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https://www.readbyqxmd.com/read/29445054/comparison-of-drug-metabolism-and-its-related-hepatotoxic-effects-in-heparg-cryopreserved-human-hepatocytes-and-hepg2-cell-cultures
#1
Yuichi Yokoyama, Yoshifumi Sasaki, Natsuko Terasaki, Taku Kawataki, Koji Takekawa, Yumiko Iwase, Toshinobu Shimizu, Seigo Sanoh, Shigeru Ohta
Differentiated HepaRG cells maintain liver-specific functions such as drug-metabolizing enzymes. In this study, the feasibility of HepaRG cells as a human hepatocyte model for in vitro toxicity assessment was examined using selected hepatotoxic compounds. First, basal drug-metabolizing enzyme activities (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, uridine 5'-diphospho-glucuronosyltransferase [UGT], and sulfotransferases [SULT]) were measured in HepaRG, human hepatocytes, and HepG2 cells. Enzyme activities in differentiated HepaRG cells were comparable to those in human hepatocytes and much higher than those in HepG2 cells, except for SULT activity...
February 14, 2018: Biological & Pharmaceutical Bulletin
https://www.readbyqxmd.com/read/29439084/evaluating-the-impact-of-type-2-diabetes-mellitus-on-cyp450-metabolic-activities-protocol-for-a-case-control-pharmacokinetic-study
#2
Sophie Gravel, Jean-Louis Chiasson, Suzanne Dallaire, Jacques Turgeon, Veronique Michaud
INTRODUCTION: Diabetes affects more than 9% of the adult population worldwide. Patients with type 2 diabetes mellitus (T2DM) show variable responses to some drugs which may be due, in part, to variability in the functional activity of drug-metabolising enzymes including cytochromes P450 (CYP450s). CYP450 is a superfamily of enzymes responsible for xenobiotic metabolism. Knowledge must be gained on the impact of T2DM and related inflammatory processes on drug metabolism and its consequences on drug response...
February 8, 2018: BMJ Open
https://www.readbyqxmd.com/read/29436156/cytochrome-p450-genetic-variation-associated-with-tamoxifen-biotransformation-in-american-indian-and-alaska-native-people
#3
Burhan A Khan, Renee Robinson, Alison E Fohner, LeeAnna I Muzquiz, Brian D Schilling, Julie A Beans, Matthew J Olnes, Laura Trawicki, Holly Frydenlund, Cindi Laukes, Patrick Beatty, Brian Phillips, Deborah Nickerson, Kevin Howlett, Denise A Dillard, Timothy A Thornton, Kenneth E Thummel, Erica L Woodahl
Despite evidence that pharmacogenetics can improve tamoxifen pharmacotherapy, there are few studies with American Indian and Alaska Native (AIAN) people. We examined variation in cytochrome P450 (CYP) genes (CYP2D6, CYP3A4, CYP3A5, and CYP2C9) and tamoxifen biotransformation in AIAN patients with breast cancer (n = 42) from the Southcentral Foundation in Alaska and the Confederated Salish and Kootenai Tribes in Montana. We tested for associations between CYP diplotypes and plasma concentrations of tamoxifen and metabolites...
February 13, 2018: Clinical and Translational Science
https://www.readbyqxmd.com/read/29432309/maternal-exposure-to-pesticides-paternal-occupation-in-the-army-police-force-and-cyp2d6-4-polymorphism-in-the-etiology-of-childhood-acute-leukemia
#4
Giovanni M Ferri, Chiara M Guastadisegno, Graziana Intranuovo, Domenica Cavone, Francesco Birtolo, Valerio Cecinati, Brigida Pappalardi, Patrizia Corsi, Luigi Vimercati, Nicola Santoro
Epidemiologic studies have suggested that parental occupations, pesticide use, environmental factors, and genetic polymorphism are involved in the etiology of childhood acute leukemia (CAL). In total, 116 cases of CAL and 162 controls were recruited and submitted to blood drawing to assess the presence of genetic polymorphisms. Parental occupations, pesticides exposure, and other potential determinants were investigated. Increased risk for CAL was associated with prenatal maternal use of insecticides/rodenticides (odds ratio [OR]=1...
February 9, 2018: Journal of Pediatric Hematology/oncology
https://www.readbyqxmd.com/read/29420304/accurate-determination-of-the-cyp2d6-1-4-xn-genotype-by-quantitative-pcr
#5
Kirsten M Pondman, Ron H N van Schaik, Jan van der Weide
BACKGROUND: CYP2D6 is responsible for the metabolism of approximately 25% of all drugs. The expression of cytochrome P450 2D6 (CYP2D6) is influenced by a combination of factors including polymorphisms in the CYP2D6 gene. Analysis of the CYP2D6 genotype is used to personalize the medication to a patient's metabolism. Although many genotypes can be determined using standard genotype analysis, in some cases, an incomplete analysis is performed. The CYP2D6 genotype *1/*4 often occurs in combination with a multiplication of the CYP2D6 gene, and is reported as (*1/*4)xN...
February 8, 2018: Drug Metabolism and Personalized Therapy
https://www.readbyqxmd.com/read/29417949/charactering-the-metabolism-of-cryptotanshinone-by-human-p450-enzymes-and-uridine-diphosphate-glucuronosyltransferases-in-vitro
#6
Jin Zeng, Yu-Juan Fan, Bo Tan, Hui-Zong Su, Yue Li, Lin-Lin Zhang, Jian Jiang, Fu-Rong Qiu
Cryptotanshinone (CT) is the main active component in the root of Salvia miltiorrhiza Bunge (SMB) that displays antibacterial, anti-inflammatory and anticancer activities. In this study, we characterized phase I and phase II metabolism of CT in human liver microsomes in vitro and identified the metabolic enzymes (CYPs and UGTs) involved. The metabolites of CT generated by CYPs were detected using LC-MS/MS and the CYP subtypes involved in the metabolic reactions were identified using chemical inhibitors of CYP enzymes and recombinant human CYP enzymes (CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4)...
February 8, 2018: Acta Pharmacologica Sinica
https://www.readbyqxmd.com/read/29413979/effect-of-tinospora-cordifolia-aqua-alcoholic-extract-on-pharmacokinetic-of-glibenclamide-in-rat-an-herb-drug-interaction-study
#7
Rajanikanta Sahu, Tausif Ahmed, Ramchandra Sangana, Ravindra Punde, Bharat Bhusan Subudhi
Tinospora cordifolia (TC) has been used as a complimentary/alternative medicine against diabetes. Considering its potential to modulate metabolic enzymes, Tinospora cordifolia extract (TCE) may influence the metabolism of the antidiabeic drug Glibenclamide following co-administration. Accordingly, this work was undertaken to evaluate impact of TCE on fate of Glibenclamide. Activity of clinically important Cytochrome P450 isoenzymes were inhibited in the order of CYP2C9 > CYP2D6 > CYP2C19 > CYP1A2 > CYP3A4...
January 10, 2018: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/29412458/oliceridine-trv130-a-novel-g-protein-biased-ligand-at-the-%C3%AE-opioid-receptor-demonstrates-a-predictable-relationship-between-plasma-concentrations-and-pain-relief-i-development-of-a-pharmacokinetic-pharmacodynamic-model
#8
Michael J Fossler, Brian M Sadler, Colm Farrell, David A Burt, Maria Pitsiu, Franck Skobieranda, David G Soergel
Conventional opioids bind to μ-opioid receptors and activate 2 downstream signaling pathways: G-protein coupling, linked to analgesia, and β-arrestin recruitment, linked to opioid-related adverse effects and limiting efficacy. Oliceridine (TRV130) is a novel G protein-biased ligand at the μ-opioid receptor that differentially activates G-protein coupling while mitigating β-arrestin recruitment. Using data derived from both phase 1 studies in healthy volunteers as well as data from a phase 2 study examining the efficacy of oliceridine for the treatment of postbunionectomy pain, we have developed a population pharmacokinetic/pharmacodynamic model linking the pharmacokinetics of oliceridine to its effect on pain, as measured by the Numeric Pain Rating Scale score...
February 7, 2018: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29409945/billion-scale-production-of-hepatocyte-like-cells-from-human-induced-pluripotent-stem-cells
#9
Tomoki Yamashita, Kazuo Takayama, Fuminori Sakurai, Hiroyuki Mizuguchi
Human induced pluripotent stem (iPS) cell-derived hepatocyte-like cells are expected to be utilized in drug screening and regenerative medicine. However, hepatocyte-like cells have not been fully used in such applications because it is difficult to produce such cells on a large scale. In this study, we tried to establish a method to mass produce hepatocyte-like cells using a three-dimensional (3D) cell culture bioreactor called the Rotary Cell Culture System (RCCS). RCCS enabled us to obtain homogenous hepatocyte-like cells on a billion scale (>109 cells)...
February 1, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29396856/the-relationship-between-the-cyp2d6-polymorphisms-and-tamoxifen-efficacy-in-adjuvant-endocrine-therapy-of-breast-cancer-patients-in-chinese-han-population
#10
Bo Lan, Fei Ma, Xiaoyu Zhai, Qiao Li, Shanshan Chen, Jiayu Wang, Ying Fan, Yang Luo, Ruigang Cai, Peng Yuan, Pin Zhang, Qing Li, Binghe Xu
Variants of the CYP2D6 gene may lead to a poor prognosis of tamoxifen (TAM)-treated patients. This study validated the association between the CYP2D6 genotype and outcomes of patients receiving TAM in adjuvant endocrine therapy. A total of 778 breast cancer patients who received adjuvant TAM (n=325) or aromatase inhibitors (AIs) (n=453) at the National Cancer Center were analyzed. Nine single nucleotide polymorphisms (SNPs) in the CYP2D6 gene were selected from online databases. The associations of each SNP genotype with disease-free survival (DFS) and clinicopathological characteristics were analyzed...
February 3, 2018: International Journal of Cancer. Journal International du Cancer
https://www.readbyqxmd.com/read/29393971/oliceridine-a-novel-g-protein-biased-ligand-at-the-%C3%AE-opioid-receptor-demonstrates-a-predictable-relationship-between-plasma-concentrations-and-pain-relief-ii-simulation-of-potential-phase-3-study-designs-using-a-pharmacokinetic-pharmacodynamic-model
#11
Michael J Fossler, Brian M Sadler, Colm Farrell, David A Burt, Maria Pitsiu, Franck Skobieranda, David G Soergel
Oliceridine is a novel G protein-biased ligand at the μ-opioid receptor that differentially activates G protein coupling while mitigating β-arrestin recruitment. Unlike morphine, oliceridine has no known active metabolites; therefore, analgesic efficacy is predictably linked to its concentration in the plasma. Oliceridine is primarily hepatically metabolized by CYP3A4 and CYP2D6. Using a pharmacokinetic/pharmacodynamic model relating oliceridine plasma concentrations to its effect on pain intensity as measured by numeric pain-rating scale (NPRS) scores, we have simulated potential dosing regimens using both fixed-dose regimens and as-needed (prn) dosing regimens in which various doses of oliceridine were administered if NPRS scores indicated moderate to severe pain (≥4 on a 0-10 scale)...
February 2, 2018: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29390987/cyp2d6-activity-and-the-risk-of-recurrence-of-plasmodium-vivax-malaria-in-the-brazilian-amazon-a-prospective-cohort-study
#12
Larissa W Brasil, Fernanda Rodrigues-Soares, Ana B Santoro, Anne C G Almeida, Andrea Kühn, Rajendranath Ramasawmy, Marcus V G Lacerda, Wuelton M Monteiro, Guilherme Suarez-Kurtz
BACKGROUND: CYP2D6 pathway mediates the activation of primaquine into active metabolite(s) in hepatocytes. CYP2D6 is highly polymorphic, encoding CYP2D6 isoforms with normal, reduced, null or increased activity. It is hypothesized that Plasmodium vivax malaria patients with defective CYP2D6 function would be at increased risk for primaquine failure to prevent recurrence. The aim of this study was to investigate the association of CYP2D6 polymorphisms and inferred CYP2D6 phenotypes with malaria recurrence in patients from the Western Brazilian Amazon, following chloroquine/primaquine combined therapy...
February 1, 2018: Malaria Journal
https://www.readbyqxmd.com/read/29389842/dihydrocodeine-overdoses-in-a-neonate-and-in-a-14-year-old-girl-who-were-both-genotyped-as-cytochrome-p450-2d6-1-10-36-comparing-developmental-ages-and-drug-monitoring-data-with-the-results-of-pharmacokinetic-modeling
#13
Makiko Shimizu, Tatsuki Kondo, Tetsuya Fukuoka, Toshihiro Tanaka, Hiroshi Yamazaki
A high activity of cytochrome P450 2D6 (CYP2D6) reportedly leads toxicity of dihydrocodeine/codeine by increasing toxic potential of their metabolite dihydromorphine/morphine, which are further metabolized to highly active dihydromorphine 6-O-glucuronide and the less active morphine 3-O-glucorinide but rapidly excreted into urine as water-soluble forms. A case of acute respiratory depression after administration of prescribed dihydrocodeine phosphate (2.0 mg/day divided TID for 2 days) to a 1-month-old baby boy genotyped as cytochrome CYP2D6*1/*10-*36 is described...
January 30, 2018: Therapeutic Drug Monitoring
https://www.readbyqxmd.com/read/29385237/clinical-pharmacogenetics-implementation-consortium-cpic-guideline-for-cyp2d6-and-tamoxifen-therapy
#14
Matthew P Goetz, Katrin Sangkuhl, Henk-Jan Guchelaar, Matthias Schwab, Michael Province, Michelle Whirl-Carrillo, W Fraser Symmans, Howard L McLeod, Mark J Ratain, Hitoshi Zembutsu, Andrea Gaedigk, Ron H van Schaik, James N Ingle, Kelly E Caudle, Teri E Klein
Tamoxifen is biotransformed by CYP2D6 to 4-hydroxytamoxifen and 4-hydroxy N-desmethyl tamoxifen (endoxifen), both with greater antiestrogenic potency than the parent drug. Patients with certain CYP2D6 genetic polymorphisms and patients who receive strong CYP2D6 inhibitors exhibit lower endoxifen concentrations and a higher risk of disease recurrence in some studies of tamoxifen adjuvant therapy of early breast cancer. We summarize evidence from the literature and provide therapeutic recommendations for tamoxifen based on CYP2D6 genotype...
January 31, 2018: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29383410/-pharmacogenetics-in-psychiatry-state-of-the-art
#15
REVIEW
D J Müller, E J Brandl, F Degenhardt, K Domschke, H Grabe, O Gruber, J Hebebrand, W Maier, A Menke, M Riemenschneider, M Rietschel, D Rujescu, T G Schulze, L Tebartz van Elst, O Tüscher, J Deckert
In this article, the current literature on pharmacogenetics of antidepressants, antipsychotics and lithium are summarized by the section of Neurobiology and Genetics of the German Society of Psychiatry, Psychotherapy and Neurology (DGPPN). The publications of international expert groups and regulatory authorities are reviewed and discussed. In Germany, a statement on pharmacogenetics was also made by the gene diagnostics committee of the Ministry of Health. The DGPPN supports two recommendations: 1) to perform CYP2D6 genetic testing prior to prescription of tricyclic antidepressants and 2) to determine the HLA-B*1502 genotype in patients of Asian origin before using carbamazepine...
January 30, 2018: Der Nervenarzt
https://www.readbyqxmd.com/read/29369497/pharmacogenetics-of-risperidone-induced-insulin-resistance-in-children-and-adolescents-with-autism-spectrum-disorder
#16
Chonlaphat Sukasem, Natchaya Vanwong, Pornpen Srisawasdi, Nattawat Ngamsamut, Nopphadol Nuntamool, Yaowaluck Hongkaew, Apichaya Puangpetch, Bhunnada Chamkrachangpada, Penkhae Limsila
The purpose of this study was to explore the association of genetic polymorphism of genes related to pharmacokinetics or pharmacodynamics with insulin resistance in children and adolescents with autism spectrum disorder (ASD) and treated with risperidone. All 89 subjects underwent measurement of fasting blood glucose and insulin levels, body weight and height. Genotyping was performed by Taqman real-time polymerase chain reaction (PCR) (pharmacokinetics genes: cytochrome P450 2D6 (CYP2D6) *4 (rs3892097), *5 (gene deletion), *10 (rs1065852), and *41 (rs28371725), ATP-binding cassette transporter B1 (ABCB1) 2677 G>T/A (rs2032582) and 3435C>T (rs1045642), and pharmacodynamics genes: dopamine receptor D2 (DRD2) Tag-SNP (C>T) (rs4436578), DRD2 Tag1A (C>T) (rs1800497), leptin gene (LEP) -2548G>A (rs7799039), ghrelin gene (GHRL) -604G>A (rs27647), and brain-derived neurotrophic factor (BDNF) 196G>A (rs6265)...
January 25, 2018: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29363498/a-novel-in-vitro-experimental-system-for-the-evaluation-of-drug-metabolism-cofactor-supplemented-permeabilized-cryopreserved-human-hepatocytes-metmax%C3%A2-cryopreserved-human-hepatocytes
#17
Albert P Li, Ming-Chih David Ho, Kirsten Amaral, Carol Loretz
We report here a novel experimental system - MetMax™ cryopreserved human hepatocytes (MMHH), for in vitro drug metabolism studies. MMHH consist of cofactor-supplemented permeabilized cryopreserved human hepatocytes. The use procedures for MMHH are significantly simplified from that for conventional cryopreserved human hepatocytes (CCHH): 1. Storage at -80o C instead of in liquid nitrogen; 2. Usage directly after thawing without centrifugation and microscopic evaluation of cell density and viability and cell density adjustment...
January 23, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29358012/once-versus-twice-daily-dosing-of-eliglustat-in-adults-with-gaucher-disease-type-1-the-phase-3-randomized-double-blind-edge-trial
#18
Joel Charrow, Cristina Fraga, Xuefan Gu, Hiroyuki Ida, Nicola Longo, Elena Lukina, Alexandre Nonino, Sebastiaan J M Gaemers, Marie-Helene Jouvin, Jing Li, Yaoshi Wu, Yong Xue, M Judith Peterschmitt
Eliglustat is a first-line oral therapy for adults with Gaucher disease type 1 (GD1) with compatible CYP2D6-metabolizer phenotypes (>90% of patients). The randomized, double-blind EDGE trial (NCT01074944, Sanofi Genzyme) evaluated once-daily eliglustat dosing compared with the approved twice-daily regimen at the same total daily dose in adults with GD1. Subjects received twice-daily dosing during a 6- to 18-month lead-in period. Only subjects who attained prespecified treatment goals for hemoglobin, platelet count, spleen and liver volumes, and bone symptoms during the lead-in period were randomized to once- or twice-daily dosing...
January 4, 2018: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/29357870/primaquine-ineligibility-in-anti-relapse-therapy-of-plasmodium-vivax-malaria-the-problem-of-g6pd-deficiency-and-cytochrome-p-450-2d6-polymorphisms
#19
EDITORIAL
J Kevin Baird, Katherine E Battle, Rosalind E Howes
The hypnozoite reservoir of Plasmodium vivax represents both the greatest obstacle and opportunity for ultimately eradicating this species. It is silent and cannot be diagnosed until it awakens and provokes a clinical attack with attendant morbidity, risk of mortality, and opportunities for onward transmission. The only licensed drug that kills hypnozoites is primaquine, which attacks the hypnozoite reservoir but imposes serious obstacles in doing so-at hypnozoitocidal doses, it invariably causes a threatening acute haemolytic anaemia in patients having an inborn deficiency in glucose-6-phosphate dehydrogenase (G6PD), affecting about 8% of people living in malaria endemic nations...
January 22, 2018: Malaria Journal
https://www.readbyqxmd.com/read/29349771/cyp2d6-protein-level-is-the-major-contributor-to-inter-individual-variability-in-cyp2d6-mediated-drug-metabolism-in-healthy-human-liver-tissue
#20
Miaoran Ning, Julio D Duarte, Leah H Rubin, Hyunyoung Jeong
CYP2D6 genetic polymorphisms are considered a major contributor to the large inter-individual variability in CYP2D6-mediated drug metabolism, but fail to explain significant portion of the variability. The aim of this study was to assess the ability of CYP2D6 activity score (AS) estimated from CYP2D6 genotype to predict CYP2D6 expression and enzyme activity. The CYP2D6 gene region was sequenced in 115 healthy human liver tissue samples to determine their CYP2D6 AS. Additionally, CYP2D6 enzyme activity, protein, and mRNA levels were estimated...
January 19, 2018: Clinical Pharmacology and Therapeutics
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