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https://www.readbyqxmd.com/read/29054193/polymorphisms-of-cytochrome-p450-are-potential-candidates-that-could-potentially-help-clinicians-on-the-treatment-of-cardiovascular-diseases-among-asian-populations
#1
López-Hernández Daniel
There are significant ethnic differences in the metabolism of some drugs that can be explained by cytochrome P450 polymorphisms and, in particular, the CYP2D6 isozyme. In addition, among patients who are not carriers of the CYP2C19 loss-of-function alleles, there is a reduced risk of stroke when clopidogrel is taken with aspirin compared to aspirin alone. These findings demonstrate that there is inter-ethnic variability in the metabolism of some drugs, which results in different responses to cardiovascular drugs in Asian versus non-Asian populations...
September 2017: Indian Heart Journal
https://www.readbyqxmd.com/read/29054049/individual-variability-in-clinical-effect-and-tolerability-of-opioid-analgesics-importance-of-drug-interactions-and-pharmacogenetics
#2
REVIEW
Vigdis Solhaug, Espen Molden
BACKGROUND: As pain is often a comorbid condition, many patients use opioid analgesics in combination with several other drugs. This implies a generally increased risk of drug interactions, which along with inherent pharmacogenetic variability and other factors may cause differences in therapeutic response of opioids. AIM: To provide an overview of interactions and pharmacogenetic variability of relevance for individual differences in effect and tolerability of opioid analgesics, which physicians and other healthcare professionals should be aware of in clinical practice...
October 17, 2017: Scandinavian Journal of Pain
https://www.readbyqxmd.com/read/29038231/evaluation-of-clinical-drug-interaction-potential-of-clofazimine-using-static-and-dynamic-modeling-approaches
#3
Ramachandra Sangana, Helen Gu, Dung Yu Chun, Heidi J Einolf
The 2016 World Health Organization treatment recommendations for drug-resistant tuberculosis (DR-TB) positioned clofazimine as a core second-line drug. Being identified as a cytochrome P450 (CYP) inhibitor in vitro, a CYP-mediated drug interaction may be likely when clofazimine is co-administered with substrates of these enzymes. The CYP-mediated drug interaction potential of clofazimine was evaluated using both static (estimation of "R1" and area under the plasma concentration-time curve ratio [AUCR] values) and dynamic (physiologically based pharmacokinetic [PBPK]) modeling approaches...
October 16, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29035842/derivation-and-characterization-of-integration-free-ipsc-line-isrm-um51-derived-from-six2-positive-renal-cells-isolated-from-urine-of-an-african-male-expressing-the-cyp2d6-4-17-variant-which-confers-intermediate-drug-metabolizing-activity
#4
Martina Bohndorf, Audrey Ncube, Lucas-Sebastian Spitzhorn, Jürgen Enczmann, Wasco Wruck, James Adjaye
SIX2-positive renal cells isolated from urine from a 51year old male of African origin bearing the CYP2D6 *4/*17 variant were reprogrammed by nucleofection of a combination of two episomal-based plasmids omitting pathway (TGFβ, MEK and GSK3β) inhibition. The induced pluripotent stem cells (iPSCs) were characterized by immunocytochemistry, embryoid body formation, DNA-fingerprinting and karyotype analysis. Comparative transcriptome analyses with human embryonic stem cell lines H1 and H9 revealed a Pearson correlation of 0...
October 7, 2017: Stem Cell Research
https://www.readbyqxmd.com/read/29031061/crassiflorone-derivatives-that-inhibit-trypanosoma-brucei-glyceraldehyde-3-phosphate-dehydrogenase-tbgapdh-and-trypanosoma-cruzi-trypanothione-reductase-tctr-and-display-trypanocidal-activity
#5
Elisa Uliassi, Giulia Fiorani, R Luise Krauth-Siegel, Christian Bergamini, Romana Fato, Giulia Bianchini, J Carlos Menéndez, Maria Teresa Molina, Eulogio López-Montero, Federico Falchi, Andrea Cavalli, Sheraz Gul, Maria Kuzikov, Bernhard Ellinger, Gesa Witt, Carolina B Moraes, Lucio H Freitas-Junior, Chiara Borsari, Maria Paola Costi, Maria Laura Bolognesi
Crassiflorone is a natural product with anti-mycobacterial and anti-gonorrhoeal properties, isolated from the stem bark of the African ebony tree Diospyros crassiflora. We noticed that its pentacyclic core possesses structural resemblance to the quinone-coumarin hybrid 3, which we reported to exhibit a dual-targeted inhibitory profile towards Trypanosoma brucei glyceraldehyde-3-phosphate dehydrogenase (TbGAPDH) and Trypanosoma cruzi trypanothione reductase (TcTR). Following this basic idea, we synthesized a small library of crassiflorone derivatives 15-23 and investigated their potential as anti-trypanosomatid agents...
October 3, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29027845/the-potent-mechanism-based-inactivation-of-cyp2d6-and-cyp3a4-with-fusidic-acid-in-in-vivo-bioaccumulation
#6
Xiu-Xian Lin, Guang-Hui Lian, Ying Xu, Qing Zhao, Jian Xiao, Shi-Fang Peng, Mei-Fang Xiao, Dong-Sheng Ouyang, Zhi-Rong Tan, Yi-Cheng Wang, Jing-Bo Peng, Wei Zhang, Yao Chen
1. The accumulation of fusidic acid (FA) after multiple doses of FA has been reported on in previous studies but the related mechanisms have not been clarified fully. In the present study, we explain the mechanisms related to the mechanism-based inactivation of CYP2D6 and CYP3A4. 2. The irreversible inhibitory effects of FA on CYP2D6 and CYP3A4 were examined via a series of experiments, including: a) time-, concentration- and NADPH-dependent inactivation, b) substrate protection in enzyme inactivation and c) partition ratio with recombinant human CYP enzymes...
October 13, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/29027194/predictive-performance-of-physiologically-based-pharmacokinetic-pbpk-modeling-of-drugs-extensively-metabolized-by-major-cytochrome-p450s-in-children
#7
Wangda Zhou, Trevor N Johnson, Khanh H Bui, S Y Amy Cheung, Jianguo Li, Hongmei Xu, Nidal Al-Huniti, Diansong Zhou
The accuracy of physiologically-based pharmacokinetic (PBPK) model prediction in children, especially those younger than 2 years old has not been systematically evaluated. The aim of this study was to characterize the pediatric predictive performance of the PBPK approach for ten drugs extensively metabolized by CYP1A2 (theophylline), CYP2C8 (desloratidine, montelukast), CYP2C9 (diclofenac), CYP2C19 (esomeprazole, lansoprazole), CYP2D6 (tramadol) and CYP3A4 (itraconazole, ondansetron, sufentanil). Model performance in children was evaluated by comparing simulated plasma concentration-time profiles with observed clinical results for each drug and age group...
October 13, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29025271/psychotropic-drugs-and-cyp2d6-in-late-life-psychiatric-and-neurological-disorders-what-do-we-know
#8
Davide Seripa, Madia Lozupone, Eleonora Stella, Giulia Paroni, Paola Bisceglia, Maddalena La Montagna, Grazia D'onofrio, Carolina Gravina, Maria Urbano, Maria Giovanna Priore, Angela Lamanna, Antonio Daniele, Antonello Bellomo, Giancarlo Logroscino, Antonio Greco, Francesco Panza
Late-life psychiatric and neurological disorders (LLPND) are interesting models to understand the potential role of pharmacogenetics in drug management, since several pharmacological approaches for treating LLPND have proven to be ineffective or deleterious, thus resulting in therapeutic failures (TF) and adverse drug reactions (ADR). Common variants in the genes encoding the cytochrome P450 (CYP) enzyme system, the 'engine room' of drug metabolism, together with well-known age-related increased polypharmacy also contributed to the prevalence of TF and ADR observed in these patients, also rising number and time of hospital readmissions and rate of institutionalizations...
October 12, 2017: Expert Opinion on Drug Safety
https://www.readbyqxmd.com/read/29023140/genetic-polymorphisms-of-cytochrome-p450-enzymes-and-transport-proteins-in-a-russian-population-and-three-ethnic-groups-of-dagestan
#9
Karin B Mirzaev, Dmitry A Sychev, Kristina A Ryzhikova, Olga D Konova, Suleiman N Mammaev, Daniyal M Gafurov, Grigorij N Shuev, Elena A Grishina, Zhannet A Sozaeva
AIM: The objective of this study was to investigate the prevalence of polymorphic markers of the CYP2C19, CYP2C9, CYP2D6, SLCO1B1, and ABCB1 genes among the three ethnic groups in Dagestan and compare it with the carrier frequency of these markers among the Russian population living in Moscow. METHODS: The study involved 186 healthy, unrelated, and chronic medication-free volunteers (53 males and 133 females) of the three ethnic groups in the Dagestan Republic: 46 Laks, 90 Avars, and 50 Dargins...
October 12, 2017: Genetic Testing and Molecular Biomarkers
https://www.readbyqxmd.com/read/29021832/pharmacogenomics-in-the-treatment-of-mood-disorders-strategies-and-opportunities-for-personalized-psychiatry
#10
REVIEW
Azmeraw T Amare, Klaus Oliver Schubert, Bernhard T Baune
Personalized medicine (personalized psychiatry in a specific setting) is a new model towards individualized care, in which knowledge from genomics and other omic pillars (microbiome, epigenomes, proteome, and metabolome) will be combined with clinical data to guide efforts to new drug development and targeted prescription of the existing treatment options. In this review, we summarize pharmacogenomic studies in mood disorders that may lay the foundation towards personalized psychiatry. In addition, we have discussed the possible strategies to integrate data from omic pillars as a future path to personalized psychiatry...
September 2017: EPMA Journal
https://www.readbyqxmd.com/read/28994497/effects-of-vernonia-cinerea-compounds-on-drug-metabolizing-cytochrome-p450s-in-human-liver-microsomes
#11
Phisit Pouyfung, Songklod Sarapusit, Pornpimol Rongnoparut
Vernonia cinerea has been widely used in traditional medicines for various diseases and shown to aid in smoking abstinence and has anticancer properties. V. cinerea bioactive compounds, including flavonoids and hirsutinolide-type sesquiterpene lactones, have shown an inhibition effect on the nicotine-metabolizing cytochrome P450 2A6 (CYP2A6) enzyme and hirsutinolides reported suppressing cancer growth. In this study, V. cinerea ethanol extract and its bioactive compounds, including four flavonoids and four hirsutinolides, were investigated for an inhibitory effect on human liver microsomal CYPs 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 using cocktail inhibition assays combined with LC-MS/MS analysis...
October 10, 2017: Phytotherapy Research: PTR
https://www.readbyqxmd.com/read/28984748/clozapine-induced-agranulocytosis-granulocytopenia-mechanisms-and-monitoring
#12
Michał Wiciński, Mateusz M Węclewicz
PURPOSE OF REVIEW: Clozapine-induced agranulocytosis/granulocytopenia (CIAG) is an uncommon condition, but potentially fatal in consequences. The pathogenesis, despite multiple experiments, is not fully elucidated. The current theory suggests reactive oxygen species - nitrenium ion as the most important factor of CIAG. In this review, mechanism and monitoring of CIAG will be discussed. RECENT FINDINGS: The mechanism of CIAG seems to have an autoimmune background, rather than toxic...
October 4, 2017: Current Opinion in Hematology
https://www.readbyqxmd.com/read/28978661/studies-on-para-methoxymethamphetamine-pmma-metabolite-pattern-and-influence-of-cyp2d6-genetics-in-human-liver-microsomes-and-authentic-samples-from-fatal-pmma-intoxications
#13
Merete Vevelstad, Elisabeth Leere Oiestad, Elisabeth Nerem, Marianne Arnestad, Inger Lise Bogen
Para-methoxymethamphetamine (PMMA) has caused numerous fatal poisonings worldwide and appears to be more toxic than other ring-substituted amphetamines. Systemic metabolism is suggested to be important for PMMA neurotoxicity, possibly through activation of minor catechol metabolites to neurotoxic conjugates. The aim of this study was to examine the metabolism of PMMA in humans, and for this purpose we used human liver microsomes (HLM) and blood samples from three cases of fatal PMMA intoxication. We also examined the impact of CYP2D6 genetics on PMMA metabolism using genotyped HLM isolated from CYP2D6 poor, population average and ultrarapid metabolizers...
October 4, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28971704/genetic-variability-of-cyp2d6-cyp2b6-cyp2c9-and-cyp2c19-genes-across-the-italian-peninsula
#14
Francesco Carano, Stefania Sarno, Sara De Fanti, Patrizia Serventi, Carla Bini, Donata Luiselli, Susi Pelotti
BACKGROUND: Environmental conditions and past migratory events may have shaped genetic heterogeneity of clinically relevant enzymes involved in the phase I metabolism of the most common therapeutic drugs. AIM: To investigate the genetic variability of CYP2D6, CYP2B6, CYP2C19 and CYP2C9 across the Italian Peninsula, by sampling only ancestrally and geographically homogeneous individuals from northern, central and southern Italy. SUBJECTS AND METHODS: A total of 25 SNPs were genotyped in 174 unrelated Italian individuals by means of multiplex PCR and minisequencing reactions...
October 3, 2017: Annals of Human Biology
https://www.readbyqxmd.com/read/28962866/in-vitro-metabolism-of-4-5-dimethoxycanthin-6-one-by-human-liver-microsomes-and-its-inhibition-on-human-cyp1a2
#15
Xiaolei Miao, Jiaojiao You, Junjun Wang, Yong Chen
AIMS: P. quassioides is a traditional Chinese medicine used for the treatment of gastroenteritis, snakebite, infection and hypertension in China. 4, 5-dimethoxycanthin-6-one is one of the main active canthinone alkaloid isolated from P. quassioides. The aim of this work was to identify the cytochrome P (CYP) 450 enzymes responsible for the metabolism of 4, 5-dimethoxycanthin-6-one (DCO) and to evaluate the inhibitory effect of DCO on CYP activity in human liver microsomes (HLM) in vitro...
September 26, 2017: Life Sciences
https://www.readbyqxmd.com/read/28960401/prediction-of-drug-drug-interactions-using-physiologically-based-pharmacokinetic-models-of-cyp450-modulators-included-in-simcyp-software
#16
Niloufar Marsousi, Jules A Desmeules, Serge Rudaz, Youssef Daali
In recent years, Physiologically-Based PharmacoKinetic (PBPK) modeling has received growing interest as a useful tool for assessment of drug PK. It has demonstrated to be informative and helpful to quantify the modification in drug exposure due to specific physio-pathological conditions, age, genetic polymorphisms, ethnicity and particularly drug-drug interactions (DDIs). In this paper, the prediction success of DDIs involving various cytochrome P450 isoenzyme (CYP) modulators namely ketoconazole (a competitive inhibitor of CYP3A), itraconazole (a competitive inhibitor of CYP3A), clarithromycin (a mechanism-based inhibitor of CYP3A), quinidine (a competitive inhibitor of CYP2D6), paroxetine (a mechanism-based inhibitor of CYP2D6), ciprofloxacin (a competitive inhibitor of CYP1A2), fluconazole (a competitive inhibitor of CYP2C9/2C19) and rifampicin (an inducer of CYP3A) were assessed using Simcyp® software...
September 28, 2017: Biopharmaceutics & Drug Disposition
https://www.readbyqxmd.com/read/28960344/inhibition-of-human-cytochromes-p450-in%C3%A2-vitro-by-ritonavir-and-cobicistat
#17
Md Amin Hossain, Timothy Tran, Tianmeng Chen, Gerd Mikus, David J Greenblatt
OBJECTIVES: Ritonavir and cobicistat are strong inhibitors of human cytochrome P450-3A (CYP3A) isoforms, and are used clinically as pharmacokinetic boosting agents for other antiretroviral drugs. Data reported by the manufacturer suggest that cobicistat is a more selective inhibitor of CYP3A than ritonavir. However, this claim has not been validated in clinical studies. This study evaluated the in-vitro inhibitory potency of ritonavir and cobicistat vs a series of human CYP isoforms. METHOD: The model system utilized human liver microsomes and isoform-selective index substrates...
September 29, 2017: Journal of Pharmacy and Pharmacology
https://www.readbyqxmd.com/read/28958623/identification-of-selective-8-piperidin-4-yloxy-quinoline-sulfone-and-sulfonamide-histamine-h1-receptor-antagonists-for-use-in-allergic-rhinitis
#18
Panayiotis A Procopiou, Alison J Ford, Paul M Gore, Ashley P Hancock, Simon T Hodgson, Duncan S Holmes, Brian E Looker, Sadie Vile, Kenneth L Clark, Ken A Saunders, Robert J Slack, Clarissa J Watts
A series of potent, selective and long-acting quinoline-based sulfonamide human H1 histamine receptor antagonists, designed for once-daily intranasal administration for the treatment of rhinitis were developed. Sulfonamide 33b had a slightly lower affinity for the H1 receptor than azelastine, had low oral bioavailability in the rat and dog, and was turned over to five major metabolites. Furthermore, 33b had longer duration of action than azelastine in guinea pigs, lower rat brain-penetration, and did not cause time dependent inhibition of CYP2D6 or CYP3A4...
September 9, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28955222/improved-prediction-of-endoxifen-metabolism-by-cyp2d6-genotype-in-breast-cancer-patients-treated-with-tamoxifen
#19
Werner Schroth, Stefan Winter, Thomas Mürdter, Elke Schaeffeler, Diana Eccles, Bryony Eccles, Balram Chowbay, Chiea C Khor, Arafat Tfayli, Nathalie K Zgheib, Michel Eichelbaum, Matthias Schwab, Hiltrud Brauch
Purpose: Prediction of impaired tamoxifen (TAM) to endoxifen metabolism may be relevant to improve breast cancer treatment, e.g., via TAM dose increase. The polymorphic cytochrome P450 2D6 (CYP2D6) strongly determines an individual's capacity for endoxifen formation, however, CYP2D6 phenotype assignments inferred from genotype widely differ between studies. Thus, we modeled plasma endoxifen predictability depending on variable CYP2D6 genotype groupings. Methods: CYP2D6 diplotype and metabolite plasma concentrations were assessed in 908 pre- and post-menopausal estrogen receptor (ER)-positive, TAM treated early breast cancer patients of Caucasian (N = 678), Middle-Eastern Arab (N = 77), and Asian (N = 153) origin...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28944677/multiplex-and-label-free-relative-quantification-approach-for-studying-protein-abundance-of-drug-metabolizing-enzymes-in-human-liver-microsomes-using-swath-ms
#20
Rohitash Jamwal, Benjamin J Barlock, Sravani Adusumalli, Ken Ogasawara, Brigitte L Simons, Fatemeh Akhlaghi
We describe a sequential windowed acquisition of all theoretical fragment ion mass spectra (SWATH-MS) based method for label-free, simultaneous, relative quantification of drug metabolism enzymes in human liver microsomes (HLM; n = 78). In-solution tryptic digestion was aided by a pressure cycling method, which allowed a 90 min incubation time, a significant reduction over classical protocols (12-18 h). Digested peptides were separated on an Acquity UHPLC Peptide BEH C18 column using a 60 min gradient method at a flow rate of 0...
October 10, 2017: Journal of Proteome Research
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