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cytochrome p450 3A4

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https://www.readbyqxmd.com/read/28346810/an-automated-multiplexed-hepatotoxicity-and-cyp-induction-assay-using-heparg-cells-in-2d-and-3d
#1
Lindsey M Ott, Karthik Ramachandran, Lisa Stehno-Bittel
Drug-induced liver injury (DILI) and drug-drug interactions (DDIs) are concerns when developing safe and efficacious compounds. We have developed an automated multiplex assay to detect hepatotoxicity (i.e., ATP depletion) and metabolism (i.e., cytochrome P450 1A [CYP1A] and cytochrome P450 3A4 [CYP3A4] enzyme activity) in two-dimensional (2D) and three-dimensional (3D) cell cultures. HepaRG cells were cultured in our proprietary micromold plates and produced spheroids. HepaRG cells, in 2D or 3D, expressed liver-specific proteins throughout the culture period, although 3D cultures consistently exhibited higher albumin secretion and CYP1A/CYP3A4 enzyme activity than 2D cultures...
March 1, 2017: SLAS Discov
https://www.readbyqxmd.com/read/28344076/inhibition-of-human-cyp3a4-and-cyp3a5-enzymes-by-gomisin-c-and-gomisin-g-two-lignan-analogs-derived-from-schisandra-chinensis
#2
Jin Zhao, Tao Sun, Yun-Feng Cao, Zhong-Ze Fang, Hong-Zhi Sun, Zhi-Tu Zhu, Kun Yang, Yong-Zhe Liu, Frank J Gonzalez, Jing-Jing Wu, Jun Yin
Gomisin C (GC) and gomisin G (GG) are two lignan analogs isolated from the Traditional Chinese Medicine Schisandra chinensis which possesses multiple pharmacological activities. However, the potential herb-drug interactions (HDI) between these lignans and other drugs through inhibiting human cytochrome P450 3A4 (CYP3A4) and CYP3A5 remains unclear. In the present study, the inhibitory action of GC and GG on CYP3A4 and CYP3A5 were investigated. The results demonstrated that both GC and GG strongly inhibited CYP3A-mediated midazolam 1'-hydroxylation, nifedipine oxidation and testosterone 6β-hydroxylation...
March 23, 2017: Fitoterapia
https://www.readbyqxmd.com/read/28343293/pharmacokinetic-and-pharmacodynamic-considerations-in-the-treatment-of-chronic-lymphocytic-leukemia-ibrutinib-idelalisib-and-venetoclax
#3
REVIEW
Madeline Waldron, Allison Winter, Brian T Hill
Management of chronic lymphocytic leukemia has changed markedly over the last several years with the emergence of several novel oral agents targeting B-cell receptor and Bcl-2 signaling pathways. For patients requiring treatment, ibrutinib, idelalisib, and venetoclax offer unique clinical benefits with a different set of therapeutic considerations compared with traditional parenteral therapy. Despite the conveniences afforded by oral therapy, these agents also carry unique logistical obstacles. Drug interactions with agents that are metabolized via the cytochrome P450 3A4 pathway are possible with all three agents...
March 25, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28339191/allosteric-activation-of-cytochrome-p450-3a4-via-progesterone-bioconjugation
#4
Vanja Polic, Karine Auclair
Human cytochrome P450 3A4 (CYP3A4) is responsible for the metabolism of the majority of drugs. As such, it is implicated in many adverse drug-drug and food-drug interactions, and is of significant interest to the pharmaceutical industry. This enzyme is known to simultaneously bind multiple ligands and display atypical enzyme kinetics, suggestive of allostery and cooperativity. As well, evidence of a postulated peripheral allosteric binding site has provoked debate around its significance and location. We report the use of bioconjugation to study the significance of substrate binding at the proposed allosteric site and its effect on CYP3A4 activity...
March 24, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/28329820/hepatocellular-toxicity-of-imidazole-and-triazole-antimycotic-agents
#5
Patrizia Haegler, Lorenz Joerin, Stephan Krähenbühl, Jamal Bouitbir
Hepatotoxicity has been described for all antimycotic azoles currently marketed. A possible mechanism involving mitochondrial dysfunction has been postulated for ketoconazole, but not for the other azoles. The aim of the current investigations was to study the toxicity of different azoles in human cell models and to find out mechanisms of their toxicity. In HepG2 cells, posaconazole and ketoconazole were cytotoxic starting at 20 and 50 µM and decreased the cellular ATP content starting at 5 and 10 µM, respectively...
January 27, 2017: Toxicological Sciences: An Official Journal of the Society of Toxicology
https://www.readbyqxmd.com/read/28327932/integrated-safety-analysis-of-rolapitant-with-coadministered-drugs-from-phase-ii-iii-trials-an-assessment-of-cyp2d6-or-bcrp-inhibition-by-rolapitant
#6
S Barbour, T Smit, X Wang, D Powers, S Arora, V Kansra, M Aapro, J Herrstedt
Background: Rolapitant, a long-acting neurokinin (NK) 1 receptor antagonist (RA), has demonstrated efficacy in prevention of chemotherapy-induced nausea and vomiting in patients administered moderately or highly emetogenic chemotherapy. Unlike other NK 1 RAs, rolapitant does not inhibit or induce cytochrome P450 (CYP) 3A4, but it does inhibit CYP2D6 and breast cancer resistance protein (BCRP). To analyze potential drug-drug interactions between rolapitant and concomitant medications, this integrated safety analysis of four double-blind, randomized phase II or III studies of rolapitant examined adverse events by use versus non-use of drug substrates of CYP2D6 or BCRP...
February 23, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28301431/cyp3a4-activity-is-markedly-lower-in-patients-with-crohn-s-disease
#7
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...
March 15, 2017: Inflammatory Bowel Diseases
https://www.readbyqxmd.com/read/28293270/effect-of-moringa-oleifera-lam-leaf-powder-on-the-pharmacokinetics-of-nevirapine-in-hiv-infected-adults-a-one-sequence-cross-over-study
#8
Tsitsi G Monera-Penduka, Charles C Maponga, Alan R Wolfe, Lubbe Wiesner, Gene D Morse, Charles F B Nhachi
BACKGROUND: Moringa oleifera Lam., an herb commonly consumed by HIV-infected people on antiretroviral therapy, inhibits cytochrome P450 3A4, 1A2 and 2D6 activity in vitro; and may alter the pharmacokinetics (PK) of antiretroviral drugs metabolized via the same pathways. However, in vitro drug interaction activity may not translate to a clinically significant effect. Therefore, the effect of moringa leaf powder on the PK of nevirapine in HIV-infected people was investigated. METHODS: Adult patients at steady-state dosing with nevirapine were admitted for 12-h intensive PK sampling following a 21-day herbal medicine washout...
2017: AIDS Research and Therapy
https://www.readbyqxmd.com/read/28291036/potential-mechanisms-of-hematological-adverse-drug-reactions-in-patients-receiving-clozapine-in-combination-with-proton-pump-inhibitors
#9
Michał Wiciński, Mateusz M Węclewicz, Mateusz Miętkiewicz, Bartosz Malinowski, Elżbieta Grześk, Joanna Klonowska
Clozapine is a second-generation antipsychotic which has proven efficacy in treating the symptoms of schizophrenia. Although clozapine therapy is associated with a number of adverse drug reactions, it is frequently used. One of the most common adverse drug reactions is gastroesophageal reflux disease which is an indication for treatment with proton pump inhibitors (PPIs). Coadministration of clozapine and PPIs increases the risk of hematological adverse drug reactions, including neutropenia and agranulocytosis...
March 2017: Journal of Psychiatric Practice
https://www.readbyqxmd.com/read/28288665/effect-of-moringa-oleifera-lam-leaf-powder-on-the-pharmacokinetics-of-nevirapine-in-hiv-infected-adults-a-one-sequence-cross-over-study
#10
Tsitsi G Monera-Penduka, Charles C Maponga, Alan R Wolfe, Lubbe Wiesner, Gene D Morse, Charles F B Nhachi
BACKGROUND: Moringa oleifera Lam., an herb commonly consumed by HIV-infected people on antiretroviral therapy, inhibits cytochrome P450 3A4, 1A2 and 2D6 activity in vitro; and may alter the pharmacokinetics (PK) of antiretroviral drugs metabolized via the same pathways. However, in vitro drug interaction activity may not translate to a clinically significant effect. Therefore, the effect of moringa leaf powder on the PK of nevirapine in HIV-infected people was investigated. METHODS: Adult patients at steady-state dosing with nevirapine were admitted for 12-h intensive PK sampling following a 21-day herbal medicine washout...
March 14, 2017: AIDS Research and Therapy
https://www.readbyqxmd.com/read/28287454/am-2201-inhibits-multiple-cytochrome-p450-and-uridine-5-diphospho-glucuronosyltransferase-enzyme-activities-in-human-liver-microsomes
#11
Ju-Hyun Kim, Soon-Sang Kwon, Tae Yeon Kong, Jae Chul Cheong, Hee Seung Kim, Moon Kyo In, Hye Suk Lee
AM-2201 is a synthetic cannabinoid that acts as a potent agonist at cannabinoid receptors and its abuse has increased. However, there are no reports of the inhibitory effect of AM-2201 on human cytochrome P450 (CYP) or uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes. We evaluated the inhibitory effect of AM-2201 on the activities of eight major human CYPs (1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4) and six major human UGTs (1A1, 1A3, 1A4, 1A6, 1A9, and 2B7) enzymes in pooled human liver microsomes using liquid chromatography-tandem mass spectrometry to investigate drug interaction potentials of AM-2201...
March 10, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28283499/metabolite-identification-reaction-phenotyping-and-retrospective-drug-drug-interaction-predictions-of-17-deacetylnorgestimate-the-active-component-of-the-oral-contraceptive-norgestimate
#12
Deepak Ahire, Sarmistha Sinha, Barry Brock, Ramaswamy Iyer, Sandhya Mandlekar, Murali Subramanian
Ortho-Tri-Cyclen® (OTC), a two drug cocktail comprising of ethinylestradiol (EE) and norgestimate (13-ethyl-17-acetoxy-18, 19-dinor-17α-pregn-4-en-20yn-3 oxime), is commonly prescribed to avert unwanted pregnancies in women of reproductive age. In vivo, norgestimate undergoes extensive and rapid deacetylation to produce 17-deacetylnorgestimate (NGMN), an active circulating metabolite that likely contributes significantly to norgestimate efficacy. Despite being of primary significance, the metabolism and reaction phenotyping of NGMN have not been previously reported...
March 10, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28280092/a-phase-i-ib-study-of-enzalutamide-alone-and-in-combination-with-endocrine-therapies-in-women-with-advanced-breast-cancer
#13
Lee S Schwartzberg, Denise Yardley, Anthony Elias, Manish Patel, Patricia M LoRusso, Howard A Burris, Ayca Gucalp, Amy Peterson, Martha Blaney, Joyce Steinberg, Jacqueline Gibbons, Tiffany A Traina
PURPOSE: Several lines of evidence support targeting the androgen signaling pathway in breast cancer. Enzalutamide is a potent inhibitor of androgen receptor signaling. Preclinical data in estrogen-expressing breast cancer models demonstrated activity of enzalutamide monotherapy and enhanced activity when combined with various endocrine therapies (ETs). Enzalutamide is a strong cytochrome P450 3A4 (CYP3A4) inducer, and ETs are commonly metabolized by CYP3A4. The pharmacokinetic (PK) interactions, safety, and tolerability of enzalutamide monotherapy and in combination with ETs were assessed in this phase I/Ib study...
March 9, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28278026/7-8-benzoflavone-binding-to-human-cytochrome-p450-3a4-reveals-complex-fluorescence-quenching-suggesting-binding-at-multiple-protein-sites
#14
Glenn A Marsch, Benjamin T Carlson, F Peter Guengerich
Human cytochrome P450 (P450) 3A4 is involved in the metabolism of one-half of marketed drugs and shows cooperative interactions with some substrates and other ligands. The interaction between P450 3A4 and the known allosteric effector 7,8-benzoflavone (α-naphthoflavone, αNF) was characterized using steady-state fluorescence spectroscopy. The binding interaction of P450 3A4 and αNF effectively quenched the fluorescence of both the enzyme and ligand. The Hill Equation and Stern-Volmer fluorescence quenching models were used to evaluate binding of ligand to enzyme...
March 1, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28270768/extracts-of-immature-orange-aurantii-fructus-immaturus-and-citrus-unshiu-peel-citri-unshiu-pericarpium-induce-p-glycoprotein-and-cytochrome-p450-3a4-expression-via-upregulation-of-pregnane-x-receptor
#15
Naoto Okada, Aki Murakami, Shiori Urushizaki, Misa Matsuda, Kazuyoshi Kawazoe, Keisuke Ishizawa
P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4) are expressed in the intestine and are associated with drug absorption and metabolism. Pregnane X receptor (PXR) is the key molecule that regulates the expression of P-gp and CYP3A4. Given that PXR activity is regulated by a variety of compounds, it is possible that unknown PXR activators exist among known medicines. Kampo is a Japanese traditional medicine composed of various natural compounds. In particular, immature orange [Aurantii fructus immaturus (IO)] and citrus unshiu peel [Citri unshiu pericarpium (CP)] are common ingredients of kampo...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28263536/effectiveness-of-human-cytochrome-p450-3a4-present-in-liposomal-and-microsomal-nanoparticles-in-formation-of-covalent-dna-adducts-by-ellipticine
#16
Miroslav Sulc, Iveta Mrizova, Tereza Cerna, Eva Frei, Tomas Eckschlager, Vojtech Adam, Katerina Kopeckova, Marie Stiborova
OBJECTIVES: Ellipticine is an anticancer agent that functions through multiple mechanisms participating in cell cycle arrest and initiation of apoptosis. This drug forms covalent DNA adducts after its enzymatic activation with cytochrome P450 (CYP), which is one of the most important ellipticine DNA-damaging mechanisms of its cytotoxic effects. The improvements of cancer treatment are the major challenge in oncology research. Nanotransporters (nanoparticles) are promising approaches to target tumor cells, frequently leading to improve drug therapeutic index...
December 18, 2016: Neuro Endocrinology Letters
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
#17
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/28255850/clinical-pharmacokinetics-of-vemurafenib
#18
REVIEW
Weijiang Zhang, Dominik Heinzmann, Joseph F Grippo
Vemurafenib is an orally administered small-molecule inhibitor of the oncogenic BRAF kinase that is indicated for the treatment of patients with unresectable or metastatic melanoma harbouring BRAF (V600) mutations. Vemurafenib is absorbed rapidly after a single oral dose of 960 mg, reaching maximum drug concentration approximately 4 h after administration. Extensive accumulation occurs after multiple dosing at 960 mg twice daily. Steady state is achieved after approximately 15-21 days and exposure at steady state is relatively constant...
March 2, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28254951/examination-of-the-human-cytochrome-p4503a4-induction-potential-of-pf-06282999-an-irreversible-myeloperoxidase-inactivator-integration-of-preclinical-in-silico-and-biomarker-methodologies-in-the-prediction-of-the-clinical-outcome
#19
Jennifer Dong, James Gosset, Odette Fahmi, Zhiwu Lin, Jeffrey Chabot, Steven Terra, Vu Le, Kristin Chidsey, Parya Nouri, Albert Kim, Leonard Buckbinder, Amit S Kalgutkar
The propensity for cytochrome P450 (CYP)3A4 induction by 2-(6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide (PF-06282999), an irreversible inactivator of myeloperoxidase, was examined in the present work. Studies using human hepatocytes revealed moderate increases in CYP3A4 messenger RNA (mRNA) and midazolam-1'-hydroxylase activity in a PF-06282999 dose-dependent fashion. At the highest tested concentration of 300 μM, PF-06282999 caused maximal induction in CYP3A4 mRNA and enzyme activity ranging from 56% - 86% and 47% - 72%, respectively, of rifampicin response across the three hepatocyte donor pools...
March 2, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28249055/weakness-and-pain-in-arms-and-legs-%C3%A2-dark-urine-%C3%A2-history-of-vertebral-osteomyelitis-%C3%A2-dx
#20
Antonios Charokopos, Tariq Muhammad, Sidana Surbhi, Andrei Brateanu
Rhabdomyolysis is a serious complication of statin treatment. Both higher statin doses and pharmacokinetic factors can raise statin levels, leading to this serious usclerelated syndrome. Co-administration of statins with drugs that are strong inhibitors of cytochrome P450 (CYP) 3A4 (the main cytochrome P450 isoform that metabolizes most statins) can increase statin levels several fold. The trigger for our patient's statin-induced rhabdomyolysis was fluconazole, a known moderate inhibitor of CYP3A4, which is comparatively weaker than certain potent azoles like itraconazole or ketoconazole...
March 2017: Journal of Family Practice
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