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CYP2C9

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https://www.readbyqxmd.com/read/28820457/role-of-cyp2c9-cyp2c19-and-ephx-polymorphism-in-the-pharmacokinetic-of-phenytoin-a-study-on-uruguayan-caucasian-subjects
#1
Natalia Guevara, Cecilia Maldonado, Manuel Uría, Raquel González, Manuel Ibarra, Silvana Alvariza, Antonella Carozzi, Carlos Azambuja, Pietro Fagiolino, Marta Vázquez
Phenytoin (PHT) oxidative route leads to its main metabolite p-hydroxyphenytoin (p-HPPH), by means of CYP2C9 and CYP2C19. Formation of p-HPPH proceeds via a reactive arene-oxide intermediate. This intermediate can also be converted into PHT dihydrodiol by microsomal epoxide hydrolase (EPHX). The three enzymes are polymorphically expressed and the genetic variants are responsible for changes in the enzyme activity. In order to evaluate the effect that these polymorphisms have on PHT metabolism, PHT and p-HPPH plasma concentrations were measured and the genotype for the three enzymes was assessed in 50 Uruguayan epileptic patients...
August 18, 2017: Pharmaceuticals
https://www.readbyqxmd.com/read/28817838/pharmacogenetic-determinants-of-outcomes-on-triplet-hepatic-artery-infusion-and-intravenous-cetuximab-for-liver-metastases-from-colorectal-cancer-european-trial-optiliv-nct00852228
#2
Francis Lévi, Abdoulaye Karaboué, Raphaël Saffroy, Christophe Desterke, Valerie Boige, Denis Smith, Mohamed Hebbar, Pasquale Innominato, Julien Taieb, Carlos Carvalho, Rosine Guimbaud, Christian Focan, Mohamed Bouchahda, René Adam, Michel Ducreux, Gérard Milano, Antoinette Lemoine
BACKGROUND: The hepatic artery infusion (HAI) of irinotecan, oxaliplatin and 5-fluorouracil with intravenous cetuximab achieved outstanding efficacy in previously treated patients with initially unresectable liver metastases from colorectal cancer. This planned study aimed at the identification of pharmacogenetic predictors of outcomes. METHODS: Circulating mononuclear cells were analysed for 207 single-nucleotide polymorphisms (SNPs) from 34 pharmacology genes...
August 17, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28815830/determinants-of-the-inhibition-of-dpre1-and-cyp2c9-by-antitubercular-thiophenes
#3
Renhe Liu, Xiaoxuan Lyu, Mei-Hui Hsu, Catherine Vilcheze, Scott G Franzblau, William R Jacobs, Gurdyal S Besra, Eric F Johnson, Klaus Fütterer, Feng Wang
Mycobacterium tuberculosis (Mtb) DprE1, an essential isomerase for the biosynthesis of the mycobacterial cell wall, is a validated target for tuberculosis (TB) drug development. Here we report the X-ray crystal structures of DprE1 and the DprE1 resistant mutant (Y314C) in complexes with TCA1 derivatives to elucidate the molecular basis of their inhibitory activities and an unconventional resistance mechanism, which enabled us to optimize the potency of the analogs. The selected lead compound showed excellent in vitro and in vivo activities, and low risk of toxicity profile except for the inhibition of CYP2C9...
August 16, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28808886/assessment-of-pharmacokinetic-interactions-between-obeticholic-acid-and-caffeine-midazolam-warfarin-dextromethorphan-omeprazole-rosuvastatin-and-digoxin-in-phase-1-studies-in-healthy-subjects
#4
Jeffrey E Edwards, Lise Eliot, Andrew Parkinson, Sharon Karan, Leigh MacConell
INTRODUCTION: Obeticholic acid (OCA), a potent and selective farnesoid X receptor agonist, is indicated for the treatment of primary biliary cholangitis (PBC). We investigated the potential drug-drug interaction effect of OCA on metabolic CYP450 enzymes and drug transporters. METHODS: Five phase 1 single-center, open-label, fixed-sequence, inpatient studies were conducted in healthy adult subjects to evaluate the effect of oral daily doses of 10 or 25 mg OCA on single-dose plasma pharmacokinetics of specific probe substrates for enzymes CYP1A2 (caffeine, R-warfarin), CYP3A (midazolam, R-warfarin), CYP2C9 (S-warfarin), CYP2D6 (dextromethorphan), CYP2C19 (omeprazole), and drug transporters, BCRP/OATP1B1/OATP1B3 (rosuvastatin), and P-gp (digoxin)...
August 14, 2017: Advances in Therapy
https://www.readbyqxmd.com/read/28805981/noncompetitive-inhibition-of-human-cyp2c9-in%C3%A2-vitro-by-a-commercial-rhodiola-rosea-product
#5
Ole Kristian Forstrønen Thu, Olav Spigset, Bent Hellum
A commercial Rhodiola rosea (R. rosea) product has previously demonstrated CYP2C9 inhibition in humans. The purpose of this study was to provide in vitro inhibitory data for this particular interaction and to classify the mechanism of the interaction. Another aim was to examine the in vitro influence of ethanol on the CYP2C9 activity. Human CYP2C9 (wild type) isolated from a baculovirus-infected cell system was incubated with 0.8 μmol/L losartan for 20 min. Sulfaphenazole was used as a positive control...
August 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28792790/recent-developments-and-future-directions-for-the-use-of-pharmacogenomics-in-cardiovascular-disease-treatments
#6
Andrew Levy, Elliot Berinstein
Cardiovascular disease is still the leading cause of death worldwide. There are many environmental and genetic factors that play a role in the development of cardiovascular disease. The treatment of cardiovascular disease is beginning to move in the direction of personalized medicine by using biomarkers from patient's genome to design more effective treatment plans. Pharmacogenomics have already uncovered many links between genetic variation and response of many different drugs. Areas covered: This article will focus on the main polymorphisms that impact the risk of adverse effects and response efficacy of statins, clopidogrel, aspirin, β-blockers, warfarin dalcetrapib and vitamin E...
August 9, 2017: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/28776468/falls-the-adverse-drug-reaction-of-the-elderly-and-the-impact-of-pharmacogenetics
#7
Katja Susanne Just, Katharina Luise Schneider, Marlen Schurig, Julia Carolin Stingl, Jürgen Brockmöller
Falls is a frequent type of adverse drug reactions causing significant morbidity and mortality in the elderly. We reviewed, with which drugs the risk of falls is relevant and might depend on genomic variation. Pharmacogenetic variability may contribute to drug-induced falls for instance mediated by impaired drug elimination due to inherited deficiency in enzymes like CYP2C9, CYP2C19 and CYP2D6. The relative role of specific genes and polymorphisms in old age may differ from younger people. Biomarkers for frailty, but also genomic biomarkers might help identifying patients at high risk for drug-induced falls...
August 4, 2017: Pharmacogenomics
https://www.readbyqxmd.com/read/28774812/cytochrome-p450-inhibition-by-three-licorice-species-and-fourteen-licorice-constituents
#8
Guannan Li, Charlotte Simmler, Luying Chen, Dejan Nikolic, Shao-Nong Chen, Guido F Pauli, Richard B van Breemen
The potential of licorice dietary supplements to interact with drug metabolism was evaluated by testing extracts of three botanically identified licorice species (Glycyrrhiza glabra L., Glycyrrhiza uralensis Fish. ex DC. and Glycyrrhiza inflata Batalin) and 14 isolated licorice compounds for inhibition of 9 cytochrome P450 enzymes using a UHPLC-MS/MS cocktail assay. G. glabra showed moderate inhibitory effects against CYP2B6, CYP2C8, CYP2C9, and CYP2C19, and weak inhibition against CYP3A4 (testosterone). In contrast, G...
July 31, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28762043/customised-in-vitro-model-to-detect-human-metabolism-dependent-idiosyncratic-drug-induced-liver-injury
#9
Laia Tolosa, Nuria Jiménez, Gabriela Pérez, José V Castell, M José Gómez-Lechón, M Teresa Donato
Drug-induced liver injury (DILI) has a considerable impact on human health and is a major challenge in drug safety assessments. DILI is a frequent cause of liver injury and a leading reason for post-approval drug regulatory actions. Considerable variations in the expression levels of both cytochrome P450 (CYP) and conjugating enzymes have been described in humans, which could be responsible for increased susceptibility to DILI in some individuals. We herein explored the feasibility of the combined use of HepG2 cells co-transduced with multiple adenoviruses that encode drug-metabolising enzymes, and a high-content screening assay to evaluate metabolism-dependent drug toxicity and to identify metabolic phenotypes with increased susceptibility to DILI...
July 31, 2017: Archives of Toxicology
https://www.readbyqxmd.com/read/28758225/metabolism-of-7-ethoxycoumarin-flavanone-and-steroids-by-cytochrome-p450-2c9-variants
#10
Tomohide Uno, Ryosuke Nakano, Kengo Kanamaru, Shinji Takenaka, Yuichi Uno, Hiromasa Imaishi
CYP2C9 is a human microsomal cytochrome P450c (CYP). Much variation in CYP2C9 levels and activity can be attributed to polymorphisms of this gene. Wild-type CYP2C9 and mutants were coexpressed with NADPH-cytochrome P450 reductase in Escherichia coli. The hydroxylase activities toward 7-ethoxycoumarin, flavanone and steroids were examined. Six CYP2C9 variants showed Soret peaks (450 nm) typical of P450 in reduced CO-difference spectra. CYP2C9.38 had the highest 7-ethoxycoumarin de-ethylase activity. All the CYP2C9 variants showed lower flavanone 6-hydroxylation activities than CYP2C9...
July 30, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28752932/development-of-genotyping-method-for-functionally-relevant-variants-of-cytochromes-p450-in-cynomolgus-macaques
#11
Y Uno, N Osada, S Sakurai, N Shimozawa, T Iwata, K Ikeo, H Yamazaki
In cynomolgus macaques (Macaca fascicularis), widely used in drug metabolism studies, CYP2C9, CYP2C76, CYP2D6, CYP3A4, and CYP3A5, important drug-metabolizing enzymes, are abundantly expressed in liver and metabolize cytochrome P450 substrates. CYP2C9 (c.334A>C), CYP2C76 (c.449TG>A), CYP2D6 (c.891A>G), CYP3A4 (IVS3 + 1G>del), and CYP3A5 (c.625A>T) substantially influence metabolic activity of enzymes, and thus are important variants in drug metabolism studies. In this study, a real-time PCR method was developed for genotyping these variants...
July 28, 2017: Journal of Veterinary Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28748348/impact-of-genetic-polymorphisms-on-phenytoin-pharmacokinetics-and-clinical-outcomes-in-the-middle-east-and-north-africa-region
#12
REVIEW
Renée Dagenais, Kyle John Wilby, Hazem Elewa, Mary H H Ensom
BACKGROUND: Genetic polymorphisms are known to influence outcomes with phenytoin yet effects in the Middle East and North Africa region are poorly understood. OBJECTIVES: The objective of this systematic review was to evaluate the impact of genetic polymorphisms on phenytoin pharmacokinetics and clinical outcomes in populations originating from the Middle East and North Africa region, and to characterize genotypic and allelic frequencies within the region for genetic polymorphisms assessed...
July 26, 2017: Drugs in R&D
https://www.readbyqxmd.com/read/28744217/the-association-of-combined-gstm1-and-cyp2c9-genotype-status-with-the-occurrence-of-hemorrhagic-cystitis-in-pediatric-patients-receiving-myeloablative-conditioning-regimen-prior-to-allogeneic-hematopoietic-stem-cell-transplantation
#13
Chakradhara Rao S Uppugunduri, Flavia Storelli, Vid Mlakar, Patricia Huezo-Diaz Curtis, Aziz Rezgui, Yves Théorêt, Denis Marino, Fabienne Doffey-Lazeyras, Yves Chalandon, Peter Bader, Youssef Daali, Henrique Bittencourt, Maja Krajinovic, Marc Ansari
Hemorrhagic cystitis (HC) is one of the complications of busulfan-cyclophosphamide (BU-CY) conditioning regimen during allogeneic hematopoietic stem cell transplantation (HSCT) in children. Identifying children at high risk of developing HC in a HSCT setting could facilitate the evaluation and implementation of effective prophylactic measures. In this retrospective analysis genotyping of selected candidate gene variants was performed in 72 children and plasma Sulfolane (Su, water soluble metabolite of BU) levels were measured in 39 children following treatment with BU-CY regimen...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28740425/efficacy-of-piroxicam-for-postoperative-pain-after-lower-third-molar-surgery-associated-with-cyp2c8-3-and-cyp2c9
#14
Adriana Maria Calvo, Paulo Zupelari-Gonçalves, Thiago José Dionísio, Daniel Thomas Brozoski, Flávio Augusto Faria, Carlos Ferreira Santos
OBJECTIVE: Nonsteroidal anti-inflammatory drugs (NSAIDs) are metabolized by the cytochrome P450 enzymes (CYPs), predominantly CYP2C8 and CYP2C9. The aim of this study was to evaluate the possible association of polymorphisms in the CYP2C8*3 and CYP2C9 genes with the clinical efficacy of oral piroxicam (20 mg daily for 4 days) after lower third molar surgeries with regard to postoperative pain, swelling, trismus, adverse reactions, need for rescue medication and the volunteer's overall satisfaction...
2017: Journal of Pain Research
https://www.readbyqxmd.com/read/28737453/the-metabolism-and-drug-drug-interaction-potential-of-the-selective-prostacyclin-receptor-agonist-selexipag
#15
Carmela Gnerre, Jérôme Segrestaa, Swen Seeland, Päivi Äänismaa, Thomas Pfeifer, Stephane Delahaye, Ruben de Kanter, Tomohiko Ichikawa, Tetsuhiro Yamada, Alexander Treiber
- The metabolism of selexipag has been studied in vivo in man and the main excreted metabolites were identified. Also, metabolites circulating in human plasma have been structurally identified and quantified. - The main metabolic pathway of selexipag in man is the formation of the active metabolite ACT-333679. Other metabolic pathways include oxidation and dealkylation reactions. All primary metabolites undergo subsequent hydrolysis of the sulphonamide moiety to their corresponding acids. ACT-333679 undergoes conjugation with glucuronic acid and aromatic hydroxylation to P10, the main metabolite detected in human faeces...
July 24, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28730856/in-vitro-drug-drug-interactions-of-budesonide-inhibition-and-induction-of-transporters-and-cytochrome-p450-enzymes
#16
Nancy Chen, Donghui Cui, Qing Wang, Zhiming Wen, Richard D Finkelman, Devin Welty
1. Budesonide is a glucocorticoid used in the treatment of several respiratory and gastrointestinal inflammatory diseases. Glucocorticoids have been demonstrated to induce cytochrome P450 (CYP) 3A and the efflux transporter P-glycoprotein (P-gp). This study aimed to evaluate the potential of budesonide to act as a perpetrator or a victim of transporter- or CYP-mediated drug-drug interactions (DDIs). 2. In vitro studies were conducted for P-gp, breast cancer resistance protein and organic anion and cation transporters (OATP1B1, OATP1B3, OAT1, OAT3, OCT2) in transporter-transfected cells...
July 21, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28723731/the-combined-effect-of-cyp2b6-genotype-and-other-candidate-genes-on-a-steady-state-serum-concentration-of-methadone-in-opioid-maintenance-treatment
#17
Marianne K Kringen, Fatemeh Chalabianloo, Jean-Paul Bernard, Jørgen G Bramness, Espen Molden, Gudrun Høiseth
BACKGROUND: A considerable inter-individual variability in methadone pharmacokinetics is seen in patients on methadone maintenance treatment. The aim of this study was to clarify the impact of the reduced function CYP2B6*6 variant allele together with variants in other candidate genes on a steady-state methadone concentration in a naturalistic setting. METHODS: Information of methadone serum concentration, dose, age, gender and CYP2C9, CYP2C19, and CYP2D6 genotypes were collected from a routine therapeutic drug monitoring (TDM) database while variant alleles in CYP2B6 and CYP3A5 were retrospectively genotyped...
July 18, 2017: Therapeutic Drug Monitoring
https://www.readbyqxmd.com/read/28693194/combination-of-lenalidomide-and-low-dose-dexamethasone-therapy-promotes-the-anticoagulant-activity-of-warfarin-in-patients-with-immunoglobulin-light-chain-amyloidosis
#18
Fumiaki Kitazawa, Shin-Ichi Fuchida, Fumitaka Ise, Yoko Kado, Kumi Ueda, Takatoshi Kokufu, Akira Okano, Mayumi Hatsuse, Satoshi Murakami, Yuko Nakayama, Kohji Takara, Chihiro Shimazaki
The present study aimed to evaluate the drug interactions between warfarin and combination chemotherapy with lenalidomide and low-dose dexamethasone in immunoglobulin light-chain (AL) amyloidosis patients with unstable international normalized ratios (INR). The changes to INR values over time in 3 AL amyloidosis patients treated with warfarin and a combination of lenalidomide and low-dose dexamethasone between March 2011 and February 2015 were analyzed retrospectively. The mean INR value was 1.52 prior to the combination chemotherapy, and the value increased 1...
July 2017: Oncology Letters
https://www.readbyqxmd.com/read/28689179/genetics-and-clinical-response-to-warfarin-and-edoxaban-in-patients-with-venous-thromboembolism
#19
Alexander G Vandell, Joseph Walker, Karen S Brown, George Zhang, Min Lin, Michael A Grosso, Michele F Mercuri
OBJECTIVE: The aim of this study was to investigate whether genetic variants can identify patients with venous thromboembolism (VTE) at an increased risk of bleeding with warfarin. METHODS: Hokusai-venous thromboembolism (Hokusai VTE), a randomised, multinational, double-blind, non-inferiority trial, evaluated the safety and efficacy of edoxaban versus warfarin in patients with VTE initially treated with heparin. In this subanalysis of Hokusai VTE, patients genotyped for variants in CYP2C9 and VKORC1 genes were divided into three warfarin sensitivity types (normal, sensitive and highly sensitive) based on their genotypes...
July 8, 2017: Heart: Official Journal of the British Cardiac Society
https://www.readbyqxmd.com/read/28687336/polymorphisms-of-cyp2c8-cyp2c9-and-cyp2c19-and-risk-of-coronary-heart-disease-in-russian-population
#20
Alexey Polonikov, Alexander Kharchenko, Marina Bykanova, Svetlana Sirotina, Irina Ponomarenko, Anna Bocharova, Kseniya Vagaytseva, Vadim Stepanov, Olga Bushueva, Mikhail Churnosov, Maria Solodilova
Epoxyeicosatrienoic acids (EETs) are important vasoactive products of arachidonic acid metabolism with a wide range of biological actions in the cardiovascular system. The present study investigated whether single nucleotide polymorphisms (SNP) of genes coding cytochrome P450 2C subfamily, enzymes involved in biosynthesis of EETs, are associated with the risk of coronary heart disease (CHD). A total of 1255 unrelated Russian subjects comprising 561 patients with angiographically diagnosed CHD and 694 age- and sex-matched healthy subjects were included in the study...
July 4, 2017: Gene
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