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CYP3A4/5

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https://www.readbyqxmd.com/read/29454157/nanofibrous-plga-electrospun-scaffolds-modified-with-type-i-collagen-influence-hepatocyte-function-and-support-viability-in-vitro
#1
Jessica H Brown, Prativa Das, Michael D DiVito, David Ivancic, Lay Poh Tan, Jason A Wertheim
A major challenge of maintaining primary hepatocytes in vitro is progressive loss of hepatocyte-specific functions, such as protein synthesis and cytochrome P450 (CYP450) catalytic activity. We developed a three-dimensional (3D) nanofibrous scaffold made from poly(L-lactide-co-glycolide) (PLGA) polymer using a newlyoptimizedwet electrospinning techniquethat resulted in a highly porous structure that accommodated inclusion of primary human hepatocytes. Extracellular matrix (ECM) proteins (type I collagen or fibronectin) at varying concentrations were chemically linked to electrospun PLGA using amine coupling to develop an in vitro culture system containing the minimal essential ECM components of the liver micro-environment that preserve hepatocyte function in vitro...
February 14, 2018: Acta Biomaterialia
https://www.readbyqxmd.com/read/29439571/characterized-in-vitro-metabolism-kinetics-of-alkyl-organophosphate-flame-retardants-in-fish-liver-and-intestinal-microsomes
#2
Rui Hou, Chao Huang, Kaifeng Rao, Yiping Xu, Zijian Wang
Tris(2-butoxyethyl) phosphate (TBOEP) and tris(n-butyl) phosphate (TNBP) are the most commonly used alkyl organophosphate esters (alkyl-OPEs), and they increasingly accumulate in organisms and create potential health hazards. This study examined the metabolism of TNBP and TBOEP in Carassius carassius liver and intestinal microsomes and the production of their corresponding mono-hydroxylated and dealkylated metabolites. After 140 min of incubation with fish liver microsomes, the rapid depletion of TNBP and TBOEP were both best fitted to Michaelis-Menten model (at administrated concentrations ranged from 0...
February 13, 2018: Environmental Science & Technology
https://www.readbyqxmd.com/read/29439084/evaluating-the-impact-of-type-2-diabetes-mellitus-on-cyp450-metabolic-activities-protocol-for-a-case-control-pharmacokinetic-study
#3
Sophie Gravel, Jean-Louis Chiasson, Suzanne Dallaire, Jacques Turgeon, Veronique Michaud
INTRODUCTION: Diabetes affects more than 9% of the adult population worldwide. Patients with type 2 diabetes mellitus (T2DM) show variable responses to some drugs which may be due, in part, to variability in the functional activity of drug-metabolising enzymes including cytochromes P450 (CYP450s). CYP450 is a superfamily of enzymes responsible for xenobiotic metabolism. Knowledge must be gained on the impact of T2DM and related inflammatory processes on drug metabolism and its consequences on drug response...
February 8, 2018: BMJ Open
https://www.readbyqxmd.com/read/29427135/guiding-dose-adjustment-of-amlodipine-after-co-administration-with-ritonavir-containing-regimens-using-a-physiologically-based-pharmacokinetic-pharmacodynamic-model
#4
Dwaipayan Mukherjee, Jiuhong Zha, Rajeev M Menon, Mohamad Shebley
Amlodipine, a commonly prescribed anti-hypertensive drug, shows increased systemic exposure with cytochrome P450 (CYP) 3A inhibitors. Ritonavir (RTV) is a potent mechanism-based and reversible CYP3A inhibitor and moderate inducer that is used as a pharmacokinetic enhancer in several antiviral treatment regimens. Drug-drug interaction (DDI) between RTV and amlodipine is due to mixed inhibition and induction of CYP3A4, which is challenging to predict without a mechanistic model that accounts for the complexity of both mechanisms occurring simultaneously...
February 9, 2018: Journal of Pharmacokinetics and Pharmacodynamics
https://www.readbyqxmd.com/read/29399736/oxygen-drives-hepatocyte-differentiation-and-phenotype-stability-in-liver-cell-lines
#5
Martien van Wenum, Aziza A A Adam, Vincent A van der Mark, Jung-Chin Chang, Manon E Wildenberg, Erik J Hendriks, Aldo Jongejan, Perry D Moerland, Thomas M van Gulik, Ronald P Oude Elferink, Robert A F M Chamuleau, Ruurdtje Hoekstra
The in vitro generation of terminally differentiated hepatocytes is an unmet need. We investigated the contribution of oxygen concentration to differentiation in human liver cell lines HepaRG and C3A. HepaRG cells were cultured under hypoxia (5%O2), normoxia (21%O2) or hyperoxia (40%O2). Cultures were analysed for hepatic functions, gene transcript levels, and protein expression of albumin, hepatic transcription factor CEBPα, hepatic progenitor marker SOX9, and hypoxia inducible factor (HIF)1α. C3A cells were analysed after exposure to normoxia or hyperoxia...
February 4, 2018: Journal of Cell Communication and Signaling
https://www.readbyqxmd.com/read/29393278/effect-of-oridonin-on-cytochrome-p450-expression-and-activities-in-heparg-cell
#6
Yi-Wen Zhang, Xiao-Wei Zheng, Yu-Jia Liu, Luo Fang, Zong-Fu Pan, Mei-Hua Bao, Ping Huang
Oridonin, the major terpene found in Rabdosia rubescens, is widely used as a dietary supplement or therapeutic drug. However, the effects of oridonin on major CYP450s are still unclear. As oridonin can enhance the effect of other clinical drugs, in this study, we investigated the influence of oridonin on CYP450s mRNA expression and its impact on activities in human HepaRG cell to evaluate the safety by studying its potential drug interaction. HepaRG cells were cultured with series concentrations of oridonin (1, 5, 10, and 20 μmol/L), and the major CYP450s mRNA and protein expression, as well as enzyme activities were analyzed by real-time polymerase chain reaction, Western blot analysis and UPLC-MS/MS-based metabolite assay...
January 26, 2018: Pharmacology
https://www.readbyqxmd.com/read/29381358/3-r-4-r-6-2-bromo-4-fluorophenyl-5-ethoxycarbonyl-2-thiazol-2-yl-3-6-dihydropyrimidin-4-yl-methyl-morpholin-2-yl-propanoic-acid-hec72702-a-novel-hepatitis-b-virus-capsid-inhibitor-based-on-clinical-candidate-gls4
#7
Qingyun Ren, Xinchang Liu, Guanghua Yan, Biao Nie, Zhifu Zou, Jing Li, Yunfu Chen, Yu Wei, Jianzhou Huang, Zhonghua Luo, Baohua Gu, Siegfried Goldmann, Jiancun Zhang, Yingjun Zhang
The inhibition of hepatitis B virus (HBV) capsid assembly is a novel strategy for the development of chronic hepatitis B (CHB) therapeutics. On the basis of the preclinical properties and clinical results of GLS4, we carried out further investigation to seek a better candidate compound with appropriate anti-HBV potency, reduced hERG activity, decreased CYP enzyme induction, and improved pharmacokinetic (PK) properties. To this end, we have successfully found that morpholine carboxyl analogues with comparable anti-HBV activities to that of GLS4 showed decreased hERG activities, but they displayed strong CYP3A4 induction in a concentration-dependent manner, except for morpholine propionic acid analogues...
January 30, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29377228/developmental-pharmacogenetics-of-cyp2c19-in-neonates-and-young-infants-omeprazole-as-a-probe-drug
#8
Wei Zhao, Stéphanie Leroux, Valérie Biran, Evelyne Jacqz-Aigrain
BACKGROUND: Although substantial progress has been made in understanding of ontogeny of drug metabolism, there is still a gap of knowledge in developmental pharmacogenetics in neonates. We hypothesized that both age and pharmacogenetics might explain the developmental pattern of CYP2C19. We conducted a population pharmacokinetic-pharmacogenetic study to quantify the developmental pharmacogenetics of CYP2C19 in neonates and young infants using omeprazole as a probe drug. METHODS: Pharmacokinetic samples were collected from 51 Caucasian neonates and young infants, who were receiving omeprazole treatment...
January 28, 2018: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29362093/functional-characterization-of-naturally-occurring-wild-soybean-mutant-sg-5-lacking-astringent-saponins-using-whole-genome-sequencing-approach
#9
Hafiz Mamoon Rehman, Muhammad Amjad Nawaz, Zahid Hussain Shah, Seung Hwan Yang, Gyuhwa Chung
Triterpenoid saponins are one of the most highly accumulated groups of functional components in soybean (Glycine max) and the oxidative reactions during their biosynthesis are required for their aglycone diversity. Natural mutants of soyasaponins in wild soybean (Glycine soja) are valuable resources for establishing the soyasaponin biosynthesis pathway and breeding new soybean varieties. In this study, we investigated the genetic mechanism behind the absence of group A saponins in a Korean wild soybean mutant, CWS5095...
February 2018: Plant Science: An International Journal of Experimental Plant Biology
https://www.readbyqxmd.com/read/29359661/colchicine-pharmacokinetics-and-mechanism-of-action
#10
Christos Angelidis, Zoi Kotsialou, Charalampos Kossyvakis, Agathi-Rosa Vrettou, Achilleas Zacharoulis, Fotios Kolokathis, Vasilios Kekeris, Georgios Giannopoulos
Colchicine is a tricyclic, lipid-soluble alkaloid derived from the plant of the Lily family Colchicum autumnale, sometimes called the "autumn crocus". It is predominantly metabolized in the gastrointestinal tract. Two proteins, P-glycoprotein (P-gp) and CYP3A4 seem to play a pivotal role, governing its pharmacokinetic. The commonest side effects are gastrointestinal (nausea, vomiting and particularly dose-related-diarrhea) occurring in 5-10% of patients. Colchicine exerts its unique action mainly through inhibition of microtubule polymerization...
January 22, 2018: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/29345044/preclinical-characterisation-of-absorption-distribution-metabolism-and-excretion-properties-of-tak-063
#11
Kimio Tohyama, Miyako Sudo, Akio Morohashi, Suguru Kato, Junzo Takahashi, Yoshihiko Tagawa
TAK-063 is currently being developed to treat schizophrenia. In this study, we investigated the absorption, distribution, metabolism and excretion (ADME) properties of TAK-063 using several paradigms. Following oral administration of TAK-063 at 0.3 mg/kg, bioavailability of TAK-063 was 27.4% in rats and 49.5% in dogs with elimination half-lives of 3.1 hr in rats and 3.7 hr in dogs. TAK-063 is a highly permeable compound without P-glycoprotein (P-gp) or breast cancer resistance protein substrate liability and can be readily absorbed into systemic circulation via the intestine...
January 17, 2018: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29343979/the-influence-of-cyp3a5-polymorphisms-on-haloperidol-treatment-in-patients-with-alcohol-addiction
#12
Mikhail Sergeevich Zastrozhin, Elena Anatolievna Grishina, Kristina Anatolievna Ryzhikova, Valery Valerievich Smirnov, Ludmila Mikhailovna Savchenko, Evgeny Alekseevich Bryun, Dmitry Alekseevich Sychev
Background: Isoenzymes CYP2D6 and CYP3A4, the activity of which varies widely, are involved in metabolism of haloperidol and may influence its profile of efficacy and safety. Objective: The primary aim of this study was to estimate the relationship between CYP3A5 gene polymorphism, activity of the CYP3A isoenzyme, and the risk of development of adverse drug reactions by haloperidol in patients with alcohol abuse. Methods: Sixty-six male alcohol-addicted patients participated in the study...
2018: Pharmacogenomics and Personalized Medicine
https://www.readbyqxmd.com/read/29338933/physiological-based-pharmacokinetic-modeling-to-estimate-in%C3%A2-vivo-ki-of-ketoconazole-on-renal-p-gp-using-human-drug-drug-interaction-study-result-of-fesoterodine-and-ketoconazole
#13
Masayo Oishi, Yuma Takano, Yutaka Torita, Bimal Malhotra, Koji Chiba
This study was conducted to estimate in vivo inhibition constant (Ki) of ketoconazole on renal P-glycoprotein (P-gp) using human drug-drug interaction (DDI) study result of fesoterodine and ketoconazole. Fesoterodine is a prodrug which is extensively hydrolyzed by non-specific esterases to the active metabolite 5-hydroxymethyl tolterodine (5-HMT). 5-HMT is then further metabolized via Cytochrome P450 (CYP) 2D6 and CYP3A4. It is reported that 5-HMT is a substrate of P-gp whereas fesoterodine is not. Renal clearance of 5-HMT is approximately two-times greater than renal glomerular filtration rate...
November 15, 2017: Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/29333880/pharmacogenetic-analysis-of-opioid-dependence-treatment-dose-and-dropout-rate
#14
Richard C Crist, James Li, Glenn A Doyle, Alex Gilbert, Bryan M Dechairo, Wade H Berrettini
BACKGROUND: Currently, no pharmacogenetic tests for selecting an opioid-dependence pharmacotherapy have been approved by the US Food and Drug Administration. OBJECTIVES: Determine the effects of variants in 11 genes on dropout rate and dose in patients receiving methadone or buprenorphine/naloxone (ClinicalTrials.gov Identifier: NCT00315341). METHODS: Variants in six pharmacokinetic genes (CYP1A2, CYP2B6, CYP2C19, CYP2C9, CYP2D6, CYP3A4) and five pharmacodynamic genes (HTR2A, OPRM1, ADRA2A, COMT, SLC6A4) were genotyped in samples from a 24-week, randomized, open-label trial of methadone and buprenorphine/naloxone for the treatment of opioid dependence (n = 764; 68...
January 15, 2018: American Journal of Drug and Alcohol Abuse
https://www.readbyqxmd.com/read/29325225/influence-of-cyp2d6-cyp3a4-cyp3a5-and-abcb1-polymorphisms-on-pharmacokinetics-and-safety-of-aripiprazole-in-healthy-volunteers
#15
Carmen Belmonte, Dolores Ochoa, Manuel Román, Miriam Saiz-Rodríguez, Aneta Wojnicz, Clara Isabel Gómez-Sánchez, Samuel Martín-Vilchez, Francisco Abad-Santos
The aim of this study was to investigate the effect of polymorphisms in cytochrome P450 (CYP) 2D6, CYP3A4 and CYP3A5 enzymes and in P-glycoprotein (P-gp) on the pharmacokinetics and safety of aripiprazole and, its active metabolite, dehydro-aripiprazole, in 148 healthy volunteers from 6 bioequivalence trials receiving a single oral dose of aripiprazole. The plasma concentrations of both analytes were measured by LC-MS/MS. CYP2D6 (*3,*4,*5,*6,*7,*9 and copy number variations), CYP3A4 (*20 and *22), CYP3A5*3 and C3435T, C1236T and G2677T/A in ABCB1 gene were determined...
January 11, 2018: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29311093/characterization-of-the-preclinical-pharmacology-of-the-new-2-aminomethylphenol-jpc-3210-for-malaria-treatment-and-prevention
#16
Geoffrey W Birrell, Gavin D Heffernan, Guy A Schiehser, John Anderson, Arba L Ager, Pablo Morales, Donna MacKenzie, Karin van Breda, Marina Chavchich, Laura R Jacobus, G Dennis Shanks, David P Jacobus, Michael D Edstein
The new 2-aminomethylphenol JPC-3210 has potent in vitro antimalarial activity against multidrug-resistant Plasmodium falciparum lines, low cytotoxicity and high in vivo efficacy against murine malaria. Here we report on the pharmacokinetics of JPC-3210 in mice and monkeys and in vitro screening assays including the inhibition of cytochrome (CYP) P450 isozymes. In mice JPC-3210 is rapidly absorbed, has extensive tissue distribution with a brain tissue to plasma concentration ratio of about 5.4 and a lengthy plasma elimination half-life of about 4...
January 8, 2018: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/29310431/the-binding-specificity-determines-the-cytochrome-p450-3a4-mediated-enantioselective-metabolism-of-metconazole
#17
Shulin Zhuang, Leili Zhang, Tingjie Zhan, Liping Lu, Lu Zhao, Haifei Wang, Joseph A Morrone, Weiping Liu, Ruhong Zhou
Cytochrome CYP3A4 is the most promiscuous enzyme mediating biotransformations of ~50% of clini-cally used drugs with many of them chiral molecules. Probing the interactions between CYP3A4 and chiral chemicals is thus essential for the elucidation of molecular mechanisms of the enantioselective metabolism. We developed a step-wise restrained molecular dynamics (MD) method to model the hu-man CYP3A4 in a complex with the cis-Metconazole (MEZ) isomers and performed conventional MD simulations with a total simulation time of 2...
January 8, 2018: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/29304859/a-phase-1-evaluation-of-the-pharmacokinetic-pharmacodynamic-interaction-of-the-anti-malarial-agents-kaf156-and-piperaquine
#18
F Joel Leong, Jay Prakash Jain, Yiyan Feng, Budhaditya Goswami, Daniel S Stein
BACKGROUND: KAF156 is a novel imidazolopiperazine anti-malarial with activity against pre-erythrocytic liver stages, asexual and sexual blood stages. Based on in vitro data, a two-way pharmacokinetic interaction was hypothesized for KAF156 use in combination with piperaquine (PPQ) as both drugs are CYP3A4 substrates and inhibitors. Potential combination effects on the QT interval were also assessed. METHODS: This was an open-label, parallel-group, single-dose study in healthy volunteers randomized to three parallel arms (1:1:1) of 800 mg KAF156 + 1280 mg PPQ, 800 mg KAF156 alone and 1280 mg PPQ alone...
January 5, 2018: Malaria Journal
https://www.readbyqxmd.com/read/29301387/pharmacogenetics-of-vascular-risk-factors-in-alzheimer-s-disease
#19
REVIEW
Ramón Cacabelos, Arun Meyyazhagan, Juan C Carril, Pablo Cacabelos, Óscar Teijido
Alzheimer's disease (AD) is a polygenic/complex disorder in which genomic, epigenomic, cerebrovascular, metabolic, and environmental factors converge to define a progressive neurodegenerative phenotype. Pharmacogenetics is a major determinant of therapeutic outcome in AD. Different categories of genes are potentially involved in the pharmacogenetic network responsible for drug efficacy and safety, including pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes. However, most drugs exert pleiotropic effects that are promiscuously regulated for different gene products...
January 3, 2018: Journal of Personalized Medicine
https://www.readbyqxmd.com/read/29297772/assessment-of-drug-drug-interaction-potential-and-pbpk-modeling-of-cc-223-a-potent-inhibitor-of-the-mammalian-target-of-rapamycin-kinase
#20
Zeen Tong, Rangaraj Narayanan, Christian Atsriku, Jim Nissel, Yan Li, Hong Liu, Xiaomin Wang, Sekhar Surapaneni
1. CC-223 was studied in vitro for metabolism and drug-drug interactions (DDI), and in clinic for interaction with ketoconazole. 2. In vitro, human metabolites of CC-223 included O-desmethyl CC-223 (M1), keto (M2), N-oxide (M3), and imine (M13), with M1 being the most prominent metabolite. 3. CC-223 was metabolized by CYP2C9 and CYP3A, while metabolism of M1 was mediated by CYP2C8 and CYP3A. Ketoconazole increased CC-223 and M1 exposure by 60-70% in healthy volunteers. 4. CC-223 (IC50 ≥ 27 µM) and M1 (IC50 ≥ 46 µM) were inhibitors of CYP2C9 and CYP2C19 in human liver microsomes...
January 3, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
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