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https://www.readbyqxmd.com/read/29031061/crassiflorone-derivatives-that-inhibit-trypanosoma-brucei-glyceraldehyde-3-phosphate-dehydrogenase-tbgapdh-and-trypanosoma-cruzi-trypanothione-reductase-tctr-and-display-trypanocidal-activity
#1
Elisa Uliassi, Giulia Fiorani, R Luise Krauth-Siegel, Christian Bergamini, Romana Fato, Giulia Bianchini, J Carlos Menéndez, Maria Teresa Molina, Eulogio López-Montero, Federico Falchi, Andrea Cavalli, Sheraz Gul, Maria Kuzikov, Bernhard Ellinger, Gesa Witt, Carolina B Moraes, Lucio H Freitas-Junior, Chiara Borsari, Maria Paola Costi, Maria Laura Bolognesi
Crassiflorone is a natural product with anti-mycobacterial and anti-gonorrhoeal properties, isolated from the stem bark of the African ebony tree Diospyros crassiflora. We noticed that its pentacyclic core possesses structural resemblance to the quinone-coumarin hybrid 3, which we reported to exhibit a dual-targeted inhibitory profile towards Trypanosoma brucei glyceraldehyde-3-phosphate dehydrogenase (TbGAPDH) and Trypanosoma cruzi trypanothione reductase (TcTR). Following this basic idea, we synthesized a small library of crassiflorone derivatives 15-23 and investigated their potential as anti-trypanosomatid agents...
October 3, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29027194/predictive-performance-of-physiologically-based-pharmacokinetic-pbpk-modeling-of-drugs-extensively-metabolized-by-major-cytochrome-p450s-in-children
#2
Wangda Zhou, Trevor N Johnson, Khanh H Bui, S Y Amy Cheung, Jianguo Li, Hongmei Xu, Nidal Al-Huniti, Diansong Zhou
The accuracy of physiologically-based pharmacokinetic (PBPK) model prediction in children, especially those younger than 2 years old has not been systematically evaluated. The aim of this study was to characterize the pediatric predictive performance of the PBPK approach for ten drugs extensively metabolized by CYP1A2 (theophylline), CYP2C8 (desloratidine, montelukast), CYP2C9 (diclofenac), CYP2C19 (esomeprazole, lansoprazole), CYP2D6 (tramadol) and CYP3A4 (itraconazole, ondansetron, sufentanil). Model performance in children was evaluated by comparing simulated plasma concentration-time profiles with observed clinical results for each drug and age group...
October 13, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29024493/pharmacokinetics-and-pharmacodynamics-of-meloxicam-in-east-asian-populations-the-role-of-ethnicity-on-drug-response
#3
T Aoyama, Y Ishida, M Kaneko, A Miyamoto, Y Saito, M Tohkin, S Kawai, Y Matsumoto
We aimed to reanalyze the differences in the pharmacokinetics (PKs) of meloxicam in East Asian populations based on a population approach using previously published data and to investigate the factors found in population pharmacokinetic (PK) analysis that affect the pharmacodynamics (PDs) of meloxicam. Population PK analysis was performed in 119 healthy male subjects (30 Japanese, 30 Chinese, 29 Korean, and 30 Caucasian) under strictly controlled trial conditions with regulated meals and a single lot of the drug...
October 12, 2017: CPT: Pharmacometrics & Systems Pharmacology
https://www.readbyqxmd.com/read/29023392/disposition-metabolism-and-histone-deacetylase-and-acetyltransferase-inhibition-activity-of-tetrahydrocurcumin-and-other-curcuminoids
#4
Júlia T Novaes, Ryan Lillico, Casey L Sayre, Kalyanam Nagabushnam, Muhammed Majeed, Yufei Chen, Emmanuel A Ho, Ana Luísa de P Oliveira, Stephanie E Martinez, Samaa Alrushaid, Neal M Davies, Ted M Lakowski
Tetrahydrocurcumin (THC), curcumin and calebin-A are curcuminoids found in turmeric (Curcuma longa). Curcuminoids have been established to have a variety of pharmacological activities and are used as natural health supplements. The purpose of this study was to identify the metabolism, excretion, antioxidant, anti-inflammatory and anticancer properties of these curcuminoids and to determine disposition of THC in rats after oral administration. We developed a UHPLC-MS/MS assay for THC in rat serum and urine. THC shows multiple redistribution phases with corresponding increases in urinary excretion rate...
October 12, 2017: Pharmaceutics
https://www.readbyqxmd.com/read/29023140/genetic-polymorphisms-of-cytochrome-p450-enzymes-and-transport-proteins-in-a-russian-population-and-three-ethnic-groups-of-dagestan
#5
Karin B Mirzaev, Dmitry A Sychev, Kristina A Ryzhikova, Olga D Konova, Suleiman N Mammaev, Daniyal M Gafurov, Grigorij N Shuev, Elena A Grishina, Zhannet A Sozaeva
AIM: The objective of this study was to investigate the prevalence of polymorphic markers of the CYP2C19, CYP2C9, CYP2D6, SLCO1B1, and ABCB1 genes among the three ethnic groups in Dagestan and compare it with the carrier frequency of these markers among the Russian population living in Moscow. METHODS: The study involved 186 healthy, unrelated, and chronic medication-free volunteers (53 males and 133 females) of the three ethnic groups in the Dagestan Republic: 46 Laks, 90 Avars, and 50 Dargins...
October 12, 2017: Genetic Testing and Molecular Biomarkers
https://www.readbyqxmd.com/read/29022838/pharmacogenomics-of-triazole-antifungal-agents-implications-for-safety-tolerability-and-efficacy
#6
Jarrett R Amsden, Paul O Gubbins
Introduction Triazole antifungal agents are prescribed to treat invasive fungal infections in neutropenic and non-neutropenic patients. These antifungal agents are substrates and inhibitors of cytochrome P450 (CYP). Genetic polymorphisms in CYP2C9, CYP2C19 and CYP3A5 can lead to large population-specific variations in drug efficacy and safety, optimal dosing, or contribute to drug interactions associated with this class. Areas covered This manuscript reviews the pharmacogenomics (i.e. the influence of genetics on drug disposition) of triazole antifungal agents related to their CYP-mediated metabolism and summarizes their implications on triazole efficacy, safety, and tolerability...
October 12, 2017: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/28992765/phenotyping-of-cyp-4501a2-activity-by-total-overnight-salivary-caffeine-assessment-tosca-in-patients-on-warfarin-treatment-a-cross-sectional-study
#7
Giovanni Tarantino, Domenico Capone, Paola Contaldi, Adriana Gianno, Mosca Teresa, Antonella Tufano
Warfarin is an oral anticoagulant, commonly used for primary and secondary prevention of venous and arterial thromboembolic events. The drug is characterized by narrow therapeutic index, widespread individual variability in clinical response, and high rates of adverse events, particularly bleeding complications. For these reasons, a close monitoring of the dosage, using the frequent assessment of coagulation status by means of International Normalized Ratio value, is mandatory. Warfarin is metabolized by hepatic cytochrome P-450...
January 1, 2017: Clinical and Applied Thrombosis/hemostasis
https://www.readbyqxmd.com/read/28990182/effect-of-chronic-kidney-disease-on-nonrenal-elimination-pathways-a-systematic-assessment-of-cyp1a2-cyp2c8-cyp2c9-cyp2c19-and-oatp
#8
Ming-Liang Tan, Kenta Yoshida, Ping Zhao, Lei Zhang, Thomas D Nolin, Micheline Piquette-Miller, Aleksandra Galetin, Shiew-Mei Huang
Our recent studies have shown that chronic kidney disease (CKD) affects the pharmacokinetics (PKs) of cytochrome P450 (CYP)2D6-metabolized drugs, whereas effects were less evident on CYP3A4/5. Therefore, the effect of CKD on the disposition of CYP1A2-metabolized, CYP2C8-metabolized, CYP2C9-metabolized, CYP2C19-metabolized, and organic anion-transporting polypeptide (OATP)-transported drugs was investigated. We identified dedicated CKD studies with 6, 5, 6, 4, and 12 "model" substrates for CYP1A2, CYP2C8, CYP2C9, CYP2C19, and OATP, respectively...
October 9, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28986475/pediatric-cytochrome-p450-activity-alterations-in-nonalcoholic-steatohepatitis
#9
Hui Li, Canet J Mark, John D Clarke, Dean Billheimer, Stavra A Xanthakos, Joel E Lavine, Robert P Erickson, Nathan J Cherrington
Variable drug responses(VDRs) are dependent upon individual variation in the activity of drug-metabolizing enzymes including cytochrome P450s(CYPs). As the most common chronic liver disease in children and adults, nonalcoholic steatohepatitis(NASH) has been identified as a source of significant inter-individual variation in hepatic drug metabolism. Compared to adults, children present age-related differences in pharmacokinetics and pharmacodynamics. The purpose of this study was to determine the impact of fatty liver disease severity on the activity of a variety of CYPs in children and adolescents...
October 6, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28976882/genetic-polymorphisms-of-cyp2c9-cyp2c19-and-cyp3a5-in-kosovar-population
#10
Valon Krasniqi, Aleksandar Dimovski, Hasime Qorraj Bytyqi, Aleksandar Eftimov, Livija Šimičević, Nada Božina
Cytochrome P450 genetic polymorphisms are responsible for individual variations in drug metabolism and drug-drug interactions. They are very important for pharmacogenetics, and their frequency varies across different populations. There is a big gap in the knowledge about the CYP gene family polymorphisms in the population of Kosovo, and the aim of our study was to fill that gap by determining the frequency of the most important variant alleles of CYP2C9, CYP2C19, and CYP3A5 in 234 nonrelated Kosovars. The allele frequencies of CYP2C9*2 and 2C9*3 were 17...
September 26, 2017: Arhiv za Higijenu Rada i Toksikologiju
https://www.readbyqxmd.com/read/28976264/epistatic-interactions-among-cyp2c19-2-cyp3a4-and-gstp1-on-the-cyclophosphamide-therapy-in-lupus-nephritis-patients
#11
Konda Kumaraswami, Shiva Krishna Katkam, Amita Aggarwal, Aman Sharma, Ramesh Manthri, Vijay Kumar Kutala, Liza Rajasekhar
AIM: To investigate the impact of genetic variants in CYP2C9, CYP2C19, CYP3A4, GSTT1, GSTM1 and GSTP1 on the efficacy of cyclophosphamide (CYC) therapy in patients with lupus nephritis. MATERIALS & METHODS: Lupus nephritis patients (n = 220) treated with CYC were included in the study. RESULTS: Logistic regression analysis identified CYP2C19*2 as an independent predictor of CYC therapeutic failure (odds ratio [OR]: 2.69; p = 0.0043). Bivariate and trivariate analysis showed the subjects harboring CYP2C19*2 and GSTP1 (OR: 3...
October 4, 2017: Pharmacogenomics
https://www.readbyqxmd.com/read/28973620/effect-of-genotype-guided-warfarin-dosing-on-clinical-events-and-anticoagulation-control-among-patients-undergoing-hip-or-knee-arthroplasty-the-gift-randomized-clinical-trial
#12
Brian F Gage, Anne R Bass, Hannah Lin, Scott C Woller, Scott M Stevens, Noor Al-Hammadi, Juan Li, Tomás Rodríguez, J Philip Miller, Gwendolyn A McMillin, Robert C Pendleton, Amir K Jaffer, Cristi R King, Brandi DeVore Whipple, Rhonda Porche-Sorbet, Lynnae Napoli, Kerri Merritt, Anna M Thompson, Gina Hyun, Jeffrey L Anderson, Wesley Hollomon, Robert L Barrack, Ryan M Nunley, Gerard Moskowitz, Victor Dávila-Román, Charles S Eby
Importance: Warfarin use accounts for more medication-related emergency department visits among older patients than any other drug. Whether genotype-guided warfarin dosing can prevent these adverse events is unknown. Objective: To determine whether genotype-guided dosing improves the safety of warfarin initiation. Design, Setting, and Patients: The randomized clinical Genetic Informatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis included patients aged 65 years or older initiating warfarin for elective hip or knee arthroplasty and was conducted at 6 US medical centers...
September 26, 2017: JAMA: the Journal of the American Medical Association
https://www.readbyqxmd.com/read/28972767/structural-basis-of-single-nucleotide-polymorphisms-in-cytochrome-p450-2c9
#13
Keiko Maekawa, Motoyasu Adachi, Yumiko Matsuzawa, Qinghai Zhang, Ryota Kuroki, Yoshiro Saito, Manish B Shah
Single-nucleotide polymorphisms in drug-metabolizing cytochrome P450 (CYP) enzymes are important contributors to interindividual differences in drug metabolism leading to adverse drug reactions. Despite their extensive characterization and importance in pharmacogenetics of clinical drugs, the structural basis of CYP polymorphisms has remained scant. Here we report the crystal structures of human CYP2C9 and its polymorphic variants, *3 (I359L) and *30 (A477T), with an antihypertensive drug losartan. The structures show distinct interaction and occupation of losartan in the active site, the access channel, and the peripheral binding site...
October 3, 2017: Biochemistry
https://www.readbyqxmd.com/read/28971704/genetic-variability-of-cyp2d6-cyp2b6-cyp2c9-and-cyp2c19-genes-across-the-italian-peninsula
#14
Francesco Carano, Stefania Sarno, Sara De Fanti, Patrizia Serventi, Carla Bini, Donata Luiselli, Susi Pelotti
BACKGROUND: Environmental conditions and past migratory events may have shaped genetic heterogeneity of clinically relevant enzymes involved in the phase I metabolism of the most common therapeutic drugs. AIM: To investigate the genetic variability of CYP2D6, CYP2B6, CYP2C19 and CYP2C9 across the Italian Peninsula, by sampling only ancestrally and geographically homogeneous individuals from northern, central and southern Italy. SUBJECTS AND METHODS: A total of 25 SNPs were genotyped in 174 unrelated Italian individuals by means of multiplex PCR and minisequencing reactions...
October 3, 2017: Annals of Human Biology
https://www.readbyqxmd.com/read/28962866/in-vitro-metabolism-of-4-5-dimethoxycanthin-6-one-by-human-liver-microsomes-and-its-inhibition-on-human-cyp1a2
#15
Xiaolei Miao, Jiaojiao You, Junjun Wang, Yong Chen
AIMS: P. quassioides is a traditional Chinese medicine used for the treatment of gastroenteritis, snakebite, infection and hypertension in China. 4, 5-dimethoxycanthin-6-one is one of the main active canthinone alkaloid isolated from P. quassioides. The aim of this work was to identify the cytochrome P (CYP) 450 enzymes responsible for the metabolism of 4, 5-dimethoxycanthin-6-one (DCO) and to evaluate the inhibitory effect of DCO on CYP activity in human liver microsomes (HLM) in vitro...
September 26, 2017: Life Sciences
https://www.readbyqxmd.com/read/28960401/prediction-of-drug-drug-interactions-using-physiologically-based-pharmacokinetic-models-of-cyp450-modulators-included-in-simcyp-software
#16
Niloufar Marsousi, Jules A Desmeules, Serge Rudaz, Youssef Daali
In recent years, Physiologically-Based PharmacoKinetic (PBPK) modeling has received growing interest as a useful tool for assessment of drug PK. It has demonstrated to be informative and helpful to quantify the modification in drug exposure due to specific physio-pathological conditions, age, genetic polymorphisms, ethnicity and particularly drug-drug interactions (DDIs). In this paper, the prediction success of DDIs involving various cytochrome P450 isoenzyme (CYP) modulators namely ketoconazole (a competitive inhibitor of CYP3A), itraconazole (a competitive inhibitor of CYP3A), clarithromycin (a mechanism-based inhibitor of CYP3A), quinidine (a competitive inhibitor of CYP2D6), paroxetine (a mechanism-based inhibitor of CYP2D6), ciprofloxacin (a competitive inhibitor of CYP1A2), fluconazole (a competitive inhibitor of CYP2C9/2C19) and rifampicin (an inducer of CYP3A) were assessed using Simcyp® software...
September 28, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28960344/inhibition-of-human-cytochromes-p450-in%C3%A2-vitro-by-ritonavir-and-cobicistat
#17
Md Amin Hossain, Timothy Tran, Tianmeng Chen, Gerd Mikus, David J Greenblatt
OBJECTIVES: Ritonavir and cobicistat are strong inhibitors of human cytochrome P450-3A (CYP3A) isoforms, and are used clinically as pharmacokinetic boosting agents for other antiretroviral drugs. Data reported by the manufacturer suggest that cobicistat is a more selective inhibitor of CYP3A than ritonavir. However, this claim has not been validated in clinical studies. This study evaluated the in-vitro inhibitory potency of ritonavir and cobicistat vs a series of human CYP isoforms. METHOD: The model system utilized human liver microsomes and isoform-selective index substrates...
September 29, 2017: Journal of Pharmacy and Pharmacology
https://www.readbyqxmd.com/read/28951277/efficient-substrate-screening-and-inhibitor-testing-of-human-cyp4z1-using-permeabilized-recombinant-fission-yeast
#18
Qi Yan, David Machalz, Andy Zöllner, Erik J Sorensen, Gerhard Wolber, Matthias Bureik
We have established a protocol for the preparation of permeabilized fission yeast cells (enzyme bags) that recombinantly express human cytochrome P450 enzymes (CYPs). A direct comparison of CYP3A4 activity gave an eightfold higher space-time yield for enzyme bag-catalyzed biotransformation as compared to whole-cell biotransformation, even though the total number of cells employed was lower by a factor of 150. Biotransformation of the luminogenic substrate Luciferin-H using CYP2C9-containing enzyme bags proceeded efficiently and stably for 24h...
September 23, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28944677/multiplex-and-label-free-relative-quantification-approach-for-studying-protein-abundance-of-drug-metabolizing-enzymes-in-human-liver-microsomes-using-swath-ms
#19
Rohitash Jamwal, Benjamin J Barlock, Sravani Adusumalli, Ken Ogasawara, Brigitte L Simons, Fatemeh Akhlaghi
We describe a sequential windowed acquisition of all theoretical fragment ion mass spectra (SWATH-MS) based method for label-free, simultaneous, relative quantification of drug metabolism enzymes in human liver microsomes (HLM; n = 78). In-solution tryptic digestion was aided by a pressure cycling method, which allowed a 90 min incubation time, a significant reduction over classical protocols (12-18 h). Digested peptides were separated on an Acquity UHPLC Peptide BEH C18 column using a 60 min gradient method at a flow rate of 0...
October 10, 2017: Journal of Proteome Research
https://www.readbyqxmd.com/read/28941798/assessment-of-the-inhibition-risk-of-shikonin-on-cytochrome-p450-via-cocktail-inhibition-assay
#20
Shuowen Tang, Ang Chen, Xiaojing Zhou, Li Zeng, Mingyao Liu, Xin Wang
Shikonin is a naphthoquinone pigment extracted from roots of Lithospermum erythrorhizon Sieb. et Zucc. (Boraginaceae), and possesses various pharmaceutical activities, such as anti-inflammation and anti-cancer effects. In addition, shikonin as a natural red colorant for food garnishment and cosmetics ingredient is widely used in the world. However, the inhibition risk of shikonin on cytochrome P450 (CYP) remains unclear. The aim of this study was to investigate the potential inhibition of shikonin against CYP1A2, CYP2B1/6, CYP2C9/11, CYP2D1/6, CYP2E1 and CYP3A2/4 activities in human and rat liver microsomes through cocktail approach in vitro...
September 21, 2017: Toxicology Letters
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