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cytochrome p450 3A4

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https://www.readbyqxmd.com/read/29453687/impact-of-boosted-antiretroviral-therapy-on-the-pharmacokinetics-and-efficacy-of-clopidogrel-and-prasugrel-active-metabolites
#1
Niloufar Marsousi, Youssef Daali, Pierre Fontana, Jean-Luc Reny, Virginie Ancrenaz-Sirot, Alexandra Calmy, Serge Rudaz, Jules Alexandre Desmeules, Caroline Flora Samer
BACKGROUND AND OBJECTIVES: Prasugrel and clopidogrel are inhibitors of the ADP-P 2 Y 12 platelet receptor used in acute coronary syndrome patients. They require bioactivation via isoenzymes such as cytochrome P450 (CYP) 3A4, CYP2C19 and CYP2B6. Ritonavir and cobicistat are potent CYP3A inhibitors, prescribed as pharmacokinetic (PK) enhancers in the treatment of human immunodeficiency virus (HIV) infection. METHODS: In this study, the impact of boosted antiretroviral therapies (ARTs) on the PK of clopidogrel and prasugrel active metabolites (AMs), and on the efficacy of prasugrel and clopidogrel, were evaluated in a randomized crossover clinical trial...
February 16, 2018: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/29453492/application-of-physiologically-based-pharmacokinetic-modeling-to-the-prediction-of-drug-drug-and-drug-disease-interactions-for-rivaroxaban
#2
Ruijuan Xu, Weihong Ge, Qing Jiang
PURPOSE: Rivaroxaban is a direct oral anticoagulant with a large inter-individual variability. The present study is to develop a physiologically based pharmacokinetic (PBPK) model to predict several scenarios in clinical practice. METHODS: A whole-body PBPK model for rivaroxaban, which is metabolized by the cytochrome P450 (CYP) 3A4/5, 2J2 pathways and excreted via kidneys, was developed to predict the pharmacokinetics at different doses in healthy subjects and patients with hepatic or renal dysfunction...
February 17, 2018: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29450233/pharmacogenomics-guided-policy-in-opioid-use-disorder-oud-management-an-ethnically-diverse-case-based-approach
#3
Earl B Ettienne, Edwin Chapman, Mary Maneno, Adaku Ofoegbu, Bradford Wilson, Beverlyn Settles-Reaves, Melissa Clarke, Georgia Dunston, Kevin Rosenblatt
Introduction: Opioid use disorder (OUD) is characterized by a problematic pattern of opioid use leading to clinically-significant impairment or distress. Opioid agonist treatment is an integral component of OUD management, and buprenorphine is often utilized in OUD management due to strong clinical evidence for efficacy. However, interindividual genetic differences in buprenorphine metabolism may result in variable treatment response, leaving some patients undertreated and at increased risk for relapse...
December 2017: Addictive Behaviors Reports
https://www.readbyqxmd.com/read/29440179/role-of-c-jun-n-terminal-kinase-in-pregnane-x-receptor-mediated-induction-of-human-cytochrome-p4503a4-in-vitro
#4
Guncha Taneja, Chun Chu, Paramahamsa Maturu, Bhagavatula Moorthy, Romi Ghose
Cytochrome P450 (CYP) 3A4 is the most abundant drug metabolizing enzyme and is responsible for the metabolism of ~50% of clinically available drugs. Induction of CYP3A4 impacts the disposition of its substrates and leads to harmful clinical consequences such as failure of therapy. In order to prevent such undesirable consequences, molecular mechanisms of regulation of CYP3A4 need to be fully understood. CYP3A4 induction is primarily regulated by the xenobiotic nuclear receptor, pregnane-X-receptor (PXR). After ligand binding, PXR is transported to the nucleus, where it binds to the CYP3A4 promoter and induces its gene expression...
February 12, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29421559/enrichment-of-high-functioning-human-ips-cell-derived-hepatocyte-like-cells-for-pharmaceutical-research
#5
Kazuo Takayama, Yasuko Hagihara, Yukiko Toba, Kiyotoshi Sekiguchi, Fuminori Sakurai, Hiroyuki Mizuguchi
Human iPS cell-derived hepatocyte-like cells are expected to be utilized in pharmaceutical research. However, the purity of high-functioning hepatocyte-like cells is not high enough. In particular, the purity of cytochrome P450 3A4 (CYP3A4), which is a representative hepatic drug-metabolizing enzyme, positive cells is still quite low (approximately 20%). To address this problem, we established the CYP3A4-NeoR-EGFP transgenic reporter human iPS cell line (CYP3A4-NeoR-EGFP iPS cells) by using genome editing technology...
January 18, 2018: Biomaterials
https://www.readbyqxmd.com/read/29414036/theoretical-insights-into-imidazolidine-oxidation-of-imidacloprid-by-cytochrome-p450-3a4
#6
Mei Lin Zheng, Chao Rui Li, Qun Hua Bai, Hong Xiao, Wei Hu, Ying Xue, Jie Ying Gao
The metabolic mechanisms for imidazolidine oxidation of imidacloprid (IMI) by cytochrome P450 3A4 (CYP3A4) have been investigated using quantum mechanical/molecular mechanical (QM/MM) calculations. The binding mode of CYP3A4 with IMI is examined by molecular docking in collaboration with molecular dynamics (MD) simulations. The results show that there are six amino acid residues, involving Arg192, Phe195, Ile349, Ala285, Phe284 and Phe88, closely distributed around the IMI. The binding free energy analysis exhibits that the CYP3A4-IMI binding structure is stabilized by electrostatic interaction and van der Waals interaction...
January 12, 2018: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/29414024/metabolism-of-flavonolignans-in-human-hepatocytes
#7
Jiří Vrba, Barbora Papoušková, Lenka Roubalová, Martina Zatloukalová, David Biedermann, Vladimír Křen, Kateřina Valentová, Jitka Ulrichová, Jan Vacek
This study examined the in vitro biotransformation of eight structurally related flavonolignans, namely silybin, 2,3-dehydrosilybin, silychristin, 2,3-dehydrosilychristin, silydianin, 2,3-dehydrosilydianin, isosilybin A and isosilybin B. The metabolic transformations were performed using primary cultures of human hepatocytes and recombinant human cytochromes P450 (CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4). The metabolites produced were analyzed by ultra-performance liquid chromatography coupled with tandem mass spectrometry...
January 30, 2018: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/29412463/the-drug-drug-interaction-profile-of-presatovir
#8
Yan Xin, Winnie Weng, Bernard P Murray, Eugene J Eisenberg, Jason W Chien, John Ling, Jeffrey A Silverman
Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infections in young children. Presatovir (previously GS-5806) is a novel, orally administered RSV fusion inhibitor with a favorable safety profile and proven antiviral efficacy in preclinical and clinical studies. In vitro, presatovir is a substrate of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) and hepatic uptake transporters organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 and is slowly metabolized by cytochrome P450 (CYP) 3A4 and CYP3A5...
February 7, 2018: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29394111/functional-characterization-of-21-cyp3a4-variants-on-amiodarone-metabolism-in-vitro
#9
Cheng-Cheng Yang, Xiang Zheng, Teng-Hui Liu, Chen-Chen Wang, Peng-Fei Tang, Zhe Chen, Bo-Wen Zhang, Ping Fang, Guo-Xin Hu, Jian-Ping Cai
Cytochrome P450 3A4 (CYP3A4)is an important member of the cytochrome P450 enzyme superfamily, with 33 allelic variants reported previously. Genetic polymorphisms of CYP3A4 can produce a significantly effect on the efficacy and safety of some drugs, so the purpose of this study was to clarify the catalytic characteristics of 22 CYP3A4 allelic isoforms, including 6 novel variants in Han Chinese population, on the oxidative metabolism of amiodarone in vitro. Wild-type CYP3A4*1 and other variants expressed by insect cells system were incubated respectively with 10-500 μM substrate for 40 min at 37°C and terminated at -80°C immediately...
February 2, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29382727/membrane-embedded-substrate-recognition-by-cytochrome-p450-3a4
#10
John C Hackett
Cytochrome P450 3A4 (CYP3A4) is the dominant xenobiotic-metabolizing enzyme in the liver and intestine and is involved in the disposition of more than 50% of drugs. Owing to its ability to bind multiple substrates, its reaction kinetics are complex, and its association with the microsomal membrane confounds our understanding of how this enzyme recognizes and recruits diverse substrates. Testosterone (TST) hydroxylation is the prototypical CYP3A4 reaction, displaying positive homotropic cooperativity with three binding sites...
January 30, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29374135/sulfenylation-of-human-liver-and-kidney-microsomal-cytochromes-p450-and-other-drug-metabolizing-enzymes-as-a-response-to-redox-alteration
#11
Matt Albertolle, Thanh T N Phan, Ambra Pozzi, F Peter Guengerich
The lumen of the endoplasmic reticulum (ER) provides an oxidizing environment to aid in the formation of disulfide bonds, which is tightly regulated by both antioxidant proteins and small molecules. On the cytoplasmic side of the ER, cytochrome P450 (P450) proteins have been identified as a superfamily of enzymes that are important in the formation of endogenous chemicals as well as in the detoxication of xenobiotics. Our previous report described oxidative inhibition of P450 Family 4 enzymes via oxidation of the heme-thiolate cysteine to a sulfenic acid (-SOH) (Albertolle, M...
January 26, 2018: Molecular & Cellular Proteomics: MCP
https://www.readbyqxmd.com/read/29363349/drug-metabolism-in-early-infancy-opioids-as-an-illustration
#12
Tamara van Donge, Paola Mian, Dick Tibboel, John van den Anker, Karel Allegaert
Drug dosing in infants frequently depends on body weight as a crude indicator for maturation. Fentanyl (metabolized by Cytochrome P450 3A4) and morphine (glucuronidated by UDP-glucuronosyltransferase-2B7) served as model drugs to provide insight in maturation patterns of these enzymes and provide understanding of the impact of non-maturational factors to optimize dosing in infants. Areas covered: Systematic searches on metabolism and population pharmacokinetic (Pop-PK) models for fentanyl and morphine were performed...
January 24, 2018: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/29353349/daclatasvir-a-review-of-preclinical-and-clinical-pharmacokinetics
#13
REVIEW
Yash Gandhi, Timothy Eley, Aberra Fura, Wenying Li, Richard J Bertz, Tushar Garimella
Daclatasvir is a first-in-class, highly selective, hepatitis C virus, non-structural protein 5a polymerase replication complex inhibitor with picomolar potency and broad genotypic coverage in vitro. Daclatasvir undergoes rapid absorption, with a time to reach maximum plasma concentration of 1-2 h and an elimination half-life of ~ 10 to 14 h observed in single-ascending dose studies. Steady state was achieved by day 4 in multiple-ascending dose studies. Daclatasvir can be administered without regard to food or pH modifiers...
January 20, 2018: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/29330782/characterization-of-the-pharmacokinetics-of-vilaprisan-bioavailability-excretion-biotransformation-and-drug-drug-interaction-potential
#14
Marcus-Hillert Schultze-Mosgau, Joachim Höchel, Olaf Prien, Torsten Zimmermann, Ashley Brooks, Jim Bush, Antje Rottmann
BACKGROUND AND OBJECTIVES: In-vitro data suggest that clearance of vilaprisan is mediated by cytochrome P450 3A4 (oxidation) and aldoketoreductases (reduction). To fully understand the elimination and biotransformation pathways of vilaprisan, a selective progesterone receptor modulator, and to quantify the impact of cytochrome P450 3A4 inhibition on the pharmacokinetics of vilaprisan, two clinical studies in healthy postmenopausal women were conducted. METHODS: In study 1, pharmacokinetics, mass balance, and metabolite patterns were determined after single oral administration of 5 mg of [14C]-labeled vilaprisan in six subjects...
January 12, 2018: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/29330715/case-series-analysis-of-new-zealand-reports-of-rapid-intense-potentiation-of-warfarin-by-roxithromycin
#15
Ruth L Savage, Michael V Tatley
INTRODUCTION: We undertook an analysis of all the reports to the New Zealand Centre for Adverse Reactions Monitoring of a roxithromycin/warfarin interaction after two recent reports described intense rapid warfarin potentiation. The interaction was first published in 1995. Cytochrome P450 3A4 inhibition has been the proposed mechanism but has limited biologic plausibility. There are suggestions that the clinical significance of the interaction may be increased by severe illness, polypharmacy, renal dysfunction, older age and increased warfarin sensitivity...
January 12, 2018: Drug Safety: An International Journal of Medical Toxicology and Drug Experience
https://www.readbyqxmd.com/read/29329342/ternary-copper-ii-complex-nci60-screening-toxicity-studies-and-evaluation-of-efficacy-in-xenograft-models-of-nasopharyngeal-carcinoma
#16
Munirah Ahmad, Shazlan-Noor Suhaimi, Tai-Lin Chu, Norazlin Abdul Aziz, Noor-Kaslina Mohd Kornain, D S Samiulla, Kwok-Wai Lo, Chew-Hee Ng, Alan Soo-Beng Khoo
Copper(II) ternary complex, [Cu(phen)(C-dmg)(H2O)]NO3 was evaluated against a panel of cell lines, tested for in vivo efficacy in nasopharyngeal carcinoma xenograft models as well as for toxicity in NOD scid gamma mice. The Cu(II) complex displayed broad spectrum cytotoxicity against multiple cancer types, including lung, colon, central nervous system, melanoma, ovarian, and prostate cancer cell lines in the NCI-60 panel. The Cu(II) complex did not cause significant induction of cytochrome P450 (CYP) 3A and 1A enzymes but moderately inhibited CYP isoforms 1A2, 2C9, 2C19, 2D6, 2B6, 2C8 and 3A4...
2018: PloS One
https://www.readbyqxmd.com/read/29310511/cytochrome-p450-2a6-and-other-human-p450-enzymes-in-the-oxidation-of-flavone-and-flavanone
#17
Kensaku Kakimoto, Norie Murayama, Shigeo Takenaka, Haruna Nagayoshi, Young-Ran Lim, Vitchan Kim, Donghak Kim, Hiroshi Yamazaki, Masayuki Komori, F Peter Guengerich, Tsutomu Shimada
1. We previously reported that flavone and flavanone interact spectrally with cytochrome P450 (P450 or CYP) 2A6 and 2A13 and other human P450s and inhibit catalytic activities of these P450 enzymes. In this study, we studied abilities of CYP1A1, 1A2, 1B1, 2A6, 2A13, 2C9, and 3A4 to oxidize flavone and flavanone. 2. Human P450s oxidized flavone to 6- and 5-hydroxylated flavones, seven uncharacterized mono-hydroxylated flavones, and five di-hydroxylated flavones. CYP2A6 was most active in forming 6-hydroxy- and 5-hydroxyflavones and several mono- and di-hydroxylated products...
January 9, 2018: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29310431/the-binding-specificity-determines-the-cytochrome-p450-3a4-mediated-enantioselective-metabolism-of-metconazole
#18
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/29291439/novel-non-sulfonamide-5-ht6-receptor-partial-inverse-agonist-in-a-group-of-imidazo-4-5-b-pyridines-with-cognition-enhancing-properties
#19
David Vanda, Miroslav Soural, Vittorio Canale, Séverine Chaumont-Dubel, Grzegorz Satała, Tomasz Kos, Petr Funk, Veronika Fülöpová, Barbora Lemrová, Paulina Koczurkiewicz, Elżbieta Pękala, Andrzej J Bojarski, Piotr Popik, Philippe Marin, Paweł Zajdel
A small library of novel 3H-imidazo[4,5-b]pyridine and 1H-imidazo[4,5-c]pyridine derivatives was designed and synthesized as non-sulfonamide 5-HT6 receptor ligands. In vitro evaluation allowed to identify compound 17 (2-ethyl-3-(3-fluorobenzyl)-7-(piperazin-1-yl)-3H-imidazo[4,5-b]pyridine) as potent 5-HT6 receptor partial inverse agonist in Gs signaling (Ki = 6 nM, IC50 = 17.6 nM). Compound 17 displayed high metabolic stability, favorable cytochrome P450 isoenzyme (2D6, 3A4) profile, did not affect PgP-protein binding, without evoking mutagenic effects...
December 16, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29283173/cyp3a4-inducer-and-inhibitor-strongly-affect-the-pharmacokinetics-of-triptolide-and-its-derivative-in-rats
#20
Ye Xu, Yi-Fan Zhang, Xiao-Yan Chen, Da-Fang Zhong
Triptolide is the most active ingredient of Tripterygium wilfordii Hook F, which is used to treat rheumatoid arthritis. (5R)-5-Hydroxytriptolide is a hydroxylation derivative of triptolide with a reduced toxicity. To investigate the metabolic enzymes of the two compounds and the drug-drug interactions with enzyme inducers or inhibitors, a series of in vitro and in vivo experiments were conducted. In vitro studies using recombinant human cytochrome P450 enzyme demonstrated that cytochrome P450 3A4 (CYP3A4) was predominant in the metabolism of triptolide and (5R)-5-hydroxytriptolide, accounting for 94...
December 28, 2017: Acta Pharmacologica Sinica
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