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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
#1
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/29778080/atrazine-xenobiotic-nuclear-receptor-interactions-induce-cardiac-inflammation-and-endoplasmic-reticulum-stress-in-quail-coturnix-coturnix-coturnix
#2
Xue-Nan Li, Yu-Zhu Zuo, Lei Qin, Wei Liu, Yan-Hua Li, Jin-Long Li
Atrazine (ATR) is one of the most extensively used herbicide that eventually leaches into groundwater and surface water from agricultural areas. Exposure to ATR does harm to the health of human and animals, especially the heart. However, ATR exposure caused cardiotoxicity in bird remains unclear. To evaluate ATR-exerted potential cardiotoxicity in heart, quail were exposed with 0, 50, 250, and 500 mg/kg BW/day ATR by gavage treatment for 45 days. Cardiac histopathological alternation was observed in ATR-induced quail...
May 9, 2018: Chemosphere
https://www.readbyqxmd.com/read/29777510/clopidogrel-pharmacogenetics-in-iranian-patients-undergoing-percutaneous-coronary-intervention
#3
Nejat Mahdieh, Ahmad Rabbani, Ata Firouzi, Ali Zahedmehr, Maryam Hoseinimoghaddam, Sedigheh Saeidi, Hamidreza Sanati, Hosseinali Basiri, Feridoun Noohi, Bahareh Rabbani, Majid Maleki
Clopidogrel is used in patients with coronary syndromes and at risk of thrombotic events or receiving percutaneous coronary intervention (PCI) for reducing heart attack and stroke. Here we present genotype and phenotype study of Iranian patients undergoing PCI treated with clopidogrel during a 6-month period of follow-up; common variants of CYP2C19, CYP3A5, CYP3A4, and ABCB1 genes were determined as well as the patients' cardiovascular outcomes to find out the effect of these variants individually and in combination...
May 18, 2018: Cardiovascular Toxicology
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
#4
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/29773500/an-analysis-on-distribution-and-inter-relationships-of-biomarkers-under-rivaroxaban-in-japanese-patients-with-non-valvular-atrial-fibrillation-cvi-aro-1
#5
Shinya Suzuki, Takeshi Yamashita, Hidefumi Kasai, Takayuki Otsuka, Koichi Sagara
Prothrombin time (PT) has been widely used for measuring anticoagulation intensity under rivaroxaban therapy, but precise information has not been well established yet. Consecutive 96 non-valvular atrial fibrillation (NVAF) under rivaroxaban between Jan/June, 2015 were recruited. Serum concentration (SC) and PT with 5 representative reagents available in Japan (Neoplastin Plus®, Thromborel S®, Thrombocheck PT®, Thrombocheck PT Plus®, and Recombiplastin®) at 2-4 hours after (peak) and before intake of rivaroxaban (trough) were measured at outpatient clinic in the cardiovascular institute (CVI ARO study 1)...
March 15, 2018: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29767851/risk-factors-for-vitamin-d-deficiency-in-sickle-cell-disease
#6
Jin Han, Xu Zhang, Santosh L Saraf, Michel Gowhari, Robert E Molokie, Johara Hassan, Shivi Jain, Binal N Shah, Taimur Abbasi, Roberto F Machado, Victor R Gordeuk
Vitamin D deficiency (VDD), 25-OHD levels <20 ng/ml, is prevalent among patients with sickle cell disease (SCD) and is linked to acute and chronic pain and bone fracture in this population. There is limited literature regarding VDD-associated risk factors for SCD. We examined potential clinical and genomic parameters associated with VDD in 335 adults with SCD in a cross-sectional study. VDD was present in 65% of adult SCD patients, and 25-OHD levels independently and positively correlated with older age (P < 0·001) and vitamin D supplementation (P < 0·001)...
May 16, 2018: British Journal of Haematology
https://www.readbyqxmd.com/read/29765150/phase-i-studies-of-azd1208-a-proviral-integration-moloney-virus-kinase-inhibitor-in-solid-and-haematological-cancers
#7
Jorge Cortes, Kenji Tamura, Daniel J DeAngelo, Johann de Bono, David Lorente, Mark Minden, Geoffrey L Uy, Hagop Kantarjian, Lisa S Chen, Varsha Gandhi, Robert Godin, Karen Keating, Kristen McEachern, Karthick Vishwanathan, Janet Elizabeth Pease, Emma Dean
BACKGROUND: Proviral integration Moloney virus (PIM) kinases (PIM1, 2 and 3) are overexpressed in several tumour types and contribute to oncogenesis. AZD1208 is a potent ATP-competitive PIM kinase inhibitor investigated in patients with recurrent or refractory acute myeloid leukaemia (AML) or advanced solid tumours. METHODS: Two dose-escalation studies were performed to evaluate the safety and tolerability, and to define the maximum tolerated dose (MTD), of AZD1208 in AML and solid tumours...
May 16, 2018: British Journal of Cancer
https://www.readbyqxmd.com/read/29762875/in-vivo-assessment-of-the-effect-of-cyp1a2-inhibition-and-induction-on-pomalidomide-pharmacokinetics-in-healthy-subjects
#8
Yan Li, Liangang Liu, Xiaomin Wang, Chengyue Zhang, Josephine Reyes, Matthew Hoffmann, Maria Palmisano, Simon Zhou
Pomalidomide is an immunomodulatory drug, and the dosage of 4 mg per day taken orally on days 1-21 of repeated 28-day cycles has been approved in the European Union and the United States to treat patients with relapsed/refractory multiple myeloma. In vitro data showed that pomalidomide is a substrate of multiple cytochrome P450 (CYP) isozymes and that its oxidative metabolism is mediated primarily by CYP1A2 and CYP3A4, with minor contributions from CYP2C19 and CYP2D6. The effect of CYP1A2 inhibition by fluvoxamine (a strong CYP1A2 inhibitor) and CYP1A2 induction by smoking on pomalidomide pharmacokinetics in healthy subjects has been assessed in 2 separate phase 1 open-label, single-dose studies...
May 15, 2018: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29761173/liver-enriched-transcription-factor-expression-relates-to-chronic-hepatic-failure-in-humans
#9
Jorge Guzman-Lepe, Eduardo Cervantes-Alvarez, Alexandra Collin de l'Hortet, Yang Wang, Wendy M Mars, Yoshinao Oda, Yuki Bekki, Masahiro Shimokawa, Huanlin Wang, Tomoharu Yoshizumi, Yoshihiko Maehara, Aaron Bell, Ira J Fox, Kazuki Takeishi, Alejandro Soto-Gutierrez
The mechanisms by which the liver fails in end-stage liver disease remain elusive. Disruption of the transcription factor network in hepatocytes has been suggested to mediate terminal liver failure in animals. However, this hypothesis remains unexplored in human subjects. To study the relevance of transcription factor expression in terminal stages of chronic liver failure in humans, we analyzed the expression of liver-enriched transcription factors (LETFs) hepatocyte nuclear factor (HNF)4α, HNF1α, forkhead box protein A2 (FOXA2), CCAAT/enhancer-binding protein (CEBP)α, and CEBPβ...
May 2018: Hepatology Communications
https://www.readbyqxmd.com/read/29753067/drug-interaction-study-of-flavonoids-toward-cyp3a4-and-their-quantitative-structure-activity-relationship-qsar-analysis-for-predicting-potential-effects
#10
Yannan Li, Jing Ning, Yan Wang, Chao Wang, Chengpeng Sun, Xiaokui Huo, Zhenlong Yu, Lei Feng, Baojing Zhang, Xiangge Tian, Xiaochi Ma
The high risk of herb-drug interactions (HDIs) mediated by the herbal medicines and dietary supplements which containing abundant flavonoids had become more and more frequent in our daily life. In our study, the inhibition activities of 44 different structures of flavonoids toward human CYPs were systemically evaluated for the first time. According to our results, a remarkable structure-dependent inhibition behavior toward CYP3A4 was observed in vitro. Some flavonoids such as licoflavone (12) and irilone (30) exhibited the selective inhibition toward CYP3 A4 rather than other major human CYPs...
May 9, 2018: Toxicology Letters
https://www.readbyqxmd.com/read/29749249/hplc-high-resolution-mass-spectrometry-with-polarity-switching-for-increasing-throughput-of-human-in-vitro-cocktail-drug-drug-interaction-assay
#11
Ragu Ramanathan, Anima Ghosal, Lakshmi Ramanathan, Kate Comstock, Helen Shen, Dil Ramanathan
AIM: Evaluation of HPLC-high-resolution mass spectrometry (HPLC-HRMS) full scan with polarity switching for increasing throughput of human in vitro cocktail drug-drug interaction assay. MATERIALS & METHODS: Microsomal incubates were analyzed using a high resolution and high mass accuracy Q-Exactive mass spectrometer to collect integrated qualitative and quantitative (Qual/Quant) data. RESULTS: Within assay, positive-to-negative polarity switching HPLC-HRMS method allowed quantification of eight and two probe compounds in the positive and negative ionization modes, respectively, while monitoring for LOR and its metabolites...
May 11, 2018: Bioanalysis
https://www.readbyqxmd.com/read/29746397/impact-of-drug-interactions-on-clobazam-and-n-desmethylclobazam-concentrations-in-pediatric-patients-with-epilepsy
#12
Gabrielle R Russell, Stephanie J Phelps, Chasity M Shelton, James W Wheless
BACKGROUND: Clobazam (CLB) is approved as adjunctive treatment for seizures associated with Lennox-Gastaut syndrome in patients ≥2 years of age. It is converted to an active metabolite N-desmethylclobazam (NCLB) by CYP3A4, which is then broken down to an inactive metabolite by CYP2C19. This study characterizes the impact of CYP3A4 and CYP2C19 drug interactions on CLB and NCLB serum concentrations (Cp) and concentration/dose (Cp/D) ratios in pediatric patients with epilepsy. METHODS: This was a retrospective chart review including patients >1 month of age, who received CLB between April 2012 and March 2017...
May 4, 2018: Therapeutic Drug Monitoring
https://www.readbyqxmd.com/read/29744867/p-glycoprotein-mdr1-abcb1-restricts-brain-accumulation-and-cytochrome-p450-3a-cyp3a-limits-oral-availability-of-the-novel-alk-ros1-inhibitor-lorlatinib
#13
Wenlong Li, Rolf W Sparidans, Yaogeng Wang, Maria C Lebre, Els Wagenaar, Jos H Beijnen, Alfred H Schinkel
Lorlatinib (PF-06463922) is a promising oral anaplastic lymphoma kinase (ALK) and ROS1 inhibitor currently in Phase III clinical trials for treatment of non-small cell lung cancer (NSCLC) containing an ALK rearrangement. With therapy-resistant brain metastases a major concern in NSCLC, lorlatinib was designed to have high membrane and blood-brain barrier permeability. We investigated the roles of the multidrug efflux transporters ABCB1 and ABCG2, and the multispecific drug-metabolizing enzyme CYP3A in plasma pharmacokinetics and tissue distribution of lorlatinib using genetically modified mouse strains...
May 9, 2018: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29744741/effect-of-naltrexone-hydrochloride-on-cytochrome-p450-1a2-2c9-2d6-and-3a4-activity-in-human-liver-microsomes
#14
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/29741901/stereoselective-metabolism-of-omeprazole-by-cytochrome-p-450-2c19-and-3a4-mechanistic-insights-from-dft-study
#15
Kalyanashis Jana, Tusar Bandyopadhyay, Bishwajit Ganguly
The efficacy of S-omeprazole as proton pump inhibitor compared to its enantiomer R-omeprazole is studied using density functional theoretical calculations. The pharmacokinetic studies suggest that the efficacy of S-omeprazole presumably depends on metabolic pathway and excretion from the human body. The DFT calculations at SMDWater -B3LYP-D3/6-311+G(d,p)/LANL2DZ//B3LYP/6-31G(d)/LANL2DZ with triradicaloid model active species, [Por•+ FeIV (SH)O], of the CYP2C19 enzyme with high spin quartet and low spin doublet states demonstrate C-H bond activation mechanism through a two-state rebound process for hydroxylation of R-omeprazole and S-omeprazole...
May 9, 2018: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/29739809/application-of-physiologically-based-pharmacokinetic-modeling-in-understanding-bosutinib-drug-drug-interactions-importance-of-intestinal-p-glycoprotein
#16
Shinji Yamazaki, Cho-Ming Loi, Emi Kimoto, Chester Costales, Manthena V Varma
Bosutinib is an orally available Src/Abl tyrosine kinase inhibitor indicated for the treatment of patients with Ph+ chronic myelogenous leukemia at a clinically recommended dose of 500 mg once daily. Clinical results indicated that increases in bosutinib oral exposures were supra-proportional at the lower doses (50 to 200 mg) and approximately dose-proportional at the higher doses (200 to 600 mg). Bosutinib is a substrate of CYP3A4 and P-glycoprotein and exhibits pH-dependent solubility with moderate intestinal permeability...
May 8, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29738669/cypreact-a-software-tool-for-in-silico-reactant-prediction-for-human-cytochrome-p450-enzymes
#17
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/29736778/effects-of-polymorphisms-in-nr1i2-cyp3a4-and-abc-transporters-on-the-steady-state-plasma-trough-concentrations-of-bosutinib-in-japanese-patient-with-chronic-myeloid-leukemia
#18
Maiko Abumiya, Akiko Mita, Saori Takahashi, Tomoko Yoshioka, Yoshihiro Kameoka, Naoto Takahashi, Masatomo Miura
We investigated the effects of polymorphisms in NR1I2 (7635A>G, 8055C>T), CYP3A4 (20230G>A), ABCB1 (1199G>A, 1236C>T, 2677G>T/A, 3435C>T), and ABCG2 (421C>A) on the mean plasma trough concentrations (C0 ) of bosutinib at the steady-state in 30 Japanese patients with chronic myeloid leukemia. Bosutinib C0 values were monitored using high-performance liquid chromatography. The median coefficient of variation (CV) value of the bosutinib C0 for one patient (intrapatient) during bosutinib therapy was 25...
May 7, 2018: Medical Oncology
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
#19
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/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
#20
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
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