was used to measure fat loading in the hepatocytes and the consumption of free fatty acids (FFA) from culture medium was monitored...
January 14, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/28118673/an-appraisal-of-drug-drug-interactions-with-green-tea-camellia-sinensis
#20
Ahmed A Albassam, John S Markowitz
This review summarizes published in vitro, animal, and clinical studies investigating the effects of green tea (Camellia sinensis) extract and associated catechins on drug-metabolizing enzymes and drug transporters. In vitro studies suggest that green tea extract and its main catechin, (-)-epigallocatechin-3-gallate, to varying degrees, inhibit the activity of CYP1A1, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2D6, and CYP3A4. UGT1A1 and UGT1A4 isoforms were also inhibited by (-)-epigallocatechin-3-gallate. Animal studies suggest green tea extract and/or (-)-epigallocatechin-3-gallate significantly increase the bioavailability of diltazem, verapamil, tamoxifen simvastatin, 5-fluorouracil, and nicardipine...
January 24, 2017: Planta Medica
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