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https://www.readbyqxmd.com/read/29775322/prediction-of-human-cytochrome-p450-inhibition-using-a-multi-task-deep-autoencoder-neural-network
#1
Xiang Li, Youjun Xu, Luhua Lai, Jianfeng Pei
Adverse side effects of drug-drug interactions induced by human cytochrome P450 (CYP450) inhibition is an important consideration in drug discovery. It is highly desirable to develop computational models that can predict the inhibitive effect of a compound against a specific CYP450 isoform. In this study, we developed a multi-task model for concurrent inhibition prediction of five major CYP450 isoforms, namely 1A2, 2C9, 2C19, 2D6, and 3A4. The model was built by training multi-task autoencoder deep neural network (DNN) on a large dataset containing more than 13000 compounds, extracted from PubChem BioAssay Database...
May 18, 2018: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/29768713/clinical-drug-drug-interaction-potential-of-bfe1224-prodrug-of-antifungal-ravuconazole-using-two-types-of-cocktails-in-healthy-subjects
#2
Yasuyuki Ishii, Yuko Ito, Shunji Matsuki, Kasumi Sanpei, Osamu Ogawa, Kenji Takeda, Edgar L Schuck, Naoto Uemura
BFE1224, prodrug of ravuconazole, is a novel, once-daily, oral, triazole antifungal drug, and currently in development for the treatment of onychomycosis. The clinical drug-drug interaction (DDI) potential of BFE1224 with cytochrome P450 (CYP) and transporter was assessed by using two types of cocktails in healthy subjects in separate clinical studies. The CYP and transporter cocktails consisted of caffeine/tolbutamide/omeprazole/dextromethorphan/midazolam used in study 1 and digoxin/rosuvastatin used in study 2...
May 16, 2018: Clinical and Translational Science
https://www.readbyqxmd.com/read/29746911/n-demethylation-of-n-methyl-4-aminoantipyrine-the-main-metabolite-of-metamizole
#3
Fabio Bachmann, Urs Duthaler, Deborah Rudin, Stephan Krähenbühl, Manuel Haschke
Metamizole is an old analgesic used frequently in some countries. Active metabolites of metamizole are the non-enzymatically generated N-methyl-4-aminoantipyrine (4-MAA) and its demethylation product 4-aminoantipyrine (4-AA). Previous studies suggested that 4-MAA demethylation can be performed by hepatic cytochrome P450 (CYP) 3A4, but the possible contribution of other CYPs remains unclear. Using human liver microsomes (HLM), liver homogenate and HepaRG cells, we could confirm 4-MAA demethylation by CYPs. Based on CYP induction (HepaRG cells) and CYP inhibition (HLM) we could identify CYP2B6, 2C8, 2C9 and 3A4 as major contributors to 4-MAA demethylation...
May 8, 2018: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/29746595/insights-into-molecular-mechanisms-of-drug-metabolism-dysfunction-of-human-cyp2c9-30
#4
Maxime Louet, Céline M Labbé, Charline Fagnen, Cassiano M Aono, Paula Homem-de-Mello, Bruno O Villoutreix, Maria A Miteva
Cytochrome P450 2C9 (CYP2C9) metabolizes about 15% of clinically administrated drugs. The allelic variant CYP2C9*30 (A477T) is associated to diminished response to the antihypertensive effects of the prodrug losartan and affected metabolism of other drugs. Here, we investigated molecular mechanisms involved in the functional consequences of this amino-acid substitution. Molecular dynamics (MD) simulations performed for the active species of the enzyme (heme in the Compound I state), in the apo or substrate-bound state, and binding energy analyses gave insights into altered protein structure and dynamics involved in the defective drug metabolism of human CYP2C9...
2018: PloS One
https://www.readbyqxmd.com/read/29744741/effect-of-naltrexone-hydrochloride-on-cytochrome-p450-1a2-2c9-2d6-and-3a4-activity-in-human-liver-microsomes
#5
Haitham AlRabiah, Abdul Ahad, Gamal A E Mostafa, Fahad I Al-Jenoobi
BACKGROUND AND OBJECTIVE: Cytochrome P450 (CYP) 1A2, 2C9, 2D6, and 3A4 are the most important phase I drug-metabolizing enzymes in the liver, but there is a dearth of literature available on the effects of naltrexone hydrochloride on these major enzymes present in the human liver. Thus, in the present study, the effect of naltrexone hydrochloride on the activity of CYP1A2, 2C9, 2D6, and 3A4 using human liver microsomes (HLM) was investigated. METHODS: A selective probe for CYP1A2, 2C9, 2D6, and 3A4 was incubated with HLM with or without naltrexone hydrochloride...
May 9, 2018: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29735753/metabolism-and-disposition-of-siponimod-a-novel-selective-s1p1-s1p5-agonist-in-healthy-volunteers-and-in-vitro-identification-of-human-cytochrome-p450-enzymes-involved-in-its-oxidative-metabolism
#6
Ulrike Glaenzel, Yi Jin, Robert Nufer, Wenkui Li, Kirsten Schroer, Sylvie Adam-Stitah, Sjoerd Peter van Marle, Eric Legangneux, Hubert Borell, Alexander David James, Axel Meissner, Gian Camenisch, Anne Gardin
Siponimod, a next generation selective sphingosine-1-phosphate receptor modulator, is currently being investigated for the treatment of secondary progressive multiple sclerosis. We investigated the absorption, distribution, metabolism and excretion of a single oral dose of [14 C]siponimod 10 mg in four healthy male subjects. Mass balance, blood and plasma radioactivity, and plasma siponimod concentrations were measured. Metabolite profiles were determined in plasma, urine and feces. Metabolite structures were elucidated using mass spectrometry and comparison with reference compounds...
May 7, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29693578/a-metabolism-based-synergy-for-total-coumarin-extract-of-radix-angelicae-dahuricae-and-ligustrazine-on-migraine-treatment-in-rats
#7
Shan Feng, Xin He, Peiru Zhong, Jinyi Zhao, Cong Huang, Zhuohan Hu
Radix Angelicae dahuricae , containing coumarins, which might affect cytochrome P450 enzyme (CYP450) activity, has been co-administered with ligustrazine, a substrate of CYP450s, for the clinical treatment of migraine. However, whether a pharmacokinetic-based synergy exists between Radix Angelicae dahuricae and ligustrazine is still unknown. In this study, the total coumarin extract (TCE) of Radix Angelicae dahuricae (50 mg/kg, orally) reinforced the anti-migraine activity of ligustrazine by declining head scratching, plasma calcitonin gene-related peptide, and serum nitric oxide, as well as increasing plasma endothelin levels in rats ( p < 0...
April 25, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29676195/in-vitro-inhibitory-effects-of-sophocarpine-on-human-liver-cytochrome-p450-enzymes
#8
Jingwei Zhang, Chuansheng Li, Jingfa Zhang, Fan Zhang
1. Sophocarpine is a biologically active component isolated from the foxtail-like sophora herb and seed that is often orally administered for the treatment of cancer and chronic bronchial asthma. However, whether sophocarpine affects the activity of human liver cytochrome P450 (CYP) enzymes remains unclear. 2. In this study, the inhibitory effects of sophocarpine on the eight human liver CYP isoforms (CYP1A2, 3A4, 2A6, 2E1, 2D6, 2C9, 2C19, and 2C8) were investigated in vitro using human liver microsomes (HLMs)...
April 20, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
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
#9
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&ndash;drug interactions, the inhibitory effects of EAM-2201 on major drug-metabolizing enzymes, cytochrome P450s (CYPs) and uridine 5&prime;-diphospho-glucuronosyltransferases (UGTs) were evaluated in pooled human liver microsomes using liquid chromatography&ndash;tandem mass spectrometry (LC-MS/MS)...
April 16, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29651213/genetic-polymorphism-of-cyp2c9-among-sistani-ethnic-group-in-gorgan
#10
Abdoljalal Marjani, Aman Mohammad Gharanjik
Cytochrome P450 2C9 (CYP2C9) is involved in metabolism of many important drugs and its genotype variations is thought to affect drug efficacy and the treatment process. The aim of this study was to assess the distribution of CYP2C9 allele and genotypic variants in Sistani ethnic group, living in Gorgan, South East of Caspian Sea and North East of Iran. This study included 140 Sistani, referred to the health center of Gorgan. CYP2C9 genotyping was carried out by polymerase chain reaction-restriction fragment length polymorphism technique...
April 2018: Indian Journal of Clinical Biochemistry: IJCB
https://www.readbyqxmd.com/read/29628024/the-association-between-cyp2c9-2c19-polymorphisms-and-phenytoin-maintenance-doses-in-asian-epileptic-patients-a-systematic-review-and-meta-analysis
#11
Kai Liao, Yong Liu, Chun-Zhi Ai, Xi Yu, Wei Li
OBJECTIVE: Therapeutic response to phenytoin (PHT), a first-line antiepileptic drug (AED), is highly variable, in part likely due to genetic factors. Genetic polymorphisms in cytochrome P450 (CYP) 2C9 and CYP2C19 are expected to affect the metabolism of PHT and consequently affect its maintenance doses. We aimed to clarify the effects of genetic polymorphisms in both enzymes on daily PHT maintenance dosage in Asian epileptic patients by meta-analysis. MATERIALS AND METHODS: A systematic literature search was conducted in PubMed and EMBASE for relevant studies published prior to April 14, 2017...
April 9, 2018: International Journal of Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29626440/in-vivo-and-in-vitro-diclofenac-5-hydroxylation-mediated-primarily-by-cytochrome-p450-3a-enzymes-in-common-marmoset-livers-genotyped-for-p450-2c19-variants
#12
Kazuyuki Nakanishi, Shotaro Uehara, Takashi Kusama, Takashi Inoue, Kanami Shimura, Yusuke Kamiya, Norie Murayama, Makiko Shimizu, Yasuhiro Uno, Erika Sasaki, Hiroshi Yamazaki
Common marmosets (Callithrix jacchus) are potentially useful nonhuman primate models for preclinical studies. An anti-inflammatory drug, diclofenac is reportedly metabolized mainly by human cytochrome P450 (P450) 2C9 to 4'-hydroxydiclofenac and minorly by P450 3A4 to 5-hydroxydiclofenac that leads to reactive intermediates. In this study, in vivo pharmacokinetics in six marmosets and in vitro metabolism in nine marmoset liver microsomes were analyzed using diclofenac to evaluate marmosets as preclinical drug metabolism models...
April 4, 2018: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29622878/the-influence-of-cyp2c9-and-vkorc1-gene-polymorphisms-on-the-response-to-warfarin-in-egyptians
#13
Ahmed M L Bedewy, Salah Showeta, Mostafa Hasan Mostafa, Lamia Saeed Kandil
Warfarin is the most commonly used drug for chronic prevention of thromboembolic events, it also ranks high among drugs that cause serious adverse events. The variability in dose requirements has been attributed to inter-individual differences in medical, personal, and genetic factor. Cytochrome P-450 2C9 is the principle enzyme that terminates the anticoagulant effect of warfarin by catalyzing the conversion of the pharmacologically more potent S-enantiomer to its inactive metabolites. Warfarin exerts its effect by inhibition of vitamin K epoxide reductase...
April 2018: Indian Journal of Hematology & Blood Transfusion
https://www.readbyqxmd.com/read/29618712/cytochrome-p450-dependent-drug-oxidation-activities-in-commercially-available-hepatocytes-derived-from-human-induced-pluripotent-stem-cells-cultured-for-3-weeks
#14
Norie Murayama, Hiroshi Yamazaki
Hepatocyte-like cells differentiated from human induced pluripotent stem (iPS) cells are of great interest for applications in pharmacological research. For drug metabolism testing, commercially available hepatocytes derived from human iPS cells are generally recommended to be used 1 week after seeding on plates. In this study, however, after 3-4 weeks of culture according to the manufacturer's instructions, human cytochrome P450 (P450) 2C9- and 2C19-dependent diclofenac 4'-hydroxylation and omeprazole 5-hydroxylation activities of the iPS-derived hepatocytes had significantly increased above the activities at 1 week and had reached levels similar to those in HepaRG cells, a human hepatocyte-like cell line...
2018: Journal of Toxicological Sciences
https://www.readbyqxmd.com/read/29616291/the-role-of-hepatic-cytochrome-p450s-in-the-cytotoxicity-of-dronedarone
#15
Si Chen, Qiangen Wu, Baitang Ning, Matthew Bryant, Lei Guo
Dronedarone is used to treat patients with cardiac arrhythmias and has been reported to be associated with liver injury. Our previous mechanistic work demonstrated that DNA damage-induced apoptosis contributes to the cytotoxicity of dronedarone. In this study, we examined further the underlying mechanisms and found that after a 24-h treatment of HepG2 cells, dronedarone caused cytotoxicity, G1-phase cell cycle arrest, suppression of topoisomerase II, and DNA damage in a concentration-dependent manner. We also investigated the role of cytochrome P450s (CYPs)-mediated metabolism in the dronedarone-induced toxicity using our previously established HepG2 cell lines expressing individually 14 human CYPs (1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5, and 3A7)...
April 3, 2018: Archives of Toxicology
https://www.readbyqxmd.com/read/29588194/using-chemical-bond-based-method-to-predict-site-of-metabolism-for-five-biotransformations-mediated-by-cyp-3a4-2d6-and-2c9
#16
XuYan Fu, ShuaiBing He, Li Du, ZhaoLei Lv, Yi Zhang, Qian Zhang, Yun Wang
Although it has been proposed for decades to predict site of metabolism (SOM) by in silico methods, identifying SOM correctly remains an unsolved fundamental problem and is an active area of research. In our prior works, we proposed a chemical bond-based approach to construction of SOM prediction models by integrating chemical bond descriptors and drug-metabolizing enzymes data. Although it has been evaluated with both 10-fold cross-validation and independent validation, we believe comparisons between this method and prior methods using publicly accessible external datasets are indispensable and more desirable...
March 24, 2018: Biochemical Pharmacology
https://www.readbyqxmd.com/read/29577257/pharmacogenetics-of-vitamin-k-antagonists-and-bleeding-risk-prediction-in-atrial-fibrillation
#17
María José Serna, José Miguel Rivera-Caravaca, Rocío Gonzalez-Conejero, María Asunción Esteve-Pastor, Mariano Valdés, Vicente Vicente, Gregory Y H Lip, Vanessa Roldán, Francisco Marín
BACKGROUND: Polymorphisms in the vitamin K epoxide reductase complex 1 (VKORC1) and cytochrome P450 2C9 (CYP2C9) genes increase the bleeding risk in anticoagulated atrial fibrillation (AF) patients. Here, we aimed to investigate whether VKORC1 and CYP2C9 polymorphisms improved the predictive performance for major bleeding using the HAS-BLED score. MATERIAL AND METHODS: We recruited 652 consecutive AF patients stable on vitamin K antagonist (INR 2.0-3.0) during at least the previous 6 months...
March 25, 2018: European Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29572664/identification-of-cytochrome-p450-mediated-drug-drug-interactions-at-risk-in-cases-of-gene-polymorphisms-by-using-a-quantitative-prediction-model
#18
Nicolas Fermier, Laurent Bourguignon, Sylvain Goutelle, Nathalie Bleyzac, Michel Tod
BACKGROUND AND OBJECTIVE: The magnitude of drug-drug interactions mediated by cytochrome P450 (CYP) may depend on the genotype of polymorphic cytochromes. The objective of this study was to identify drug-drug interactions with greater magnitude in CYP variant groups than in extensive metabolizers. METHODS: The in-vivo mechanistic static model was used to predict the area under the curve ratio of drug-drug interactions. Five cytochromes (CYP3A4/5, 2D6, 2C9, 2C19, 1A2) and five groups of genotypes for each polymorphic cytochrome (CYP2D6, 2C9, 2C19) were considered...
March 23, 2018: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/29538081/pharmacogenetic-variants-and-vitamin-k-deficiency-a-risk-factor-or-trigger-for-fibrosing-interstitial-pneumonias
#19
Marjolein Drent, Petal Wijnen, Aalt Bast
PURPOSE OF REVIEW: Fibrosing interstitial pneumonias are associated with various stages of fibrosis. The cause of this group of syndromes remains largely unknown. For most of these diseases, a genetic basis, environmental factors and certain triggers have been suggested as possible risk factors. Various studies have found an association between genetic polymorphisms, or the presence of certain variant alleles, and the occurrence and/or progression of interstitial pneumonias of unknown origin...
May 2018: Current Opinion in Pulmonary Medicine
https://www.readbyqxmd.com/read/29522717/altered-metabolism-of-synthetic-cannabinoid-jwh-018-by-human-cytochrome-p450-2c9-and-variants
#20
Amy L Patton, Kathryn A Seely, Azure L Yarbrough, William Fantegrossi, Laura P James, Keith R McCain, Ryoichi Fujiwara, Paul L Prather, Jeffery H Moran, Anna Radominska-Pandya
Synthetic cannabinoids (SCBs), synonymous with 'K2', 'Spice' or 'synthetic marijuana', are psychoactive drugs of abuse that frequently result in clinical effects and toxicity more severe than those classically associated with Δ9 -tetrahydrocannabinol such as extreme agitation, hallucinations, supraventricular tachycardia, syncope, and seizures. JWH-018 is one of the earliest compounds identified in various SCB products, and our laboratory previously demonstrated that JWH-018 undergoes extensive metabolism by cytochromes P450 (P450), binds to, and activates cannabinoid receptors (CBRs)...
April 6, 2018: Biochemical and Biophysical Research Communications
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