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https://www.readbyqxmd.com/read/28632894/flavonoids-as-modulators-of-metabolic-enzymes-and-drug-transporters
#1
REVIEW
Anca Miron, Ana Clara Aprotosoaie, Adriana Trifan, Jianbo Xiao
Flavonoids, natural compounds found in plants and in plant-derived foods and beverages, have been extensively studied with regard to their capacity to modulate metabolic enzymes and drug transporters. In vitro, flavonoids predominantly inhibit the major phase I drug-metabolizing enzyme CYP450 3A4 and the enzymes responsible for the bioactivation of procarcinogens (CYP1 enzymes) and upregulate the enzymes involved in carcinogen detoxification (UDP-glucuronosyltransferases, glutathione S-transferases (GSTs))...
June 20, 2017: Annals of the New York Academy of Sciences
https://www.readbyqxmd.com/read/28630772/severe-rhabdomyolysis-due-to-presumed-drug-interactions-between-atorvastatin-with-amlodipine-and-ticagrelor
#2
Iouri Banakh, Kavi Haji, Ross Kung, Sachin Gupta, Ravindranath Tiruvoipati
Atorvastatin and ticagrelor combination is a widely accepted therapy for secondary prevention of ischaemic heart disease. However, rhabdomyolysis is a well-known rare side effect of statins which should be considered when treatments are combined with cytochrome P450 3A4 enzyme inhibitors. We report a case of atorvastatin and ticagrelor associated severe rhabdomyolysis that progressed to multiorgan failure requiring renal replacement therapy, inotropes, intubation, and mechanical ventilation. Despite withdrawal of the precipitating cause and the supportive measures including renal replacement therapy, creatinine kinase increased due to ongoing rhabdomyolysis rapidly progressing to upper and lower limbs weakness...
2017: Case Reports in Critical Care
https://www.readbyqxmd.com/read/28618157/liver-microsomal-lipid-enhances-the-activity-and-redox-coupling-of-co-localised-cytochrome-p450-reductase-cytochrome-p450-3a4-in-nanodiscs
#3
Kang-Cheng Liu, John M X Hughes, Sam Hay, Nigel S Scrutton
The haem-containing monooxygenase cytochrome P450 3A4 (CYP3A4) and its redox partner NADPH-dependent cytochrome P450 oxidoreductase (CPR) are among the most important enzymes in human liver for metabolising drugs and xenobiotic compounds. They are membrane-bound in the endoplasmic reticulum (ER). How ER co-localisation and the complex ER phospholipid composition influence enzyme activity are not well understood. CPR and CYP3A4 were incorporated into phospholipid bilayer nanodiscs, both singly, and together in a 1:1 ratio, to investigate the significance of membrane insertion and the influence of varying membrane composition on steady-state reaction kinetics...
June 15, 2017: FEBS Journal
https://www.readbyqxmd.com/read/28616429/evaluation-of-the-interaction-of-intravenous-and-oral-voriconazole-with-oral-cyclosporine-in-iranian-hsct-patients
#4
Hamidreza Taghvaye Masoumi, Molouk Hadjibabaie, Mohammad Vaezi, Ardeshir Ghavamzadeh
OBJECTIVE: Voriconazole as a triazole antifungal agent is widely used for prophylaxis or treatment of fungal infections in allogeneic hematopoietic stem cell transplantation (HSCT). It can increase blood concentrations of other medications including cyclosporine A (CsA) which are substrates for cytochrome P450 3A4. The aim of this study was to evaluate comparatively the interaction between oral/intravenous (IV) voriconazole and oral CsA. METHODS: Twenty-nine recipients of allogeneic HSCT who had been already on a steady dose of CsA and were started on oral or IV voriconazole were evaluated in a prospective cohort study...
April 2017: Journal of Research in Pharmacy Practice
https://www.readbyqxmd.com/read/28614988/in-vitro-inhibitory-effects-of-dihydromyricetin-on-human-liver-cytochrome-p450-enzymes
#5
Lu Liu, Sen Sun, Hongbing Rui, Xiaohua Li
CONTEXT: Dihydromyricetin (DHM) is the most abundant and active flavonoid component isolated from Ampelopsis grossedentata (Hand-Mazz) W.T. Wang (Vitaceae) and it possesses numerous pharmacological activities. However, whether DHM affects the activity of human liver cytochrome P450 (CYP) enzymes remains unclear. MATERIALS AND METHODS: The inhibitory effects of DHM on eight human liver CYP isoforms (i.e., 1A2, 3A4, 2A6, 2E1, 2D6, 2C9, 2C19 and 2C8) were investigated in vitro using human liver microsomes (HLMs)...
December 2017: Pharmaceutical Biology
https://www.readbyqxmd.com/read/28610444/midostaurin-for-the-treatment-of-acute-myeloid-leukemia
#6
Mrinal M Patnaik
Midostaurin is a multikinase tyrosine kinase inhibitor acting against targets known to be expressed in hematologic malignancies, especially acute myeloid leukemia. Midostaurin combined with chemotherapy followed by single-agent maintenance therapy elicited statistically significant and clinically meaningful improvement in overall survival versus placebo in patients with newly diagnosed FLT3-mutant acute myeloid leukemia. Although gastrointestinal events were more common with midostaurin, overall the drug was relatively well tolerated...
June 14, 2017: Future Oncology
https://www.readbyqxmd.com/read/28603633/in-vitro-metabolism-of-exemestane-by-hepatic-cytochrome-p450s-impact-of-nonsynonymous-polymorphisms-on-formation-of-the-active-metabolite-17%C3%AE-dihydroexemestane
#7
Amity Peterson, Zuping Xia, Gang Chen, Philip Lazarus
Exemestane (EXE) is an endocrine therapy commonly used by postmenopausal women with hormone-responsive breast cancer due to its potency in inhibiting aromatase-catalyzed estrogen synthesis. Preliminary in vitro studies sought to identify phase I EXE metabolites and hepatic cytochrome P450s (CYP450s) that participate in EXE biotransformation. Phase I metabolites were identified by incubating EXE with HEK293-overexpressed CYP450s. CYP450s 1A2, 2C8, 2C9, 2C19, 2D6, 3A4, and 3A5 produce 17β-dihydroexemestane (17β-DHE), an active major metabolite, as well as two inactive metabolites...
June 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28590129/high-level-production-and-properties-of-the-cysteine-depleted-cytochrome-p450-3a4
#8
Irina F Sevrioukova
Human drug-metabolizing cytochrome P450 3A4 (CYP3A4) is a dynamic enzyme with a large and highly malleable active site that can fit structurally diverse compounds. Despite extensive investigations, structure-function relationships and conformational dynamics in CYP3A4 are not fully understood. This study was undertaken to engineer a well-expressed and functionally active cysteine-depleted CYP3A4 that can be used in biochemical and biophysical studies. cDNA codon optimization and screening mutagenesis were utilized to boost the level of bacterial expression of CYP3A4 and identify the least harmful substitutions for all six non-heme-ligating cysteines...
June 7, 2017: Biochemistry
https://www.readbyqxmd.com/read/28558634/differential-regulation-of-cyp3a4-and-cyp3a5-and-its-implication-in-drug-discovery
#9
Ogheneochukome Lolodi, Yue-Ming Wang, William C Wright, Taosheng Chen
Cancer cells use several mechanisms to resist the cytotoxic effects of drugs, resulting in tumor progression and invasion. One such mechanism capitalizes on the body's natural defense against xenobiotics. Recent reports indicate that components of the xenobiotic response system are upregulated in some diseases, including many cancers. Such components include the pregnane X receptor and the cytochrome P450 3A4 and 3A5 enzymes. Intense research is ongoing to understand the functional ramifications of aberrant expression of these components in diseased states with the goal of designing novel drugs that can selectively target them...
May 30, 2017: Current Drug Metabolism
https://www.readbyqxmd.com/read/28552479/biopharmaceutic-parameters-pharmacokinetics-transport-and-cyp-mediated-drug-interactions-of-iiim-017-a-novel-nitroimidazooxazole-analogue-with-anti-tuberculosis-activity
#10
Gurleen Kour, Parvinder Pal Singh, Asha Bhagat, Zabeer Ahmed
Nitroimidazoles are emerging as a new class of therapeutic agents with potent anti-tubercular activity. CSIR-IIIM has synthesized a novel nitrohydroimidazooxazole (NHIO) analogue, IIIM-017 with a MIC of 0.37μg/ml (against H37Rv). Here, we aim at further exploration of physicochemical properties and preclinical absorption, metabolism, disposition and pharmacokinetics of IIIM-017. In this study, in silico physicochemical parameters, lipophilicity, permeability, transport, hepatotoxicity, CYP mediated drug interactions and pharmacokinetics of IIIM-017 were investigated...
May 26, 2017: European Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28546420/alterations-of-histone-modifications-contribute-to-pregnane-x-receptor-mediated-induction-of-cyp3a4-by-rifampicin
#11
Liang Yan, Yiting Wang, Jingyang Liu, Yali Nie, Xiaobo Zhong, Quancheng Kan, Lirong Zhang
Cytochrome P450 3A4 (CYP3A4) is one of the major drug-metabolizing enzymes in human and is responsible for the metabolism of 60% of the clinically used drugs. Many drugs are able to induce the expression of CYP3A4, which usually causes drug-drug interactions and adverse drug reactions. This study aims to explore the role of histone modifications in rifampicin-induced expression of CYP3A4 in LS174T cells. We found that the induction of CYP3A4 mRNA by rifampicin in LS174T cells was associated with increased levels of histone H3 lysine 4 trimethylation (H3K4me3) and H3 acetylation and a decreased level of histone H3 lysine 27 trimethylation (H3K27me3) in the CYP3A4 promoter...
May 25, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28539103/possible-oxcarbazepine-inductive-effects-on-aripiprazole-metabolism-a-case-report
#12
Ian R McGrane, Joshua G Loveland, Jose de Leon
Oxcarbazepine is a cytochrome P450 (CYP) 3A4 inducer, which is structurally similar to carbamazepine. Although lacking Food and Drug Administration approval, oxcarbazepine is sometimes prescribed to treat aggressive behavior in youth with autism spectrum disorder (ASD). These youths may also be taking second-generation antipsychotics, some of which are substrates of the CYP3A4 metabolic pathway. The combination of these medications may result in decreased serum antipsychotic concentrations, potentially reducing effectiveness...
January 1, 2017: Journal of Pharmacy Practice
https://www.readbyqxmd.com/read/28496040/induction-of-human-cytochrome-p450-3a-enzymes-in-cultured-placental-cells-by-thalidomide-and-relevance-to-bioactivation-and-toxicity
#13
Norie Murayama, Yasuhiro Kazuki, Daisuke Satoh, Kazuya Arata, Tasuku Harada, Norio Shibata, F Peter Guengerich, Hiroshi Yamazaki
Evidence has been presented for auto-induced human cytochrome P450 3A enzyme involvement in the teratogenicity and clinical outcome of thalidomide due to oxidation to 5-hydroxythalidomide and subsequent metabolic activation in livers. In this study, more relevant human placenta preparations and placental BeWo cells showed low but detectable P450 3A4/5 mRNA expression and drug oxidation activities. Human placental microsomal fractions from three subjects showed detectable midazolam 1´- and 4-hydroxylation and thalidomide 5-hydroxylation activities...
2017: Journal of Toxicological Sciences
https://www.readbyqxmd.com/read/28495902/regio-and-stereo-selective-oxidation-of-a-cardiovascular-drug-metoprolol-mediated-by-cytochrome-p450-2d-and-3a-enzymes-in-marmoset-livers
#14
Shotaro Uehahara, Sakura Ishii, Yasuhiro Uno, Takashi Inoue, Erika Sasaki, Hiroshi Yamazaki
A β-blocker metoprolol is one of the in vivo probes for human cytochrome P450 (P450) 2D6. Investigation of non-human primate P450 enzymes helps improve accuracy of the extrapolation of pharmacokinetic data from animals into humans. Common marmosets (Callithrix jacchus) are a potential primate model for preclinical research, but detailed roles of marmoset P450 enzymes in metoprolol oxidations remained unknown. In this study, regio- and stereo-selectivity of metoprolol oxidations by a variety of P450 enzymes in marmoset and human livers were investigated in vitro...
May 11, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28484907/inhibition-of-cytochrome-p450-and-uridine-5-diphospho-glucuronosyltransferases-by-mam-2201-in-human-liver-microsomes
#15
Tae Yeon Kong, Ju-Hyun Kim, Soon-Sang Kwon, Jae Chul Cheong, Hee Seung Kim, Moon Kyo In, Hye Suk Lee
MAM-2201, a synthetic cannabinoid, is a potent agonist of the cannabinoid receptors and is increasingly used as an illicit recreational drug. The inhibitory effects of MAM-2201 on major drug-metabolizing enzymes such as cytochrome P450s (CYPs) and uridine 5'-diphospho-glucuronosyltransferases (UGTs) have not yet been investigated although it is widely abused, sometimes in combination with other drugs. We evaluated the inhibitory effects of MAM-2201 on eight major human CYPs (CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4) and six UGTs (UGTs 1A1, 1A3, 1A4, 1A6, 1A9, and 2B7) of pooled human liver microsomes; we thus explored potential MAM-2201-induced drug interactions...
May 8, 2017: Archives of Pharmacal Research
https://www.readbyqxmd.com/read/28463066/structural-basis-of-pesticide-detection-by-enzymatic-biosensing-a-molecular-docking-and-md-simulation-study
#16
Mohd Shahbaaz, Suvardhan Kanchi, Myalowenkosi Sabela, Krishna Bisetty
Designing of rapid, facile, selective, and cost-effective biosensor technology is a growing area for the detection of various classes of pesticides. The biosensor with these features can be achieved only through the various bio-components using different transducers. This study, therefore, focuses on the usage of molecular docking, specificity tendencies, and capabilities of proteins for the detection of pesticides. Accordingly, the four transducers, acetylcholinesterase (ACH), cytochromes P450 (CYP), glutathione S-transferase (GST), and protein kinase C (PKC) were selected based on their applications including neurotransmitter, metabolism, detoxification enzyme, and protein phosphorylation...
May 18, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28460548/clinical-pharmacology-of-neurokinin-1-receptor-antagonists-for-the-treatment-of-nausea-and-vomiting-associated-with-chemotherapy
#17
REVIEW
Bernardo Rapoport, Teresa Smit
Five NK-1 RA formulations are commercially available to treat the delayed phase of chemotherapy-induced nausea and vomiting (CINV) occurring between days 2-5 post chemotherapy (aprepitant oral capsule and suspension, fosaprepitant intravenous infusion, netupitant/palonosetron capsules and rolapitant tablet) but no direct comparative studies have been conducted to determine their relative clinical utility. Areas covered: Information on pharmacology and safety of the NK-1 RAs derived from PubMed showed that all bind the NK-1 receptor with high affinity and selectivity...
June 2017: Expert Opinion on Drug Safety
https://www.readbyqxmd.com/read/28446877/exploring-the-role-of-cyp3a4-mediated-drug-metabolism-in-the-pharmacological-modulation-of-nitric-oxide-production
#18
José Pérez-Del Palacio, Caridad Díaz, Noemí Vergara, Francesca Algieri, Alba Rodríguez-Nogales, Nuria de Pedro, M Elena Rodríguez-Cabezas, Olga Genilloud, Julio Gálvez, Francisca Vicente
Nitric-oxide synthase, the enzyme responsible for mammalian nitric oxide generation, and cytochrome P450, the major enzymes involved in drug metabolism, share striking similarities. Therefore, it makes sense that cytochrome P450 drug mediated biotransformations might play an important role in the pharmacological modulation of nitric oxide synthase. In this work, we have undertaken an integrated in vitro assessment of the hepatic metabolism and nitric oxide modulation of previously described dual inhibitors (imidazoles and macrolides) of these enzymes in order assess the implication of CYP450 activities over production of nitric oxide...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28444958/role-of-cytochrome-p450-3a4-and-1a2-phenotyping-in-patients-with-advanced-non-small-cell-lung-cancer-nsclc-receiving-erlotinib-treatment
#19
Zinnia P Parra-Guillen, Peter B Berger, Manuel Haschke, Massimiliano Donzelli, Daria Winogradova, Bogumila Pfister, Martin Früh, Charlotte Kloft, Stephan Krähenbühl, Silke Gillessen, Markus Joerger
Erlotinib is metabolized by cytochrome p450 (CYP) 3A and CYP1A. This study assessed CYP3A4 (midazolam) and CYP1A2 (caffeine) phenotyping in plasma and dried blood spots (DBS) for predicting the pharmacokinetics and toxicity of erlotinib in 36 patients with advanced NSCLC. On day 1, erlotinib 150 mg OD. was initiated, and the 2 oral probe drugs midazolam (2mg) and caffeine (100mg) were added on day 1. Plasma and DBS were collected for erlotinib, OSI-420 and probe drugs for up to 6 hr on day 1 and 2-weekly up to week 10...
April 26, 2017: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/28444482/synthesis-pharmacological-evaluation-and-molecular-docking-of-pyranopyrazole-linked-1-4-dihydropyridines-as-potent-positive-inotropes
#20
Rakesh Kumar, Neha Yadav, Rodolfo Lavilla, Daniel Blasi, Jordi Quintana, José Manuel Brea, María Isabel Loza, Jordi Mestres, Mamta Bhandari, Ritu Arora, Rita Kakkar, Ashok K Prasad
1,4-Dihydropyridines are well-known calcium channel blockers, but variations in the substituents attached to the ring have resulted in their role reversal making them calcium channel activators in some cases. We describe the microwave-assisted eco-friendly approach for the synthesis of pyranopyrazole-1,4-dihydropyridines, a new class of 1,4-DHPs, under solvent-free conditions in good yield, and screen them for various in silico, in vitro and in vivo activities. The in vivo experimentation results show that the compounds possess positive inotropic effect, and the docking results validate their good binding with calcium channels...
April 25, 2017: Molecular Diversity
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