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CYP2C9

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https://www.readbyqxmd.com/read/29218998/vkorc1-1639a-allele-influences-warfarin-maintenance-dosage-among-blacks-receiving-warfarin-anticoagulation-a-retrospective-cohort-study
#1
Fatima Donia Mili, Tenecia Allen, Paula Weinstein Wadell, W Craig Hooper, Christine De Staercke, Christopher J Bean, Cathy Lally, Harland Austin, Nanette K Wenger
AIM: The study objectives were to investigate the association between selected CYP2C9 and VKORC1 single nucleotide polymorphisms with serious bleeding or thrombotic risk, and to estimate mean daily maintenance dose of warfarin and international normalized ratio measurements among Blacks receiving warfarin anticoagulation. METHODS: We conducted a retrospective cohort study among 230 Black adults receiving warfarin for a minimum of three consecutive months with a confirmed date of first dosage...
December 8, 2017: Future Cardiology
https://www.readbyqxmd.com/read/29205295/protein-abundance-of-clinically-relevant-drug-metabolizing-enzymes-in-the-human-liver-and-intestine-a-comparative-analysis-in-paired-tissue-specimens
#2
M Drozdzik, D Busch, J Lapczuk, J Müller, M Ostrowski, M Kurzawski, S Oswald
The work revises and complements existing findings on the distribution of drug metabolizing enzymes' in the first-pass effect organs. We explored gene expression (qPCR) and protein abundance (LC-MS/MS) of CYP1A2, CYP2B6, CYP2C8/9/19, CYP2D6, CYP2E1, CYP3A4/5, UGT1A1/3, UGT2B7/15 in the liver, duodenum, jejunum, ileum and colon in paired tissues from 9 organ donors. All proteins were detected in the liver, but in the intestine CYP2C9/19, CYP2D6, CYP3A4/5, UGT1A1/3 and UGT2B7 were found. CYP3A4 showed comparable abundance in the liver and jejunum, whereas other enzymes were markedly higher in the hepatic tissue...
December 5, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29182754/pharmacogenetics-based-warfarin-dosing-in-patients-with-cardiac-valve-replacement-the-effects-of-cyp2c9-and-vkorc1-gene-polymorphisms
#3
Negin Farzamikia, Ebrahim Sakhinia, Abbas Afrasiabirad
Many lines of evidence suggest that warfarin dosing variability is significantly associated with cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) variant alleles. Therefore, we investigated the influence of CYP2C9*2 (430C/T), *3 (1075A/C) and VKORC1 (-1639G/A) polymorphisms on warfarin dose requirements in patients who underwent cardiac valve surgery during the postoperative period.A total of 100 patients with heart valve replacement who had a prescribed target international normalized ratio (INR) range of 2-3 were enrolled in the study...
November 22, 2017: Laboratory Medicine
https://www.readbyqxmd.com/read/29181698/pharmacokinetics-of-cyp2c9-cyp2c19-and-cyp2d6-substrates-in-healthy-chinese-and-european-subjects
#4
Sijie Lu, R A Nand, J S Yang, Gang Chen, A S Gross
PURPOSE: The aim of this analysis is to compare the pharmacokinetics of drug substrates in healthy Chinese and European subjects of aligned CYP2C9, CYP2C19, or CYP2D6 enzyme activity, providing further insight into drivers of interethnic differences in pharmacokinetics. METHODS: Following identification of appropriate drug substrates, a comprehensive and structured literature search was conducted to identify single-dose pharmacokinetic data in healthy Chinese or European subjects with reported CYP2C9, CYP2C19, or CYP2D6 activity (genotype or phenotype)...
November 27, 2017: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29181084/clinical-pharmacogenomics-patient-perspectives-of-pharmacogenomic-testing-and-the-incidence-of-actionable-test-results-in-a-chronic-disease-cohort
#5
Chandrama Mukherjee, Kevin M Sweet, Jasmine A Luzum, Mahmoud Abdel-Rasoul, Michael F Christman, Joseph P Kitzmiller
Aim: This study aimed to examine pharmacogenomic test results and patient perspectives at an academic cardiovascular medicine clinic. Patients & methods: Test results for three common cardiovascular drug-gene tests (warfarin-CYP2C9-VKORC1, clopidogrel-CYP2C19 and simvastatin-SLCO1B1) of 208 patients in the Ohio State University-Coriell Personalized Medicine Collaborative were examined to determine the incidence of potentially actionable test results. A post-hoc, anonymous, patient survey was also conducted...
September 2017: Personalized Medicine
https://www.readbyqxmd.com/read/29176011/estimation-of-fractions-metabolized-by-hepatic-cyp-enzymes-using-a-concept-of-inter-system-extrapolation-factors-isefs-a-comparison-with-the-chemical-inhibition-method
#6
Ken-Ichi Umehara, Felix Huth, Helen Gu, Hilmar Schiller, Tycho Heimbach, Handan He
BACKGROUND: For estimation of fractions metabolized (fm) by different hepatic recombinant human CYP enzymes (rhCYP), calculation of inter-system extrapolation factors (ISEFs) has been proposed. METHODS: ISEF values for CYP1A2, CYP2C19 and CYP3A4/5 were measured. A CYP2C9 ISEF was taken from a previous report. Using a set of compounds, fractions metabolized by CYP enzymes (fm,CYP) values calculated with the ISEFs based on rhCYP data were compared with those from the chemical inhibition data...
November 27, 2017: Drug Metabolism and Personalized Therapy
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
#7
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/29168292/evaluation-of-the-effect-of-quercetin-treatment-on-cyp2c9-enzyme-activity-of-diclofenac-in-healthy-human-volunteers
#8
Satish Kumar Bedada, Prasad Neerati
The purpose of present study was to evaluate the effect of quercetin on pharmacokinetics of diclofenac sodium (DIC) in healthy volunteers. The open-label, 2 period, sequential study was conducted in 12 healthy volunteers. DIC 100 mg was administered during control and after quercetin phases. Quercetin 500 mg was administered twice daily for 10 days during quercetin phase. Treatment with quercetin significantly enhanced maximum plasma concentration (Cmax ), area under the curve (AUC0-∞ ), and half life, while significantly decreased elimination rate constant (kel ) and apparent oral clearance (CL/F) of DIC compared with control...
November 23, 2017: Phytotherapy Research: PTR
https://www.readbyqxmd.com/read/29156869/impact-of-ggcx-polymorphisms-on-warfarin-dose-requirements-in-atrial-fibrillation-patients
#9
Nian-Xin Jiang, Ying-Hui Xu, Jing-Wen Xia, Bing Jiang, Yan-Song Li
Background/aim: Warfarin is a common anticoagulant with large interindividual differences and a narrow therapeutic range. The polymorphisms of gamma-glutamyl carboxylase (GGCX) are important genetic factors for warfarin dose requirements. Materials and methods: Polymerase chain reaction and direct sequencing methods were used to detect the GGCX rs699664 genotype in 215 atrial fibrillation (AF) patients with warfarin administration. The effects on warfarin dose by different genotypes were analyzed. A warfarin dosing algorithm was developed based on age, height, CYP2C9, VKORC1, and GGCX genotype...
August 23, 2017: Turkish Journal of Medical Sciences
https://www.readbyqxmd.com/read/29148818/dissociation-constants-of-cytochrome-p450-2c9-cytochrome-p450-reductase-complexes-in-a-lipid-bilayer-membrane-depend-on-nadph-a-single-protein-tracking-study
#10
Carlo Barnaba, Evan Taylor, James A Brozik
Cytochrome P450-Reductase (CPR) is a versatile NADPH-dependent electron donor located in the cytoplasmic side of the endoplasmic reticulum. It is an electron transferase that is able to deliver electrons to a variety of membrane-bound oxidative partners, including the drug-metabolizing enzymes of the cytochrome P450s (P450). CPR is also stoichiometrically limited compared to its oxidative counterparts and hypotheses have arisen about possible models that can overcome the stochiometric imbalance, including quaternary organization of P450 and diffusion-limited models...
November 17, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29137842/comparison-of-pharmacokinetics-of-newly-discovered-aromatase-inhibitors-by-a-cassette-microdosing-approach-in-healthy-japanese-subjects
#11
Hiroyuki Kusuhara, Tadayuki Takashima, Hisako Fujii, Tsutomu Takashima, Masaaki Tanaka, Akira Ishii, Shusaku Tazawa, Kazuhiro Takahashi, Kayo Takahashi, Hidekichi Tokai, Tsuneo Yano, Makoto Kataoka, Akihiro Inano, Suguru Yoshida, Takamitsu Hosoya, Yuichi Sugiyama, Shinji Yamashita, Taisuke Hojo, Yasuyoshi Watanabe
The aim of the present study is to investigate the pharmacokinetics of our newly developed aromatase inhibitors (cetrozole and TMD-322) in healthy subjects by a cassette microdose strategy. A cocktail of cetrozole and TMD-322 was administered intravenously or orally (1.98 μg for each drug) to six healthy volunteers in a crossover fashion. Anastrozole (1.98 μg) was also included in the oral cocktail. Total body clearance and bioavailability were 12.1 ± 7.1 mL/min/kg and 34.9 ± 32.3% for cetrozole, and 16...
September 21, 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29136336/effect-of-polymorphisms-on-the-pharmacokinetics-pharmacodynamics-and-safety-of-sertraline-in-healthy-volunteers
#12
Miriam Saiz-Rodríguez, Carmen Belmonte, Manuel Román, Dolores Ochoa, Dora Koller, María Talegón, María C Ovejero-Benito, Rosario López-Rodríguez, Teresa Cabaleiro, Francisco Abad-Santos
Sertraline is a selective serotonin reuptake inhibitor (SSRI) widely metabolized in the liver by cytochrome P450 (CYP) enzymes. Besides, it is a P-glycoprotein substrate. Moreover, serotonin transporters and serotonin receptors are involved in its efficacy and safety. The aim of the present study was to evaluate the role of polymorphisms of metabolizing enzymes, transporters and receptors on the pharmacokinetics, pharmacodynamics and tolerability of sertraline in healthy volunteers. Forty-six healthy volunteers (24 men and 22 women) receiving a 100-mg single oral dose of sertraline were genotyped for 17 genetic variants of CYP enzymes (CYP2B6, CYP2C9, CYP2C19, CYP2D6), ATP binding cassette subfamily B member 1 (ABCB1), Solute carrier family 6 member 4 (SLC6A4), 5-Hydroxytryptamine receptor 2A (HTR2A) and 5-Hydroxytryptamine receptor 2C (HTR2C) genes...
November 14, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29119932/relevance-of-cyp2c9-function-in-valproate-therapy
#13
Katalin Monostory, Andrea Nagy, Katalin Toth, Tamas Budi, Adam Kiss, Mate Deri, Gabor Csukly
Genetic polymorphisms of drug metabolizing enzymes can substantially modify the pharmacokinetics of a drug and eventually its efficacy or toxicity; however, inferring a patient's drug metabolizing capacity merely from his or her genotype can lead to false prediction. Non-genetic host factors (age, sex, disease states) and environmental factors (nutrition, co-medication) can transiently alter the enzyme expression and activities resulting in genotype-phenotype mismatch. Although valproic acid is a well-tolerated anticonvulsant, pediatric patients are particularly vulnerable to valproate injury that can be partly attributed to the age-related differences in metabolic pathways...
November 9, 2017: Current Neuropharmacology
https://www.readbyqxmd.com/read/29119333/physiologically-based-pharmacokinetic-modelling-of-cytochrome-p450%C3%A2-2c9-related-tolbutamide-drug-interactions-with-sulfaphenazole-and-tasisulam
#14
Everett J Perkins, Maria Posada, P Kellie Turner, Jill Chappell, Wee Teck Ng, Chris Twelves
BACKGROUND AND OBJECTIVES: Cytochrome P450 2C9 (CYP2C9) is involved in the biotransformation of many commonly used drugs, and significant drug interactions have been reported for CYP2C9 substrates. Previously published physiologically based pharmacokinetic (PBPK) models of tolbutamide are based on an assumption that its metabolic clearance is exclusively through CYP2C9; however, many studies indicate that CYP2C9 metabolism is only responsible for 80-90% of the total clearance. Therefore, these models are not useful for predicting the magnitude of CYP2C9 drug-drug interactions (DDIs)...
November 8, 2017: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29105855/dicloxacillin-induces-cyp2c19-cyp2c9-and-cyp3a4-in-vivo-and-in-vitro
#15
Tore Bjerregaard Stage, Magnus Graff, Susan Wong, Louise Ladebo Rasmussen, Flemming Nielsen, Anton Pottegård, Kim Brøsen, Deanna L Kroetz, S Cyrus Khojasteh, Per Damkier
AIM: The aim of this study was to study potential cytochrome P450 induction by dicloxacillin. METHODS: We performed an open-label randomized two-phase 5-drug clinical pharmacokinetic cocktail crossover study in 12 healthy men with and without pretreatment with 1g dicloxacillin three times daily for 10 days. Plasma and urine was collected over 24 hours and the concentration of all five drugs and their primary metabolites was determined using a LC-MS/MS method. Cryopreserved primary human hepatocytes were exposed to dicloxacillin for 48h and changes in gene expression and enzyme activity of CYP3A4, CYP2C9, CYP2B6 and CYP1A2 was investigated...
November 4, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29100760/comparative-study-on-the-interaction-between-3-cyp2c9-allelic-isoforms-and-benzbromarone-by-using-lc-ms-ms-method
#16
Lingli He, Chuan Li, Xuyuan Liu, Qingqing Yang, Haizhi Zhang, Weiren Xu, Luyong Zhang, Changxiao Liu
Benzbromarone is a uricosuric drug metabolized predominantly by cytochrome P450 2C9 from in vitro findings. Human CYP2C9 exhibits extensive genetic polymorphism and numbers of clinic studies have demonstrated that CYP2C9 genetic polymorphism has a significant influence on the pharmacokinetics of benzbromarone. But in vitro study on the interaction between CYP2C9 allelic isoforms and benzbromarone was rare. Here, an LC-MS/MS method was established and validated to determine the concentration of benzbromarone in different CYP2C9 enzyme incubation systems for the drug-enzyme interaction study...
October 31, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/29099769/influence-of-amlodipine-enantiomers-on-human-microsomal-cytochromes-p450-stereoselective-time-dependent-inhibition-of-cyp3a-enzyme-activity
#17
Kristyna Krasulova, Ondrej Holas, Pavel Anzenbacher
Amlodipine (AML) is available as a racemate, i.e., a mixture of R- and S-enantiomers. Its inhibitory potency towards nine cytochromes P450 (CYP) was studied to evaluate the drug-drug interactions between the enantiomers. Enzyme inhibition was evaluated using specific CYP substrates in human liver microsomes. With CYP3A, both enantiomers exhibited reversible and time-dependent inhibition. S-AML was a stronger reversible inhibitor of midazolam hydroxylation: the Ki values of S- and R-AML were 8.95 µM, 14.85 µM, respectively...
November 3, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29081699/optimization-of-antidepressant-use-with-pharmacogenetic-strategies
#18
Clara Torrellas, Juan Carlos Carril, Ramón Cacabelos
BACKGROUND: The response rate in the pharmacological treatment of depression has been estimated to be around 50%, achieving a remission in symptomatology in only one third of the patients. Suboptimal prescription of antidepressants has been proposed as a significant explanatory factor for this therapeutic inefficacy. The use of pharmacogenetic testing might favor the optimization of pharmacotherapy in emotional disorders. However, its implementation in the clinical routine requires studies which prove its efficacy...
October 2017: Current Genomics
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
#19
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/29055218/cyp2c9-and-vkorc1-in-therapeutic-dosing-and-safety-of-acenocoumarol-treatment-implication-for-clinical-practice-in-hungary
#20
Reka Varnai, Csilla Sipeky, Lajos Nagy, Sandor Balogh, Bela Melegh
The purpose of this work was to investigate the contribution of CYP2C9 and VKORC1 to acenocoumarol (AC) dose variability, bleeding events in Hungary. The study recruited 117 patients on long-term AC therapy (INR 2-3), and 510 healthy individuals to model the findings. Patients were genotyped for alleles proved to affect lower AC overdose CYP2C9*2, CYP2C9*3, VKORC1*2. Additionally, we tested VKORC1*3, VKORC1*4 to examine their effect in patients with higher AC requirements. Most impact on dose reduction is accountable for CYP2C9*2/*3 (59%) and for VKORC1*2/*2 (45...
October 8, 2017: Environmental Toxicology and Pharmacology
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