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https://www.readbyqxmd.com/read/29353070/7-hydroxylation-of-warfarin-is-strongly-inhibited-by-sesamin-but-not-by-episesamin-caffeic-and-ferulic-acids-in-human-hepatic-microsomes
#1
Nadezhda Pilipenko, Martin Krøyer Rasmussen, Olena Doran, Galia Zamaratskaia
Warfarin is a commonly used anticoagulant drug and is a derivate of coumarin. Cytochrome P450 2C9 (CYP2C9) plays the key role in transformation of coumarin and thus, influences determination of warfarin dosage. A number of factors including dietary compounds such as sesamin, caffeic acid and ferulic acids can regulate the activity of CYP2C9. The present study tested the hypothesis that sesamin, episesamin, caffeic acid and ferulic acid decreases the rate of warfarin 7-hydroxylation via inhibition of hepatic CYP2C9...
January 15, 2018: Food and Chemical Toxicology
https://www.readbyqxmd.com/read/29341245/pharmacokinetic-pharmacodynamic-drug-drug-interactions-of-avatrombopag-when-co-administered-with-dual-or-selective-cyp2c9-and-cyp3a-interacting-drugs
#2
Maiko Nomoto, Cynthia A Zamora, Edgar Schuck, Peter Boyd, Min-Kun Chang, Jagadeesh Aluri, Y Amy Siu, W George Lai, Sanae Yasuda, Jim Ferry, Bhaskar Rege
AIMS: Avatrombopag, a thrombopoietin receptor agonist, is a substrate of cytochrome P450 (CYP) 2C9 and CYP3A. We assessed three drug-drug interactions of avatrombopag as a victim with dual or selective CYP2C9/3A inhibitors and inducers. METHODS: This was a 3-part, open-label study. Forty-eight healthy subjects received single 20 mg doses of avatrombopag alone or with one of 3 CYP2C9/3A inhibitors or inducers: fluconazole 400 mg once daily for 16 days, itraconazole 200 mg twice daily on Day 1 and 200 mg once daily on Days 2-16, or rifampin 600 mg once daily for 16 days...
January 16, 2018: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29336270/in-silico-ligand-based-identification-of-novel-acetylcholinesterase-inhibitors-against-alzheimer-s-disease-ad
#3
Mohammad Usman Mirza, Nazia Ikram, Nauman Mazhar, Kanzal Iman, Mehwish Riaz, Mohammad A Kamal
Alzheimer disease (AD) is a hot research topic currently across the world, characterized by the formation of β-amyloid plaques and neurofibrillary tangles. Inhibition of acetylcholinesterase (AChE) has gained much importance since the discovery of the involvement of peripheral anionic site (PAS) as an allosteric regulator of AChE. Progression of this neurodegenerative disorder causes a deficit in the cholinergic activity that leads towards cognitive decline. Therapeutic interventions in AD are largely focused upon AChE inhibitors designed essentially to prevent the loss of cholinergic function...
January 15, 2018: CNS & Neurological Disorders Drug Targets
https://www.readbyqxmd.com/read/29331654/in-vitro-and-in-vivo-metabolic-activation-of-rhein-and-characterization-of-glutathione-conjugates-derived-from-rhein
#4
Yang Xu, Xu Mao, Boyang Qin, Ying Peng, Jiang Zheng
Rhein (RH), 4,5-dihydroxyanthrauinone-2-carboxylic acid, is found in rhubarb (Dahuang), a traditional herbal medicine. RH has reportedly demonstrated multiple pharmacologic properties. Previous studies have also shown that RH induced hepatotoxicity, but the mechanisms of the adverse effect remain unknown. The major objective of the present study was to study the metabolic pathways of RH in order to identify potential reactive metabolites. One mono-hydroxylation metabolite (M1) was detected in urine and bile of rats given RH...
January 10, 2018: Chemico-biological Interactions
https://www.readbyqxmd.com/read/29329342/ternary-copper-ii-complex-nci60-screening-toxicity-studies-and-evaluation-of-efficacy-in-xenograft-models-of-nasopharyngeal-carcinoma
#5
Munirah Ahmad, Shazlan-Noor Suhaimi, Tai-Lin Chu, Norazlin Abdul Aziz, Noor-Kaslina Mohd Kornain, D S Samiulla, Kwok-Wai Lo, Chew-Hee Ng, Alan Soo-Beng Khoo
Copper(II) ternary complex, [Cu(phen)(C-dmg)(H2O)]NO3 was evaluated against a panel of cell lines, tested for in vivo efficacy in nasopharyngeal carcinoma xenograft models as well as for toxicity in NOD scid gamma mice. The Cu(II) complex displayed broad spectrum cytotoxicity against multiple cancer types, including lung, colon, central nervous system, melanoma, ovarian, and prostate cancer cell lines in the NCI-60 panel. The Cu(II) complex did not cause significant induction of cytochrome P450 (CYP) 3A and 1A enzymes but moderately inhibited CYP isoforms 1A2, 2C9, 2C19, 2D6, 2B6, 2C8 and 3A4...
2018: PloS One
https://www.readbyqxmd.com/read/29326367/organic-anion-transporter-2-mediates-hepatic-uptake-of-tolbutamide-a-cytochrome-p450-2c9-probe-drug
#6
Yi-An Bi, Sumathy Mathialagan, Laurie Tylaska, Myra Fu, Julie Keefer, Anna Vildhede, Chester Costales, A David Rodrigues, Manthena Varma
Tolbutamide is primarily metabolized by cytochrome P450 (CYP)2C9, and thus, frequently applied as a clinical probe substrate for CYP2C9 activity. However, there is a marked discrepancy in the in vitro-in vivo extrapolation of its metabolic clearance implying potential for additional clearance mechanisms. The goal of this study was to evaluate the role of hepatic uptake transport in the pharmacokinetics of tolbutamide and identify the molecular mechanism thereof. Transport studies using singly-transfected cells expressing six major hepatic uptake transporters showed that tolbutamide is a substrate to organic anion transporter (OAT)2 alone -- with transporter affinity (Km) of 19...
January 11, 2018: Journal of Pharmacology and Experimental Therapeutics
https://www.readbyqxmd.com/read/29316516/polybrominated-diphenyl-ethers-pbdes-and-hydroxylated-pbde-metabolites-oh-pbdes-in-maternal-and-fetal-tissues-and-associations-with-fetal-cytochrome-p450-gene-expression
#7
Ami R Zota, Susanna D Mitro, Joshua F Robinson, Emily G Hamilton, June-Soo Park, Emily Parry, R Thomas Zoeller, Tracey J Woodruff
BACKGROUND: Human fetal exposures to polybrominated diphenyl ethers (PBDEs) and their metabolites (OH-PBDEs) are unique from adults, and in combination with a different metabolic profile, may make fetal development more sensitive to adverse health outcomes from these exposures. However, we lack data to characterize human fetal PBDE exposures and the metabolic factors that can influence these exposures. OBJECTIVE: We examined differences between 2nd trimester maternal and fetal exposures to PBDEs and OH-PBDEs...
January 6, 2018: Environment International
https://www.readbyqxmd.com/read/29310511/cytochrome-p450-2a6-and-other-human-p450-enzymes-in-the-oxidation-of-flavone-and-flavanone
#8
Kensaku Kakimoto, Norie Murayama, Shigeo Takenaka, Haruna Nagayoshi, Young-Ran Lim, Vitchan Kim, Donghak Kim, Hiroshi Yamazaki, Masayuki Komori, F Peter Guengerich, Tsutomu Shimada
1. We previously reported that flavone and flavanone interact spectrally with cytochrome P450 (P450 or CYP) 2A6 and 2A13 and other human P450s and inhibit catalytic activities of these P450 enzymes. In this study, we studied abilities of CYP1A1, 1A2, 1B1, 2A6, 2A13, 2C9, and 3A4 to oxidize flavone and flavanone. 2. Human P450s oxidized flavone to 6- and 5-hydroxylated flavones, seven uncharacterized mono-hydroxylated flavones, and five di-hydroxylated flavones. CYP2A6 was most active in forming 6-hydroxy- and 5-hydroxyflavones and several mono- and di-hydroxylated products...
January 9, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29298995/nuclear-receptor-gene-polymorphisms-and-warfarin-dose-requirements-in-the-quebec-warfarin-cohort
#9
Payman Shahabi, Félix Lamothe, Stéphanie Dumas, Étienne Rouleau-Mailloux, Yassamin Feroz Zada, Sylvie Provost, Geraldine Asselin, Ian Mongrain, Diane Valois, Marie-Josée Gaulin Marion, Louis-Philippe Lemieux Perreault, Sylvie Perreault, Marie-Pierre Dubé
Warfarin is primarily metabolized by cytochrome 2C9, encoded by gene CYP2C9. Here, we investigated whether variants in nuclear receptor genes which regulate the expression of CYP2C9 are associated with warfarin response. We used data from 906 warfarin users from the Quebec Warfarin Cohort (QWC) and tested the association of warfarin dose requirement at 3 months following the initiation of therapy in nine nuclear receptor genes: NR1I3, NR1I2, NR3C1, ESR1, GATA4, RXRA, VDR, CEBPA, and HNF4A. Three correlated SNPs in the VDR gene (rs4760658, rs11168292, and rs11168293) were associated with dose requirements of warfarin (P = 2...
January 3, 2018: Pharmacogenomics Journal
https://www.readbyqxmd.com/read/29296562/the-potential-for-interaction-of-tolbutamide-with-pomegranate-juice-against-diabetic-induced-complications-in-rats
#10
Manodeep Chakraborty, Mohammed Gulzar Ahmed, Ananya Bhattacharjee
Background: Pomegranate can inhibit cytochrome P450 (CYP) 2C9 activity, which is largely responsible for the metabolism of sulfonylureas. The present study was undertaken to evaluate the pharmacokinetic and pharmacodynamic interaction of pomegranate and tolbutamide (TOL) against diabetic-induced complications. Methods: Diabetes was induced via administration of alloxan (150 mg/kg, intraperitoneally). Rats (n = 8) were treated with pomegranate juice (PJ) [3 mL/animal, per os (p...
December 2017: Integrative Medicine Research
https://www.readbyqxmd.com/read/29277691/genetic-polymorphisms-of-drug-metabolizing-cytochrome-p450-enzymes-in-cynomolgus-and-rhesus-monkeys-and-common-marmosets-in-preclinical-studies-for-humans
#11
REVIEW
Yasuhiro Uno, Shotaro Uehara, Hiroshi Yamazaki
Cynomolgus monkeys (Macaca fascicularis, Old World Monkeys) and common marmosets (Callithrix jacchus, New World Monkeys) have been widely, and expectedly, used as non-human primate models in drug development studies. Major drug-metabolizing cytochrome P450 (P450) enzymes information is now available that supports these primate species as animal models, and it is established that multiple forms of cynomolgus monkey and common marmoset P450 enzymes have generally similar substrate recognition functionality to human P450 enzymes...
December 22, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29273968/in-vitro-studies-and-in-silico-predictions-of-fluconazole-and-cyp2c9-genetic-polymorphism-impact-on-siponimod-metabolism-and-pharmacokinetics
#12
Yi Jin, Hubert Borell, Anne Gardin, Mike Ufer, Felix Huth, Gian Camenisch
PURPOSE: The purpose of the study is to investigate the enzyme(s) responsible for siponimod metabolism and to predict the inhibitory effects of fluconazole as well as the impact of cytochrome P450 (CYP) 2C9 genetic polymorphism on siponimod pharmacokinetics (PK) and metabolism. METHODS: In vitro metabolism studies were conducted using human liver microsomes (HLM), and enzyme phenotyping was assessed using a correlation analysis method. SimCYP, a physiologically based PK model, was developed and used to predict the effects of fluconazole and CYP2C9 genetic polymorphism on siponimod metabolism...
December 22, 2017: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29247736/metabolic-pathway-of-icotinib-in-vitro-the-differential-roles-of-cyp3a4-cyp3a5-and-cyp1a2-on-potential-pharmacokinetic-drug-drug-interaction
#13
TianHong Zhang, KeRong Zhang, Li Ma, Zheng Li, Juan Wang, YunXia Zhang, Chuang Lu, MingShe Zhu, XiaoMei Zhuang
Icotinib is the self-developed small molecule drug in China for targeted therapy of non-small-cell lung cancer. To date, systematic studies on the pharmacokinetic drug-drug interaction (DDI) of icotinib were limited. By identifying metabolite generation in human liver microsomes (HLM) and revealing the contributions of major CYPs in the formation of major metabolites, the aim of the present work is to understand the mechanisms underlying pharmacokinetic and pharmacological variability in clinic. A LC/UV/HRMS method was developed to characterize the icotinib metabolites...
December 13, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29202402/design-synthesis-and-biological-evaluation-of-a-series-of-resorcinol-based-n-benzyl-benzamide-derivatives-as-potent-hsp90-inhibitors
#14
Sun You Park, Yong Jin Oh, Yunmee Lho, Ju Hui Jeong, Kwang-Hyeon Liu, Jaeyoung Song, Soong-Hyun Kim, Eunyoung Ha, Young Ho Seo
Heat shock protein 90 (Hsp90) is a ubiquitous molecular chaperone that is responsible for the stabilization and maturation of many oncogenic proteins. Therefore, Hsp90 has emerged as an attractive target in the field of cancer chemotherapy. In this study, we report the design, synthesis, and biological evaluation of a series of Hsp90 inhibitors. In particular, compound 30f shows a significant Hsp90α inhibitory activity with IC50 value of 5.3 nM and an excellent growth inhibition with GI50 value of 0.42 μM against non-small cell lung cancer cells, H1975...
November 21, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29183231/in-silico-prediction-of-multiple-category-classification-model-for-cytochrome-p450-inhibitors-and-non-inhibitors-using-machine-learning-method
#15
J H Lee, S Basith, M Cui, B Kim, S Choi
The cytochrome P450 (CYP) enzyme superfamily is involved in phase I metabolism which chemically modifies a variety of substrates via oxidative reactions to make them more water-soluble and easier to eliminate. Inhibition of these enzymes leads to undesirable effects, including toxic drug accumulations and adverse drug-drug interactions. Hence, it is necessary to develop in silico models that can predict the inhibition potential of compounds for different CYP isoforms. This study focused on five major CYP isoforms, including CYP1A2, 2C9, 2C19, 2D6 and 3A4, that are responsible for more than 90% of the metabolism of clinical drugs...
October 2017: SAR and QSAR in Environmental Research
https://www.readbyqxmd.com/read/29182754/pharmacogenetics-based-warfarin-dosing-in-patients-with-cardiac-valve-replacement-the-effects-of-cyp2c9-and-vkorc1-gene-polymorphisms
#16
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/29176019/in-vitro-modulation-of-the-cytochrome-p450-and-abcb1-p-glycoprotein-activities-of-the-aqueous-extract-of-allophylus-cominia-l-sw-leaves
#17
Carlos L Pérez, Maria T Donato, Ivones Hernández, Miriam T Paz Lopes, Evangelina Marrero, Jose A Herrera, Maria J Gómez-Lechón, Idania Rodeiro
BACKGROUND: The aqueous extract of the Allophylus cominia (L) Sw (Sapindaceae) leaves has shown anti-diabetic, anti-obesity and anti-inflammatory properties. In the Caribbean region, it is typically used for the treatment of type-2 diabetes. METHODS: Considering the herb-drug interaction, the aim of this study was to evaluate the potential effects of the A. cominia extract on the cytochrome P450 (CYP) (rat hepatocyte model) and P-glycoprotein (P-gp) (4T1 cell line) systems...
November 25, 2017: Drug Metabolism and Personalized Therapy
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
#18
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/29136681/assessment-of-multiple-cytochrome-p450-activities-in-metabolically-inactivated-human-liver-microsomes-and-roles-of-p450-2c-isoforms-in-reaction-phenotyping-studies
#19
Norie Murayama, Kanako Yajima, Mikiko Hikawa, Kanami Shimura, Yu Ishii, Masaki Takada, Yasuhiro Uno, Masahiro Utoh, Kazuhide Iwasaki, Hiroshi Yamazaki
The fraction of substrate metabolized (fm ) can be used to estimate drug interactions and can be determined by comparison of the intrinsic clearances (CLint ) of victim drugs obtained from inhibited and uninhibited hepatic enzymes. Commercially available human liver microsomes were recently developed in which one cytochrome P450 (P450) isoform is selectively inactivated. These inactivated liver microsomes were used to evaluate the roles of P450 2C isoforms in the depletion and oxidation of probe substrates...
November 14, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/29133569/efficacy-of-tilorone-dihydrochloride-against-ebola-virus-infection
#20
Sean Ekins, Mary A Lingerfelt, Jason E Comer, Alexander N Freiberg, Jon C Mirsalis, Kathleen O'Loughlin, Anush Harutyunyan, Claire McFarlane, Carol E Green, Peter B Madrid
Tilorone dihydrochloride (tilorone) is a small-molecule, orally bioavailable drug that is used clinically as an antiviral outside of the US. A machine learning model trained on anti-Ebola virus (EBOV) screening data previously identified tilorone as a potent in vitro EBOV inhibitor, making it a candidate for the treatment of Ebola virus disease (EVD). In the present study, a series of in vitro ADMET (absorption, distribution, metabolism, excretion, toxicity) assays demonstrated the drug has excellent solubility, high Caco-2 permeability, was not a P-glycoprotein substrate and had no inhibitory activity against five human CYP450 enzymes (3A4, 2D6, 2C19, 2C9 and 1A2)...
November 13, 2017: Antimicrobial Agents and Chemotherapy
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