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https://www.readbyqxmd.com/read/29779438/metabolism-of-deltamethrin-and-cis-and-trans-permethrin-by-human-expressed-cytochrome-p450-and-carboxylesterase-enzymes
#1
Laura Hedges, Susan Brown, A Kenneth MacLeod, Audrey Vardy, Edward Doyle, Gina Song, Marjory Moreau, Miyoung Yoon, Thomas G Osimitz, Brian G Lake
1. The metabolism of the pyrethroids deltamethrin (DLM), cis-permethrin (CPM) and trans-permethrin (TPM) was studied in human expressed cytochrome P450 (CYP) and carboxylesterase (CES) enzymes. 2. DLM, CPM and TPM were metabolised by human CYP2B6 and CYP2C19, with the highest apparent intrinsic clearance (CLint ) values for pyrethroid metabolism being observed with CYP2C19. Other CYP enzymes contributing to the metabolism of one or more of the three pyrethroids were CYP1A2, CYP2C8, CYP2C9*1, CYP2D6*1, CYP3A4 and CYP3A5...
May 21, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29779093/pharmacokinetics-of-the-novel-selective-non-steroidal-mineralocorticoid-receptor-antagonist-finerenone-in-healthy-volunteers-results-from-an-absolute-bioavailability-study-and-drug-drug-interaction-studies-in-vitro-and-in-vivo
#2
Roland Heinig, Michael Gerisch, Anna Engelen, Johannes Nagelschmitz, Stephanie Loewen
BACKGROUND AND OBJECTIVES: Finerenone is a selective, non-steroidal mineralocorticoid receptor antagonist. In vivo and in vitro studies were performed to assess absolute bioavailability of finerenone, the effect of metabolic enzyme inhibitors on the pharmacokinetics of finerenone and its metabolites, the quantitative contribution of the involved enzymes cytochrome P450 (CYP) 3A4 and CYP2C8 and the relevance of gut wall versus liver metabolism. METHODS: The pharmacokinetics, safety and tolerability of finerenone (1...
May 19, 2018: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29774122/the-down-regulation-of-the-cyp2c19-gene-is-associated-with-aggressive-tumor-potential-and-the-poorer-recurrence-free-survival-of-hepatocellular-carcinoma
#3
Ryo Ashida, Yukiyasu Okamura, Keiichi Ohshima, Yuko Kakuda, Katsuhiko Uesaka, Teiichi Sugiura, Takaaki Ito, Yusuke Yamamoto, Takashi Sugino, Kenichi Urakami, Masatoshi Kusuhara, Ken Yamaguchi
Project HOPE (High-tech Omics-based Patient Evaluation) began in 2014 using integrated gene expression profiling (GEP) of cancer tissues as well as diathesis of each patient who underwent an operation at our institution. The aim of this study was to clarify the association between the expression of cytochrome P450s (CYP) genes and recurrence of hepatocellular carcinoma (HCC). The present study included 92 patients. Genes with aberrant expression were selected based on a ≥10-fold difference in the expression between tumor and non-tumor tissues...
April 24, 2018: Oncotarget
https://www.readbyqxmd.com/read/29770723/the-impact-of-azole-antifungal-drugs-on-imatinib-metabolism-in-human-liver-microsomes
#4
Xingxian Luo, Taifeng Li, Ze Yu, Xuecai Xue, Haiyang Zhao, Na Li, Liping Ma, Changqing Yang, Lin Huanglin, Wangyu Feng
1. Imatinib is widely used for the treatment of hematologic malignancies. It is common that imatinib is clinically co-prescribed with azole antifungal agents since these patients are more prone to invasive antifungal infection. The present study was to investigate the effects of azole antifungal drugs, including ketoconazole, fluconazole, voriconazole, itraconazole and posaconazole on imatinib metabolism. 2. The main metabolites, 1-OH midazolam and N-desmethyl imatinib, were determined in the absence and in the presence of various levels of ketoconazole, fluconazole, voriconazole, itraconazole and posaconazole...
May 17, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29746713/lack-of-impact-by-scy-078-a-first-in-class-oral-fungicidal-glucan-synthase-inhibitor-on-the-pharmacokinetics-of-rosiglitazone-a-substrate-for-cyp450-2c8-supports-the-low-risk-for-clinically-relevant-metabolic-drug-drug-interactions
#5
Stephen Wring, Gail Murphy, George Atiee, Christy Corr, Michele Hyman, Michael Willett, David Angulo
SCY-078, the first in a new class of β 1,3-glucan synthesis inhibitors, is being developed as an oral and intravenous antifungal treatment for Candida and Aspergillus species fungal infections. In vitro, studies indicated SCY-078 is an inhibitor of cytochrome P450 (CYP) 2C8 with markedly lower effect over other CYP isozymes. To examine clinically relevant effects of the potential interaction with SCY-078, this phase 1, open-label, 2-period crossover study evaluated the pharmacokinetic parameters of rosiglitazone, a sensitive substrate of CYP2C8 metabolism, in the absence and presence of SCY-078 dosed to therapeutically relevant SCY-078 concentration exposure after repeat dosing...
May 10, 2018: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29743122/spin1-negatively-regulated-by-mir-148-152-enhances-adriamycin-resistance-via-upregulating-drug-metabolizing-enzymes-and-transporter-in-breast-cancer
#6
Xu Chen, Ya-Wen Wang, Peng Gao
BACKGROUND: Spindlin1 (SPIN1), a protein highly expressed in several human cancers, has been correlated with tumorigenesis and development. Alterations of drug metabolizing enzymes and drug transporters are major determinants of chemoresistance in tumor cells. However, whether the metabolizing enzymes and transporters are under the control of SPIN1 in breast cancer chemoresistance has not yet been defined. METHODS: SPIN1 expression in breast cancer cells and tissues was detected by quantitative real-time PCR (qRT-PCR) and immunohistochemistry...
May 9, 2018: Journal of Experimental & Clinical Cancer Research: CR
https://www.readbyqxmd.com/read/29741432/inter-individual-variation-in-imatinib-disposition-any-role-for-prevalent-variants-of-cyp1a2-cyp2c8-cyp2c9-and-cyp3a5-in-nigerian-cml-patients
#7
Ayorinde Adehin, Babatunde A Adeagbo, Martin A Kennedy, Oluseye O Bolaji, Tiwalade A Olugbade, Rahman A Bolarinwa, Muheez A Durosinmi
Imatinib has been successful in the management of chronic myeloid leukemia (CML) but some patients experience adverse reactions or develop resistance to its use. The roles of some polymorphisms in genes encoding enzymes critical for the biotransformation of imatinib have been previously examined. This study, hence, evaluated some other unstudied functionally significant polymorphisms in CYP1A2, CYP2C8, CYP2C9, and CYP3A5. Trough imatinib blood levels and genotypes were determined in 42 CML patients by an HPLC-UV technique and a Sequenom iPLEX assay, respectively...
May 9, 2018: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/29738669/cypreact-a-software-tool-for-in-silico-reactant-prediction-for-human-cytochrome-p450-enzymes
#8
Siyang Tian, Yannick Djoumbou, Russ Greiner, David S Wishart
In silico metabolism prediction requires first predicting whether a specific molecule will interact with one or more specific metabolizing enzymes, then predicting the result of each enzymatic reaction. Here, we provide a computational tool, CypReact, for performing this first task of reactant prediction. Specically, CypReact takes as input an arbitrary molecule (specied as a SMILES string or a standard SDF file), and any one of the nine of the most important human cytochrome P450 (CYP450) enzymes -- CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4 -- and accurately predicts whether the query molecule will react with that given CYP450 enzyme...
May 8, 2018: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/29735754/an-assessment-of-the-in-vitro-inhibition-of-cytochrome-p450-enzymes-cyp-udp-glucuronsyltransferases-ugt-and-transporters-by-phosphodiester-or-phosphorothioate-linked-oligonucleotides
#9
Faraz Kazmi, Phyllis Yerino, Chase McCoy, Andrew Parkinson, David B Buckley, Brian W Ogilvie
Oligonucleotides represent an expanding class of pharmacotherapeutics in development for various indications. Typically, oligonucleotides are developed with phosphorothioate linkages for the improvement of biological stability; however limited data are available on the potential of these molecules to cause drug-drug interactions (DDIs). In the present study, two non therapeutic oligonucleotides with either phosphodiester (PD-GP and PD-Ac) or phosphorothioate (PT-GP and PT-Ac) linkages were evaluated in vitro for their potential to inhibit P450s and UGTs in both human liver microsomes (HLM) and cryopreserved human hepatocytes (CHH) and to inhibit select transporters in expression systems...
May 7, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29712725/quantitative-analysis-of-complex-drug-drug-interactions-ddis-between-cerivastatin-and-inhibitors-using-physiologically-based-pharmacokinetic-pbpk-modeling
#10
Yoshiaki Yao, Kota Toshimoto, Soo-Jin Kim, Takashi Yoshikado, Yuichi Sugiyama
Cerivastatin (CER) was withdrawn from the world market because of lethal rhabdomyolysis. Coadministrations of CER and cyclosporine A (CsA) or gemfibrozil (GEM) have been reported to increase the CER blood concentration. CsA is an inhibitor of OATP1B1 and CYP3A4, and GEM and its glucuronide (GEM-glu) inhibit OATP1B1 and CYP2C8. The purpose of this study was to describe the transporter-/enzymemediated drug-drug interactions (DDIs) of CER with CsA or GEM based on unified physiologically based pharmacokinetic (PBPK) models and to investigate whether the DDIs can be quantitatively analyzed by a bottom-up approach...
April 30, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29696643/clopidogrel-increases-dasabuvir-exposure-with-or-without-ritonavir-and-ritonavir-inhibits-the-bioactivation-of-clopidogrel
#11
Matti K Itkonen, Aleksi Tornio, Outi Lapatto-Reiniluoto, Mikko Neuvonen, Pertti J Neuvonen, Mikko Niemi, Janne T Backman
Dasabuvir is mainly metabolized by cytochrome P450 (CYP) 2C8 and is predominantly used in a regimen containing ritonavir. Ritonavir and clopidogrel are inhibitors of CYP3A4 and CYP2C8, respectively. In a randomized, cross-over study in twelve healthy subjects, we examined the impact of clinical doses of ritonavir (for 5 days), clopidogrel (for 3 days), and their combination on dasabuvir pharmacokinetics, and the effect of ritonavir on clopidogrel. Clopidogrel, but not ritonavir, increased the geometric mean AUC0-∞ of dasabuvir 4...
April 26, 2018: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29689254/inhibitory-effects-of-danshen-components-on-cyp2c8-and-cyp2j2
#12
Mei-Juan Xu, Li-Feng Jiang, Ting Wu, Ji-Hong Chu, Yi-Dan Wei, Ji-Ye Aa, Guang-Ji Wang, Hai-Ping Hao, Wen-Zheng Ju, Ping Li
The use of Chinese herbal medicines and natural products has become increasingly popular in both China and Western societies as an alternative medicine for the treatment of diseases or as a health supplement. Danshen, the dried root of Salvia miltiorrhiza (Fam.Labiatae), which is rich in phenolic acids and tanshinones, is a widely used herbal medicine for the treatment of cardio-cerebrovascular diseases. The goal of this study was to examine the inhibitory effects of fifteen components derived from Danshen on CYP2C8 and CYP2J2, which are expressed both in human liver and cardiovascular systems...
April 21, 2018: Chemico-biological Interactions
https://www.readbyqxmd.com/read/29683873/eltrombopag-induced-acute-liver-failure-in-a-pediatric-patient-a-pharmacokinetic-and-pharmacogenetic-analysis
#13
M Marano, J Serafinelli, S Cairoli, D Martinelli, M Pisani, G Palumbo, M G Cefalo, C Cecchetti, M Di Nardo, F S Falvella, B M Goffredo
Eltrombopag is an oral thrombopoietin-receptor-agonist (TPO-RA) approved for the treatment of patients with chronic idiopathic thrombocytopenic purpura (ITP), who are more than one year old, and show poor response to first-line therapy. ITP is a hematological disorder characterized by isolated thrombocytopenia in the absence of secondary causes or disorders. Eltrombopag is generally well tolerated in the pediatric population, therefore therapeutic drug monitoring (TDM) is not usually performed in clinical practice...
April 20, 2018: Therapeutic Drug Monitoring
https://www.readbyqxmd.com/read/29663414/bidirectional-pharmacokinetic-interaction-between-amodiaquine-and-pioglitazone-in-healthy-subjects
#14
Opeyemi Edema, Babatunde A Adeagbo, Ayorinde Adehin, Tiwalade A Olugbade
Amodiaquine (AQ) and pioglitazone (PGZ) are both metabolized by CYP2C8, an enzyme also inhibited by PGZ. These drugs are likely to be administered in instances of comorbidity of malaria with type 2 diabetes. This study, hence, evaluated the possibility of a drug interaction resulting from the concurrent use of both drugs. A 3-period crossover design in 10 healthy subjects, that assessed the disposition of AQ and PGZ alone and when coadministered, was implemented with the administration of single oral doses of AQ and PGZ...
April 17, 2018: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29659506/in-vitro-inhibitory-effects-of-synthetic-cannabinoid-eam-2201-on-cytochrome-p450-and-udp-glucuronosyltransferase-enzyme-activities-in-human-liver-microsomes
#15
Tae Yeon Kong, Soon-Sang Kwon, Jae Chul Cheong, Hee Seung Kim, Jin Young Kim, Hye Suk Lee
EAM-2201, a synthetic cannabinoid, is a potent agonist of the cannabinoid receptors that is widely abused as an illicit recreational drug in combination with other drugs. To evaluate the potential of EAM-2201 as a perpetrator of drug–drug interactions, the inhibitory effects of EAM-2201 on major drug-metabolizing enzymes, cytochrome P450s (CYPs) and uridine 5′-diphospho-glucuronosyltransferases (UGTs) were evaluated in pooled human liver microsomes using liquid chromatography–tandem mass spectrometry (LC-MS/MS)...
April 16, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29580941/increased-epoxyeicosatrienoic-acids-may-be-part-of-a-protective-mechanism-in-human-ulcerative-colitis-with-increased-cyp2j2-and-reduced-soluble-epoxide-hydrolase-expression
#16
Yi-Er Qiu, Jun Qin, Yang Luo, Shao-Lan Qin, Yi-Fei Mu, Ran Cun, Hou-Li Jiang, Jian-Jun Chen, Min-Hao Yu, Ming Zhong
BACKGROUND: Previous preclinical evidence has suggested that the elevation of epoxyeicosatrienoic acids (EETs) derived from the cytochrome P450 (CYP) epoxygenases-dependent metabolism of arachidonic acid has important anti-inflammatory effects. However, the levels of EETs and their synthetic and metabolic enzymes in human ulcerative colitis has not been evaluated. METHOD: To evaluate EETs and the expression of relevant CYP isoforms and the metabolizing enzyme, soluble epoxide hydrolase (sEH), tissue biopsies were collected from 16 pairs of ulcerative colitis patients' tissues and matched with adjacent non-inflamed tissues...
March 23, 2018: Prostaglandins & Other Lipid Mediators
https://www.readbyqxmd.com/read/29574693/physiologically-based-pharmacokinetic-modelling-to-identify-physiological-and-molecular-characteristics-driving-variability-in-drug-exposure
#17
Andrew Rowland, Madelé van Dyk, Ashley M Hopkins, Reham Mounzer, Thomas M Polasek, Amin Rostami-Hodjegan, Michael J Sorich
Prospectively defining the physiological and molecular characteristics most likely driving between subject variability (BSV) in drug exposure provides the opportunity to inform the assessment of biomarkers to account for this variability. A physiologically-based pharmacokinetic (PBPK) model was constructed and verified for dabrafenib. This model was then used to evaluate the physiological and molecular characteristics driving BSV in dabrafenib exposure. The capacity to discriminate a steady state dabrafenib trough concentration >48ng/mL was also evaluated...
March 25, 2018: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29572333/risk-of-clinically-relevant-pharmacokinetic-based-drug-drug-interactions-with-drugs-approved-by-the-u-s-food-and-drug-administration-between-2013-and-2016
#18
Jingjing Yu, Zhu Zhou, Jessica Tay-Sontheimer, Rene H Levy, Isabelle Ragueneau-Majlessi
A total of 103 drugs (including 14 combination drugs) were approved by the U.S. Food and Drug Administration from 2013 to 2016. Pharmacokinetic-based drug interaction profiles were analyzed using the University of Washington Drug Interaction Database and the clinical relevance of these observations was characterized based on information from New Drug Application reviews. CYP3A was identified as a major contributor to clinical drug-drug interactions (DDIs), involved in approximately 2/3 of all interactions. Transporters (alone or with enzymes) were found to participate in about half of all interactions, although most of these were weak-to-moderate interactions...
March 23, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29545948/the-drug-interaction-potential-of-daprodustat-when-coadministered-with-pioglitazone-rosuvastatin-or-trimethoprim-in-healthy-subjects
#19
Stephen Caltabiano, Kelly M Mahar, Karyn Lister, David Tenero, Ramiya Ravindranath, Borut Cizman, Alexander R Cobitz
This study was conducted to evaluate the likelihood of daprodustat to act as a perpetrator in drug-drug interactions (DDI) with the CYP2C8 enzyme and OATP1B1 transporter using the probe substrates pioglitazone and rosuvastatin as potential victims, respectively. Additionally, this study assessed the effect of a weak CYP2C8 inhibitor, trimethoprim, as a perpetrator of a DDI with daprodustat. This was a two-part study: Part A assessed the effect of coadministration of daprodustat on the pharmacokinetics of pioglitazone and rosuvastatin in 20 subjects; Part B assessed the coadministration of trimethoprim on the pharmacokinetics of daprodustat in 20 subjects...
April 2018: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/29542427/evaluation-of-herb-drug-interaction-of-synacinntm-and-individual-biomarker-through-cytochrome-450-inhibition-assay
#20
Fadzilah Adibah Abd Majid, Nur Syukriah Ab Rahman, Effendy Abd Wahid, Ain Nabihah Zainudin, Siti Nurazwa Zainol, Hassan Fahmi Ismail, Tet Soon Wong, K Vijaya Bhargava, Nirbhay Kumar Tiwari, Sanjeev Giri
Drug interaction of SynacinnTM polyherbal with known diabetic drugs is unknown. SynacinnTM contains standardized extracts of five herbal against gallic acid, curcumin, rosmarinic acid, catechin and andrographolide. SynacinnTM and its five standard markers were analysed for its possible interaction with CYP450 enzymes assay. This study was conducted using liquid chromatography-tandem mass spectroscopy (LC-MS/MS) using probe substrates using human liver microsomes against CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4(Midazolam) and CYP3A4 (Testosteron)...
March 13, 2018: Drug Metabolism Letters
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