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https://www.readbyqxmd.com/read/28627229/cobicistat-versus-ritonavir-similar-pharmacokinetic-enhancers-but-some-important-differences
#1
Alice Tseng, Christine A Hughes, Janet Wu, Jason Seet, Elizabeth J Phillips
OBJECTIVE: To describe properties of cobicistat and ritonavir; compare boosting data with atazanavir, darunavir, and elvitegravir; and summarize antiretroviral and comedication interaction studies, with a focus on similarities and differences between ritonavir and cobicistat. Considerations when switching from one booster to another are discussed. DATA SOURCES: A literature search of MEDLINE was performed (1985 to April 2017) using the following search terms: cobicistat, ritonavir, pharmacokinetic, drug interactions, booster, pharmacokinetic enhancer, HIV, antiretrovirals...
June 1, 2017: Annals of Pharmacotherapy
https://www.readbyqxmd.com/read/28614988/in-vitro-inhibitory-effects-of-dihydromyricetin-on-human-liver-cytochrome-p450-enzymes
#2
Lu Liu, Sen Sun, Hongbing Rui, Xiaohua Li
CONTEXT: Dihydromyricetin (DHM) is the most abundant and active flavonoid component isolated from Ampelopsis grossedentata (Hand-Mazz) W.T. Wang (Vitaceae) and it possesses numerous pharmacological activities. However, whether DHM affects the activity of human liver cytochrome P450 (CYP) enzymes remains unclear. MATERIALS AND METHODS: The inhibitory effects of DHM on eight human liver CYP isoforms (i.e., 1A2, 3A4, 2A6, 2E1, 2D6, 2C9, 2C19 and 2C8) were investigated in vitro using human liver microsomes (HLMs)...
December 2017: Pharmaceutical Biology
https://www.readbyqxmd.com/read/28608515/efavirenz-clearances-in-vitro-and-in-vivo-in-six-cynomolgus-monkeys-associated-with-polymorphic-cytochrome-p450-2c9-and-simulated-by-individual-physiologically-based-pharmacokinetic-models
#3
Masahiro Utoh, Tomonori Miura, Takashi Kusama, Shotaro Uehara, Makiko Shimizu, Yasuhiro Uno, Hiroshi Yamazaki
Cynomolgus monkey cytochrome P450 2C9 (formerly known as P450 2C43) variation was reportedly associated with metabolic clearance of the antiretroviral drug efavirenz in vivo (of three wild-type, one heterozygote, and two homozygote animals), being unlikely in the case of human P450 2B6-dependent efavirenz clearance. In this study, the liver microsomal elimination rates of efavirenz for the same individual animals previously treated with intravenous/oral administrations of efavirenz showed significant reductions associated with the P450 2C9 p...
June 13, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28603633/in-vitro-metabolism-of-exemestane-by-hepatic-cytochrome-p450s-impact-of-nonsynonymous-polymorphisms-on-formation-of-the-active-metabolite-17%C3%AE-dihydroexemestane
#4
Amity Peterson, Zuping Xia, Gang Chen, Philip Lazarus
Exemestane (EXE) is an endocrine therapy commonly used by postmenopausal women with hormone-responsive breast cancer due to its potency in inhibiting aromatase-catalyzed estrogen synthesis. Preliminary in vitro studies sought to identify phase I EXE metabolites and hepatic cytochrome P450s (CYP450s) that participate in EXE biotransformation. Phase I metabolites were identified by incubating EXE with HEK293-overexpressed CYP450s. CYP450s 1A2, 2C8, 2C9, 2C19, 2D6, 3A4, and 3A5 produce 17β-dihydroexemestane (17β-DHE), an active major metabolite, as well as two inactive metabolites...
June 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28553770/involvement-of-reactive-metabolites-of-diclofenac-in-cytotoxicity-in-sandwich-cultured-rat-hepatocytes
#5
Atsushi Kawase, Ryota Hashimoto, Mai Shibata, Hiroaki Shimada, Masahiro Iwaki
BACKGROUND AND OBJECTIVES: Diclofenac (DIC) is metabolized to reactive metabolites such as diclofenac acyl-β-d-glucuronide (DIC-AG). It is possible that such reactive metabolites could cause tissue damage by formation of covalent protein adducts and other modification of cellular proteins or by induction of immune responses against its covalent protein adducts. However, the detailed mechanisms of idiosyncratic drug-induced liver injury (DILI) have been unclear. The objective is to clarify the involvement of DIC-AG and 4'hydroxydiclofenac (4'OH-DIC) in acute DILI...
May 2017: International Journal of Toxicology
https://www.readbyqxmd.com/read/28552479/biopharmaceutic-parameters-pharmacokinetics-transport-and-cyp-mediated-drug-interactions-of-iiim-017-a-novel-nitroimidazooxazole-analogue-with-anti-tuberculosis-activity
#6
Gurleen Kour, Parvinder Pal Singh, Asha Bhagat, Zabeer Ahmed
Nitroimidazoles are emerging as a new class of therapeutic agents with potent anti-tubercular activity. CSIR-IIIM has synthesized a novel nitrohydroimidazooxazole (NHIO) analogue, IIIM-017 with a MIC of 0.37μg/ml (against H37Rv). Here, we aim at further exploration of physicochemical properties and preclinical absorption, metabolism, disposition and pharmacokinetics of IIIM-017. In this study, in silico physicochemical parameters, lipophilicity, permeability, transport, hepatotoxicity, CYP mediated drug interactions and pharmacokinetics of IIIM-017 were investigated...
May 26, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28540569/altered-purinergic-signaling-in-uridine-adenosine-tetraphosphate-induced-coronary-relaxation-in-swine-with-metabolic-derangement
#7
Zhichao Zhou, Oana Sorop, Vincent J de Beer, Ilkka Heinonen, Caroline Cheng, A H Jan Danser, Dirk J Duncker, Daphne Merkus
We previously demonstrated that uridine adenosine tetraphosphate (Up4A) induces potent and partially endothelium-dependent relaxation in the healthy porcine coronary microvasculature. We subsequently showed that Up4A-induced porcine coronary relaxation was impaired via downregulation of P1 receptors after myocardial infarction. In view of the deleterious effect of metabolic derangement on vascular function, we hypothesized that the coronary vasodilator response to Up4A is impaired in metabolic derangement, and that the involvement of purinergic receptor subtypes and endothelium-derived vasoactive factors (EDVFs) is altered...
May 24, 2017: Purinergic Signalling
https://www.readbyqxmd.com/read/28527150/development-of-in-silico-protocols-to-predict-structural-insights-into-the-metabolic-activation-pathways-of-xenobiotics
#8
M Kalim A Khan, Salman Akhtar, Jamal M Arif
To establish in silico model to predict the structural insight into the metabolic bioactivation pathway of xenobiotics, we considered two specific and one non-specific mammary procarcinogen [e.g., dibenzo[a,l]pyrene (DBP), 7,12-dimethylbenz[a]anthracene (DMBA), and benzo[a]pyrene (BP)]. The CYP1A1, 1B1, 2C9, 1A2 and 2B6 reported in wet-lab studies to actively metabolize DBP also showed strong binding energies (kcal/mol) of -11.50, -10.67, -10.37, -9.76 and -9.72, respectively, with inhibition constants ranging between 0...
May 19, 2017: Interdisciplinary Sciences, Computational Life Sciences
https://www.readbyqxmd.com/read/28520411/alignment-based-prediction-of-sites-of-metabolism
#9
Christina de Bruyn Kops, Nils-Ole Friedrich, Johannes Kirchmair
Prediction of metabolically labile atom positions in a molecule (sites of metabolism) is a key component of the simulation of xenobiotic metabolism as a whole, providing crucial information for the development of safe and effective drugs. In 2008, an exploratory study was published in which sites of metabolism were derived based on molecular shape- and chemical feature-based alignment to a molecule whose site of metabolism (SoM) had been determined by experiments. We present a detailed analysis of the breadth of applicability of alignment-based SoM prediction, including transfer of the approach from a structure- to ligand-based method and extension of the applicability of the models from cytochrome P450 2C9 to all cytochrome P450 isozymes involved in drug metabolism...
May 18, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28484907/inhibition-of-cytochrome-p450-and-uridine-5-diphospho-glucuronosyltransferases-by-mam-2201-in-human-liver-microsomes
#10
Tae Yeon Kong, Ju-Hyun Kim, Soon-Sang Kwon, Jae Chul Cheong, Hee Seung Kim, Moon Kyo In, Hye Suk Lee
MAM-2201, a synthetic cannabinoid, is a potent agonist of the cannabinoid receptors and is increasingly used as an illicit recreational drug. The inhibitory effects of MAM-2201 on major drug-metabolizing enzymes such as cytochrome P450s (CYPs) and uridine 5'-diphospho-glucuronosyltransferases (UGTs) have not yet been investigated although it is widely abused, sometimes in combination with other drugs. We evaluated the inhibitory effects of MAM-2201 on eight major human CYPs (CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4) and six UGTs (UGTs 1A1, 1A3, 1A4, 1A6, 1A9, and 2B7) of pooled human liver microsomes; we thus explored potential MAM-2201-induced drug interactions...
May 8, 2017: Archives of Pharmacal Research
https://www.readbyqxmd.com/read/28461575/lky-047-first-selective-inhibitor-of-cytochrome-p450-2j2
#11
Nguyen Minh Phuc, Zhexue Wu, Yuseok O, Jee-Hyun Lee, Sangtaek Oh, Gyu-Yong Song, Kwang-Hyeon Liu
Highly selective cytochrome P450 CYP2J2 (CYP2J2) inhibitors suitable for reaction phenotyping are currently not available. (7S)-(+)-(4-Nitro-phenyl)-acrylic acid, 8,8-dimethyl-2-oxo-6,7-dihydro-2H,8H-pyrano[3,2-g]chromen-7-yl-ester (LKY-047), a decursin derivative, was synthesized, and its inhibitor potencies toward CYP2J2 as well as other cytochrome P450 (P450) enzymes in human liver microsomes (HLM) were evaluated. LKY-047 was demonstrated to be a strong competitive inhibitor of CYP2J2-mediated astemizole O-demethylase and terfenadine hydroxylase activity, with Ki values of 0...
July 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28435143/estimation-of-inter-individual-variability-of-pharmacokinetics-of-cyp2c9-substrates-in-humans
#12
Koji Chiba, Keiko Shimizu, Motohiro Kato, Taichi Miyazaki, Takaaki Nishibayashi, Kazuki Terada, Yuichi Sugiyama
The activity of metabolic enzymes varies across individuals and populations. Activity varies even among individuals sharing the same genotype. Genetic polymorphisms in CYP2C9 cause significant inter-individual variability in the metabolism of its substrates. However, the variability of CYP2C9 intrinsic hepatic clearance (CLint,h,CYP2C9) among subjects of the same genotype has not been reported. In this study, we estimated the coefficient of variation (CV) for the intrinsic hepatic clearance of tolbutamide by CYP2C9 for each CYP2C9 genotype using previously reported AUCs and oral clearance (CLoral) values in a Monte Carlo simulation with a dispersion model...
April 20, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28408837/polymorphisms-of-vkorc1-and-cyp2c9-are-associated-with-warfarin-sensitivity-in-chinese-population
#13
LiQun Jia, Zanxin Wang, Jianlong Men, Heng Cai, Minxin Wei
OBJECTIVE: Warfarin is a commonly prescribed anticoagulant for prevention of thromboembolic events. Wide inter-individual dose variation, narrow therapeutic range and risk of serious bleeding result in difficulties in achieving the therapeutic effect. The present study was designed to clarify the real biological significance of the polymorphisms of VKORC1 and cytochrome P450 2C9 (CYP2C9) in warfarin metabolism. METHODS: A total of 214 patients with warfarin anticoagulant therapy were selected...
2017: Therapeutics and Clinical Risk Management
https://www.readbyqxmd.com/read/28385095/in-vitro-inhibitory-effects-of-pristimerin-on-human-liver-cytochrome-p450-enzymes
#14
Xiaoyi Hao, Jianlei Yuan, Yansen Xu, Zhao Wang, Jianzhang Hou, Tao Hu
1. Pristimerin (PTM) is a biological component isolated from Chinese herbal plant Celastrus and Maytenus spp and it possesses numerous pharmacological activities. However, whether PTM affects the activity of human liver cytochrome P450 (CYP) enzymes remains unclear. 2. In this study, the inhibitory effects of PTM on the eight human liver CYP isoforms (i.e., 1A2, 3A4, 2A6, 2E1, 2D6, 2C9, 2C19, and 2C8) were investigated in vitro using human liver microsomes (HLMs). 3. The results showed that PTM inhibited the activity of CYP1A2, 3A4, and 2C9, with IC50 values of 21...
April 7, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28374982/angiotensin-ii-receptor-blockers-inhibit-the-generation-of-epoxyeicosatrienoic-acid-from-arachidonic-acid-in-recombinant-cyp2c9-cyp2j2-and-human-liver-microsomes
#15
Asuna Senda, Yuji Mukai, Toru Hayakawa, Yuka Kato, Erik Eliasson, Anders Rane, Takaki Toda, Nobuo Inotsume
Cytochrome P450 (CYP) 2C9, CYP2C8 and CYP2J2 enzymes, which metabolize arachidonic acid to epoxyeicosatrienoic acids (EETs), have cardioprotective effects including anti-inflammation and vasodilation. We have recently shown that some angiotensin II receptor blockers (ARBs) may inhibit AA metabolism via CYP2C8. Using recombinant CYP2C9, CYP2J2, and human liver microsomes (HLMs), the aim was now to compare the ability of six different clinically used ARBs to inhibit AA metabolism in vitro. The rank order of the ARBs for the 50% inhibitory concentration (IC50 ) of AA metabolism was losartan < telmisartan < irbesartan < candesartan < olmesartan < valsartan via CYP2C9, and telmisartan < irbesartan < olmesartan < losartan < candesartan and valsartan via CYP2J2...
April 4, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/28350999/discovery-of-novel-1-2-3-4-tetrahydrobenzo-4-5-thieno-2-3-c-pyridine-derivatives-as-potent-and-selective-cyp17-inhibitors
#16
Mingliang Wang, Yanjia Fang, Shoulai Gu, Fangfang Chen, Zhengjiang Zhu, Xun Sun, Jidong Zhu
The inhibition of CYP17 to block androgen biosynthesis is a well validated strategy for the treatment of prostate cancer. Herein we reported the design, synthesis and structure-activity relationship (SAR) study for a series of novel 1,2,3,4- tetrahydrobenzo[4,5]thieno[2,3-c]pyridine derivatives. Some analogs demonstrated a potent inhibition to both rat and human CYP17 protein and reduced testosterone production in human H295R cell line. Some analogs also showed high selectivity against other CYP enzymes such as 3A4, 1A2, 2C9, 2C19 and 2D6, which may limit side effects due to drug-drug interactions...
May 26, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28340451/the-role-of-drug-drug-interactions-in-prostate-cancer-treatment-focus-on-abiraterone-acetate-prednisone-and-enzalutamide
#17
REVIEW
Marzia Del Re, Stefano Fogli, Lisa Derosa, Francesco Massari, Paul De Souza, Stefania Crucitta, Sergio Bracarda, Daniele Santini, Romano Danesi
Elderly patients with cancer may have comorbidities, each requiring additional pharmacologic treatment. Therefore, the occurrence of pharmacokinetic (PK) and pharmacodynamic (PD) interactions is very likely, and the risk of adverse reactions (ADRs), due to the narrow therapeutic window of anticancer drugs, is increased. Drug-drug interactions (DDIs) may occur in prostate cancer patients due to inhibition by abiraterone of liver cytochrome P450 (CYP)-dependent enzymes CYP2C8 and 2D6, which are involved in the metabolism of approximately 25% of all drugs, and induction by enzalutamide of CYP3A4, 2C9 and 2C19, which metabolize up to 50% of medications...
March 9, 2017: Cancer Treatment Reviews
https://www.readbyqxmd.com/read/28287454/am-2201-inhibits-multiple-cytochrome-p450-and-uridine-5-diphospho-glucuronosyltransferase-enzyme-activities-in-human-liver-microsomes
#18
Ju-Hyun Kim, Soon-Sang Kwon, Tae Yeon Kong, Jae Chul Cheong, Hee Seung Kim, Moon Kyo In, Hye Suk Lee
AM-2201 is a synthetic cannabinoid that acts as a potent agonist at cannabinoid receptors and its abuse has increased. However, there are no reports of the inhibitory effect of AM-2201 on human cytochrome P450 (CYP) or uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes. We evaluated the inhibitory effect of AM-2201 on the activities of eight major human CYPs (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4) and six major human UGTs (1A1, 1A3, 1A4, 1A6, 1A9, and 2B7) enzymes in pooled human liver microsomes using liquid chromatography-tandem mass spectrometry to investigate drug interaction potentials of AM-2201...
March 10, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28284082/simultaneous-determination-of-glipizide-and-its-four-hydroxylated-metabolites-in-human-urine-using-lc-ms-ms-and-its-application-in-urinary-phenotype-study
#19
Bo Tan, Aidong Yang, Weian Yuan, Yue Li, Lei Jiang, Jian Jiang, Furong Qiu
Cytochrome P450 (CYP) 2C9 and CYP2C19 genetic mutant could influence the plasma concentration of glipizide in human subjects, which refers to glipizide safety and adverse effects in clinic practice. A further study to investigate the relationship of the concentrations between glipizide and its metabolites in human with different CYP mutants was valuable. We firstly develop a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for simultaneous quantification of glipizide and its hydroxylated metabolites in human urine...
May 30, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28173639/bosentan-and-rifampin-interactions-modulate-influx-transporter-and-cytochrome-p450-expression-and-activities-in-primary-human-hepatocytes
#20
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...
May 1, 2017: Biomolecules & Therapeutics
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