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CYP3A4/5

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https://www.readbyqxmd.com/read/28418906/the-associations-of-genetic-polymorphisms-in-cyp1a2-and-cyp3a4-with-clinical-outcomes-of-breast-cancer-patients-in-northern-china
#1
Xianan Bai, Jingjing Xie, Shanshan Sun, Xianyu Zhang, Yongdong Jiang, Da Pang
BACKGROUND: Cytochrome P450 (CYP) 1A2 and CYP3A4 may play a role in the differentiation of clinical outcomes among breast cancer women. This study aimed to analyze the association of genetic polymorphisms in the CYP1A2 and CYP3A4 genes with clinicopathological features, protein expression and prognosis of breast cancer in the northern Chinese population. RESULTS: Firstly, SNP rs11636419, rs17861162 and rs2470890 in the CYP1A2 were significantly associated with age and menstruation status...
March 18, 2017: Oncotarget
https://www.readbyqxmd.com/read/28414290/-the-effect-of-isatin-on-protein-protein-interactions-between-cytochrome-b5-and-cytochromes-p450
#2
P V Ershov, E O Yablokov, Yu V Mezentsev, L A Kalushskiy, A V Florinskaya, A V Veselovsky, O V Gnedenko, A A Gilep, S A Usanov, A E Medvedev, A S Ivanov
Cytochromes P450 (CYP) are involved in numerous biochemical processes including metabolism of xenobiotics, biosynthesis of cholesterol, steroid hormones etc. Since some CYP catalyze indol oxidation to isatin, we have hypothesized that isatin can regulate protein-protein interactions (PPI) between components of the CYP system thus representing a (negative?) feedback mechanism. The aim of this study was to investigate a possible effect of isatin on interaction of human CYP with cytochrome b5 (CYB5A). Using the optical biosensor test system employing surface plasmon resonance (SPR) we have investigated interaction of immobilized CYB5A with various CYP in the absence and in the presence of isatin...
March 2017: Biomedit︠s︡inskai︠a︡ Khimii︠a︡
https://www.readbyqxmd.com/read/28414242/discovery-of-2-2-ethyl-6-4-2-3-hydroxyazetidin-1-yl-2-oxo-ethyl-piperazin-1-yl-8-methyl-imidazo-1-2-a-pyridin-3-yl-methyl-amino-4-4-fluorophenyl-thiazole-5-carbonitrile-glpg1690-a-first-in-class-autotaxin-inhibitor-undergoing-clinical-evaluation-for-the-treatment
#3
Nicolas Desroy, Christopher Housseman, Xavier Bock, Agnès Joncour, Natacha Bienvenu, Laëtitia Cherel, Virginie Labeguere, Emilie Rondet, Christophe Peixoto, Jean-Marie Joël Grassot, Olivier Picolet, Denis Annoot, Nicolas Triballeau, Alain Monjardet, Emanuelle Wakselman, Veronique Roncoroni, Sandrine Le Tallec, Roland Blanque, Celine Cottereaux, Nele Vandervoort, Thierry Christophe, Patrick Mollat, Marieke B A C Lamers, Marielle Auberval, Boska Hrvacic, Jovica Ralic, Line Oste, Ellen Van der Aar, Reginald Brys, Bertrand Heckmann
Autotaxin is a circulating enzyme with a major role in the production of lysophosphatic acid (LPA) species in blood. A role for the autotaxin/LPA axis has been suggested in many disease areas including pulmonary fibrosis. Structural modifications of the known autotaxin inhibitor lead compound 1, to attenuate hERG inhibition, remove CYP3A4 time-dependent inhibition and improve pharmacokinetic properties, led to the identification of clinical candidate GLPG1690 (11). Compound 11 was able to cause a sustained reduction of LPA levels in plasma in vivo and was shown to be efficacious in a bleomycin-induced pulmonary fibrosis model in mice, and in reducing extra-cellular matrix deposition in the lung whilst also reducing LPA 18:2 content in bronchoalveolar lavage fluid...
April 17, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28411281/long-term-stability-of-cryopreserved-human-hepatocytes-evaluation-of-phase-i-and-ii-drug-metabolizing-enzyme-activities-and-cyp3a4-5-induction-for-more-than-a-decade
#4
Miyako Sudo, Mitsuhiro Nishihara, Junzo Takahashi, Satoru Asahi
We evaluated the long term stability of hepatocytes stored in vapor phase of liquid nitrogen for their viability, cytochrome P450 (CYP) 1A2 activity, CYP3A4/5 activity, uridine diphosphate-glucuronosyl transferase (UGT) activity, sulfotransferase (SULT) activity, and CYP3A4/5 induction during 14 years of preservation. No substantial degradation of viability, CYP1A2 activity, UGT activity, or CYP3A4/5 induction was observed. CYP3A4/5 activity showed a slight decrease after 7 years of storage, and SULT activity gradually decreased during storage, although substantial activities remained even after 14 years...
April 14, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28407303/rifampicin-reverses-nicardipine-effect-inducing-uncontrolled-essential-hypertension
#5
Elena-Mihaela Cordeanu, Sébastien Gaertner, Alix Faller, Corina Mirea, Jean-Marc Lessinger, Veronique Kemmel, Dominique Stephan
Dihydropyridine calcium-channel blockers are a known substrate for the cytochrome P450 isoform 3A4. Rifampicin, an antitubercular agent, is one of the most potent inducers of hepatic and intestinal CYP3A4 thus increasing dihydropyridine metabolism. We report a case of a 67-year-old hypertensive female treated with a 4-drug antihypertensive regimen including a dihydropyridine (nicardipine 50mg bid), who was admitted for septic arthritis of the knee requiring antibiotic treatment with teicoplanin 400mg od and rifampicin 600mg bid...
April 13, 2017: Fundamental & Clinical Pharmacology
https://www.readbyqxmd.com/read/28393710/rolapitant-a-nk-1-receptor-antagonist-for-the-prevention-of-chemotherapy-induced-nausea-and-vomiting
#6
Bernardo Leon Rapaport
BACKGROUND: Nausea and vomiting are among the most feared side effects of chemotherapy and can prevent cancer patients from completing their treatment regimens. Rolapitant is a highly selective neurokinin-1 (NK-1) receptor antagonist with very good oral activity, central nervous system penetration and a long (180-hour) plasma half-life. Unlike other available NK-1 receptor antagonists, rolapitant does not inhibit or induce cytochrome P450 (CYP) 3A4. METHODS: Findings from recent phase II and III clinical trials of rolapitant in patients receiving highly or moderately emetogenic chemotherapy are reviewed and discussed...
April 6, 2017: Reviews on Recent Clinical Trials
https://www.readbyqxmd.com/read/28379598/sildenafil-associated-hepatoxicity-a-review-of-the-literature
#7
S Graziano, A Montana, S Zaami, M C Rotolo, A Minutillo, F P Busardò, E Marinelli
Sildenafil citrate (Viagra®) is a vasoactive agent available worldwide since 1998 for the treatment of male erectile dysfunction. It is a selective phosphodiesterase type 5-enzyme inhibitor able to potentiate the downstream effects of nitric oxide on smooth muscle relaxation and vasodilation through its effects on the cyclic guanosine monophosphate (c-GMP) pathway in the erectile tissue of the penis. When sildenafil is orally administered, it is rapidly absorbed with a maximum plasma concentration achieved within 1 h and has a terminal half-life of between 3 to 6 h...
March 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/28376844/carboxylate-derivatives-of-tributyltin-iv-complexes-as-anticancer-and-antileishmanial-agents
#8
Durdana Waseem, Arshad Farooq Butt, Ihsan-Ul Haq, Moazzam Hussain Bhatti, Gul Majid Khan
BACKGROUND: Tributyltin (IV) compounds are promising candidates for drug development. In the current study, we evaluated in-vitro and in-silico profile of carboxylate derivatives of tributyltin (IV) complexes. METHODS: ADMET and drug-likeliness properties were predicted using MetaPrint2D React, preADMET, SwissADME and Molsoft tools. SwissTargetPrediction predicted molecular targets for compounds. In-vitro bioactivity was evaluated by quantifying cytotoxicity against HepG2, THP-1 cell lines, isolated lymphocytes and leishmania promastigotes as well as measuring protein kinase (PK) inhibition activity...
April 4, 2017: Daru: Journal of Faculty of Pharmacy, Tehran University of Medical Sciences
https://www.readbyqxmd.com/read/28376352/metabolic-profiling-of-five-flavonoids-from-dragon-s-blood-in-human-liver-microsomes-using-high-performance-liquid-chromatography-coupled-with-high-resolution-mass-spectrometry
#9
Yujuan Li, Yushi Zhang, Rui Wang, Lizhong Wei, Yulin Deng, Wei Ren
Although much is known about the pharmacological activities of Dragon's Blood (DB, a traditional Chinese herb), its metabolism in human liver microsomes (HLMs) and the cytochrome P450 (CYP) enzymes has not been studied. This study aims to identify the metabolic profile of five flavonoids (loureirin A, loureirin B, loureirin C, 7,4'-dihydroxyflavone and 5,7,4'-trihydroxyflavanone) from DB in HLMs as well as the CYP enzymes that are involved in the metabolism of them. High-resolution mass spectrometry was used to characterize the structures of their metabolites and 10 cDNA-expressed CYP enzymes (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4 and CYP3A5) were used to verify which isozymes mediate in the metabolism of the metabolites...
March 27, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/28359180/influence-of-grapefruit-juice-on-pharmacokinetics-of-triptolide-in-rats
#10
Yuzhen Jia, Jie Liu, Jisen Xu
1. Triptolide, a major pharmacological component isolated from Tripterygium wilfordii Hook F (TWHF), is a substrate of both CYP3A4 and P-glycoprotein (P-gp). 2. This study investigates the effects of GFJ on the pharmacokinetics of triptolide in rats. 3. The pharmacokinetics of orally administered triptolide with or without GFJ pretreatment were investigated. A mechanistic study was also undertaken using the Caco-2 cell transwell model and rat liver microsomes incubation systems to support the in vivo pharmacokinetic data...
March 31, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28355069/design-synthesis-and-pharmacological-characterization-of-n-4-2-6-7-dimethoxy-3-4-dihydroisoquinolin-2-1h-yl-ethyl-phenyl-quinazolin-4-amine-derivatives-novel-inhibitors-reversing-p-glycoprotein-mediated-multidrug-resistance
#11
Qianqian Qiu, Baomin Liu, Jian Cui, Zheng Li, Xin Deng, Hao Qiang, Jieming Li, Chen Liao, Bo Zhang, Wei Shi, Miaobo Pan, Wenlong Huang, Hai Qian
P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a principal obstacle for successful cancer chemotherapy. A novel P-gp inhibitor with a quinazoline scaffold, 12k, was considered to be the most promising for in-depth study. 12k possessed high potency (EC50 = 57.9 ± 3.5 nM), low cytotoxicity, and long duration of activity in reversing doxorubicin (DOX) resistance in K562/A02 cells. 12k also boosted the potency of other MDR-related cytotoxic agents with different structures, increased accumulation of DOX, blocked P-gp-mediated Rh123 efflux, and suppressed P-gp ATPase activity in K562/A02 MDR cells...
April 5, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28352156/fixed-dose-combination-orally-disintegrating-tablets-to-treat-cardiovascular-disease-formulation-in-vitro-characterization-and-physiologically-based-pharmacokinetic-modeling-to-assess-bioavailability
#12
Thomas J Dennison, Julian C Smith, Raj K Badhan, Afzal R Mohammed
Cardiovascular disease (CVD) is the leading cause of death among men and women worldwide. In CVD, hypertension and dyslipidemia commonly coexist and are managed through coadministration of amlodipine and atorvastatin, respectively. The case for fixed-dose combination (FDC) oral dosage forms and orally disintegrating tablet (ODT) technology to enhance outcomes and compliance is strong. This work follows the development and characterization of single and FDC ODTs containing amlodipine and atorvastatin, followed by bioequivalence comparison between these single and FDC formulations, using in vitro dissolution and Caco-2 apparent permeability (Papp) and in silico physiologically based pharmacokinetic modeling approaches...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/28342193/metabolism-of-the-tryptamine-derived-new-psychoactive-substances-5-meo-2-me-dalt-5-meo-2-me-alcht-and-5-meo-2-me-dipt-and-their-detectability-in-urine-studied-by-gc-ms-lc-ms-n-and-lc-hr-ms-ms
#13
Achim T Caspar, Jonas B Gaab, Julian A Michely, Simon D Brandt, Markus R Meyer, Hans H Maurer
Many N,N-dialkylated tryptamines show psychoactive properties and were encountered as new psychoactive substances. The aims of the presented work were to study the phase I and II metabolism and the detectability in standard urine screening approaches (SUSA) of 5-methoxy-2-methyl-N,N-diallyltryptamine (5-MeO-2-Me-DALT), 5-methoxy-2-methyl-N-allyl-N-cyclohexyltryptamine (5-MeO-2-Me-ALCHT), and 5-methoxy-2-methyl-N,N-diisopropyltryptamine (5-MeO-2-Me-DIPT) using GC-MS, LC-MS(n) , and LC-HR-MS/MS. For metabolism studies, urine was collected over a 24-h period after administration of the compounds to male Wistar rats at 20 mg/kg body weight (BW)...
March 24, 2017: Drug Testing and Analysis
https://www.readbyqxmd.com/read/28322152/serotonin-receptor-binding-characteristics-of-geissoschizine-methyl-ether-an-indole-alkaloid-in-uncaria-hook
#14
Yasushi Ikarashi, Kyoji Sekiguchi, Kazushige Mizoguchi
Geissoschizine methyl ether (GM) is one of the indole alkaloids in Uncaria hook, and an active ingredient of yokukansan (YKS) that improves behavioral and psychological symptoms of dementia (BPSD) in patients with several types of dementia. The pharmacological action of GM has been related to various serotonin (5-HT) receptor subtypes. Here we describe previous findings and our own data to review the binding characteristics of GM to the 5-HT receptor subtypes. Competitive receptor-binding assays showed that GM bound the following 5-HT receptor subtypes: 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT4, 5-HT5A, 5-HT6, and 5-HT7...
March 20, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28301431/cyp3a4-activity-is-markedly-lower-in-patients-with-crohn-s-disease
#15
Aze Wilson, Rommel G Tirona, Richard B Kim
BACKGROUND: Disease-dependent changes in the activity of drug metabolizing enzymes and transporters, such as Cytochrome P450 (CYP) 3A4 and P-glycoprotein (P-gp), are thought to have a major influence on the disposition of shared substrates. However, little is known regarding the in vivo relevance of these 2 proteins during drug therapy for gastrointestinal diseases. Our aim was to elucidate the activity of CYP3A4 and P-gp in subjects with Crohn's disease (CD) and to evaluate their influence on budesonide pharmacokinetics...
May 2017: Inflammatory Bowel Diseases
https://www.readbyqxmd.com/read/28301096/effects-of-tenapanor-on-cytochrome-p450-mediated-drug-drug-interactions
#16
Susanne Johansson, David P Rosenbaum, Marie Ahlqvist, Helen Rollison, Mikael Knutsson, Bergur Stefansson, Marie Elebring
Tenapanor (RDX5791, AZD1722) is an inhibitor of sodium/hydrogen exchanger isoform 3 in development for the treatment of constipation-predominant irritable bowel syndrome and the treatment of hyperphosphatemia in patients with chronic kidney disease on dialysis. We aimed to investigate whether tenapanor inhibits or induces cytochrome P450s (CYPs). In vitro experiments assessing the potential of tenapanor to affect various CYPs indicated that it could inhibit CYP3A4/5 (IC50 0.4-0.7 μM). An open-label, phase 1 clinical study (NCT02140268) evaluated the pharmacokinetics of the CYP3A4 substrate midazolam when administered with and without tenapanor...
March 16, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28272018/genetic-polymorphisms-of-cytochrome-p450-enzymes-cyp2c9-cyp2c19-cyp2d6-cyp3a4-and-cyp3a5-in-the-croatian-population
#17
Lana Ganoci, Tamara Božina, Nikica Mirošević Skvrce, Mila Lovrić, Petar Mas, Nada Božina
BACKGROUND: Data on the frequency of pharmacogenetic polymorphisms in the Croatian population are limited. We determined and analyzed frequencies for the most important CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 genetic variants in the Croatian population. METHODS: 2637 subjects were included. Genotyping was performed by real-time polymerase chain reaction (PCR) using TaqMan® DME or TaqMan® SNP Genotyping Assays, and by PCR, and PCR-RFLP analysis. RESULTS: For CYP2C9, allele frequencies of *2 and *3 variant were 14...
March 1, 2017: Drug Metabolism and Personalized Therapy
https://www.readbyqxmd.com/read/28261841/a-sensitive-quantitative-assay-for-the-determination-of-propafenone-and-two-metabolites-5-hydroxypropafenone-and-n-depropylpropafenone-in-human-k2edta-plasma-using-lc-ms-ms-with-esi-operated-in-a-positive-mode
#18
Harilal Patel, Ashok Ghoghari, Chandrakant Bhatt, Shaival Shah, Anilkumar Jha, Nirmal Desai, Nuggehally R Srinivas
Propafenone is a potent antiarrhythmic agent; clinically propafenone has been used for a number of cardiac arrhythmias because it possesses multiple modes of action, via beta adrenergic receptor blockade and calcium antagonistic activity. Propafenone (PPF) exhibits extensive saturable presystemic biotransformation (first pass effect) resulting into two active metabolites; 5- hydroxypropafenone (5-OH PPF) formed by CYP2D6 and N-depropylpropafenone (NDP) formed by both CYP3A4 and CYP1A2 enzymes. A specific and sensitive LC-MS/MS method was developed and validated for quantitation of PPF, 5-OH PPF and NDP using turboion spray in a positive ion mode...
March 6, 2017: Biomedical Chromatography: BMC
https://www.readbyqxmd.com/read/28260174/effect-of-gevokizumab-on-interleukin-1%C3%AE-mediated-cytochrome-p450-3a4-and-drug-transporter-repression-in-cultured-human-hepatocytes
#19
Amélie Moreau, Marc Le Vée, Elodie Jouan, Claire Denizot, Yannick Parmentier, Olivier Fardel
BACKGROUND AND OBJECTIVES: Gevokizumab is a potent anti-interleukin (IL)-1β neutralizing monoclonal antibody (mAb), which may be used for treating inflammatory or autoimmune diseases. The present study was designed to characterize the potential effects of this mAb towards well-established IL-1β-mediated repression of hepatic drug detoxifying proteins, like cytochrome P450 (CYP) 3A4 and drug transporters. METHODS: Primary cultured human hepatocytes were exposed to various concentrations of IL-1β in the absence or presence of gevokizumab (5 µg/mL); mRNA expression and activity of CYP3A4 and transporters were next determined...
March 4, 2017: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28259126/10-6-plastoquinonyl-decyltriphenylphosphonium-skq1-does-not-increase-the-level-of-cytochromes-p450-in-rat-liver-and-human-hepatocyte-cell-culture
#20
K N Myasoedova, D N Silachev, A D Petrov
Mitochondria-targeted antioxidant SkQ1 did not increase the content of cytochromes P450 in livers of rats that were given SkQ1 in drinking water for 5 days in a dose (2.5 µmol per kg body weight) that exceeded 10 times the SkQ1 therapeutic dose. SkQ1 did not affect the levels of cytochrome P450 forms CYP1A2, CYP2B6, and CYP3A4 in monolayer cultures of freshly isolated human hepatocytes, while specific inducers of these forms (omeprazole, phenobarbital, and rifampicin, respectively) significantly increased expression of the cytochromes P450 under the same conditions...
December 2016: Biochemistry. Biokhimii︠a︡
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