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https://www.readbyqxmd.com/read/28440827/molecular-dynamics-investigations-of-membrane-bound-cyp2c19-polymorphisms-reveal-distinct-mechanisms-for-peripheral-variants-by-long-range-effects-on-the-enzymatic-activity
#1
Ying-Lu Cui, Rong-Ling Wu
Increasing sophistication in methods used to account for human polymorphisms in susceptibility to drug metabolism has been one of the success stories in the prevention of adverse drug reactions. Genetic polymorphisms in drug-metabolizing enzymes can affect enzyme activity and cause differences in treatment response or drug toxicity. CYP2C19 is one of the most highly polymorphic CYP enzymes and acts on 10-15% of drugs in current clinical use. Despite the number of experimental analyses carried out for this system, the detailed structural basis for altered catalytic properties of polymorphic CYP2C19 variants remains unexplained at the atomic level...
April 25, 2017: Molecular BioSystems
https://www.readbyqxmd.com/read/28435307/comparison-of-cyp2c9-cyp2c19-cyp2d6-abcb1-and-slco1b1-gene-polymorphism-frequency-in-russian-and-nanai-populations
#2
Dmitrij Alekseevitch Sychev, Grigorij Nikolaevich Shuev, Salavat Shejhovich Suleymanov, Kristina Anatol'evna Ryzhikova, Karin Badavievich Mirzaev, Elena Anatol'evna Grishina, Natalia Evgenievna Snalina, Zhannet Alimovna Sozaeva, Anton Mikhailovich Grabuzdov, Irina Andreevna Matsneva
BACKGROUND: The efficiency and safety of drug therapy depends on the peculiarities of functioning of the P450 cytochrome group and transporting proteins. There are significant differences for single-nucleotide polymorphism (SNP) frequency. MATERIALS AND METHODS: We studied the peculiarities of P450 cytochrome polymorphisms, SLCO1B1 transporting protein, and P-glycoprotein carriage in healthy volunteers in the Nanai ethnic group living in Russia, and compared them to the carriage of SNPs in the Russian population according to literature data...
2017: Pharmacogenomics and Personalized Medicine
https://www.readbyqxmd.com/read/28435143/estimation-of-inter-individual-variability-of-pharmacokinetics-of-cyp2c9-substrates-in-humans
#3
Koji Chiba, Keiko Shimizu, Motohiro Kato, Taichi Miyazaki, Takaaki Nishibayashi, Kazuki Terada, Yuichi Sugiyama
The activity of metabolic enzymes varies across individuals and populations. Activity varies even among individuals sharing the same genotype. Genetic polymorphisms in CYP2C9 cause significant inter-individual variability in the metabolism of its substrates. However, the variability of CYP2C9 intrinsic hepatic clearance (CLint,h,CYP2C9) among subjects of the same genotype has not been reported. In this study, we estimated the coefficient of variation (CV) for the intrinsic hepatic clearance of tolbutamide by CYP2C9 for each CYP2C9 genotype using previously reported AUCs and oral clearance (CLoral) values in a Monte Carlo simulation with a dispersion model...
April 20, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28421156/the-personalization-of-clopidogrel-antiplatelet-therapy-the-role-of-integrative-pharmacogenetics-and-pharmacometabolomics
#4
REVIEW
Arwa M Amin, Lim Sheau Chin, Dzul Azri Mohamed Noor, Muhamad Ali Sk Abdul Kader, Yuen Kah Hay, Baharudin Ibrahim
Dual antiplatelet therapy of aspirin and clopidogrel is pivotal for patients undergoing percutaneous coronary intervention. However, the variable platelets reactivity response to clopidogrel may lead to outcome failure and recurrence of cardiovascular events. Although many genetic and nongenetic factors are known, great portion of clopidogrel variable platelets reactivity remain unexplained which challenges the personalization of clopidogrel therapy. Current methods for clopidogrel personalization include CYP2C19 genotyping, pharmacokinetics, and platelets function testing...
2017: Cardiology Research and Practice
https://www.readbyqxmd.com/read/28416806/elevated-cyp2c19-expression-is-associated-with-depressive-symptoms-and-hippocampal-homeostasis-impairment
#5
M M Jukić, N Opel, J Ström, T Carrillo-Roa, S Miksys, M Novalen, A Renblom, S C Sim, E M Peñas-Lledó, P Courtet, A Llerena, B T Baune, D J de Quervain, A Papassotiropoulos, R F Tyndale, E B Binder, U Dannlowski, M Ingelman-Sundberg
No abstract text is available yet for this article.
April 18, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/28414290/-the-effect-of-isatin-on-protein-protein-interactions-between-cytochrome-b5-and-cytochromes-p450
#6
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/28412920/neuropsychiatric-and-general-interactions-of-natural-and-synthetic-cannabinoids-with-drugs-of-abuse-and-medicines
#7
Ana Lucia Arellano, Esther Papaseit, Anna Romaguera, Marta Torrens, Magi Farré
Cannabis is the most widely used illicit drug. The two most important natural cannabinoids are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). The THC content of cannabis has been increasing during the last years and recently appeared in the market a series of synthetic cannabinoids with potent agonist activity. Recreational users frequently combine cannabis with other drugs of abuse as alcohol, amphetamines and derivatives, nicotine and cocaine. In addition these subjects can be taking medicines for acute and chronic medical conditions...
April 13, 2017: CNS & Neurological Disorders Drug Targets
https://www.readbyqxmd.com/read/28408803/drug-drug-interaction-of-microdose-and-regular-dose-omeprazole-with-a-cyp2c19-inhibitor-and-inducer
#8
Gab-Jin Park, Soo Hyeon Bae, Wan-Su Park, Seunghoon Han, Min-Ho Park, Seok-Ho Shin, Young G Shin, Dong-Seok Yim
PURPOSE: A microdose drug-drug interaction (DDI) study may be a valuable tool for anticipating drug interaction at therapeutic doses. This study aimed to compare the magnitude of DDIs at microdoses and regular doses to explore the applicability of a microdose DDI study. PATIENTS AND METHODS: Six healthy male volunteer subjects were enrolled into each DDI study of omeprazole (victim) and known perpetrators: fluconazole (inhibitor) and rifampin (inducer). For both studies, the microdose (100 μg, cold compound) and the regular dose (20 mg) of omeprazole were given at days 0 and 1, respectively...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/28398139/the-association-between-high-on-treatment-platelet-reactivity-and-early-recurrence-of-ischemic-events-after-minor-stroke-or-tia
#9
Zilong Rao, Huaguang Zheng, Fei Wang, Anxin Wang, Liping Liu, Kehui Dong, Xingquan Zhao, Yilong Wang, Yibin Cao
OBJECTIVES: To evaluate the role of HTPR in predicting early recurrence of ischemic events in patients with minor ischemic stroke or high-risk TIA. METHODS: From January 2014 to September 2014, a single center continuously enrolled patients with minor ischemic stroke or high-risk TIA and gave them antiplatelet therapy consisting of aspirin with clopidogrel. HTPR was assessed by TEG after 7 days of antiplatelet therapy and detected CYP2C19 genotype. The incidence of recurrent ischemic events was assessed 3 months after onset...
April 11, 2017: Neurological Research
https://www.readbyqxmd.com/read/28396528/human-enterocytes-as-an-in-vitro-model-for-the-evaluation-of-intestinal-drug-metabolism-characterization-of-drug-metabolizing-enzyme-activities-of-cryopreserved-human-enterocytes-from-twenty-four-donors
#10
Ming-Chih David Ho, Nick Ring, Kirsten Amaral, Utkarsh Doshi, Albert Li
We report here successful isolation and cryopreservation of enterocytes from human small intestine. The enterocytes were isolated by enzyme digestion of the intestinal lumen followed by partial purification via differential centrifugation. The enterocytes were cryopreserved directly after isolation without culturing to maximize retention of in vivo drug metabolizing enzyme activities. Post-thaw viability of the cryopreserved enterocytes was consistently over 80% based on trypan blue exclusion. Cryopreserved enterocytes pooled from 8 donors (4 male and 4 female) were evaluated for their metabolism of 14 pathway-selective substrates: CYP1A2 (phenacetin hydroxylation), CYP2A6 (coumarin 7-hydroxylation), CYP2B6 (bupropion hydroxylation), CYP2C8 (paclitaxel 6α-hydroxylation), CYP2C9 (diclofenac 4-hydroxylation), CYP2C19 (s-mephenytoin 4-hydroxylation), CYP2D6 (dextromethorphan hydroxylation), CYP2E1 (chlorzoxazone 6-hydroxylation), CYP3A4 (midazolam 1'-hydroxylation and testosterone 6β-hydroxylation), CYP2J2 (astemizole O-demethylation), UDP-glucuronosyltransferase (UGT; 7-hydroxycoumarin glucuronidation), sulfotransferase (SULT; 7-hydroxycoumarin sulfation), and carboxylesterase 2 (CES2; irinotecan hydrolysis) activities...
April 10, 2017: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/28396010/analysis-of-the-variability-of-the-pharmacokinetics-of-multiple-drugs-in-young-adult-and-elderly-subjects-and-its-implications-for-acceptable-daily-exposures-and-cleaning-validation-limits
#11
REVIEW
Anthony J Streeter, Ellen C Faria
The elderly constitute a significant, potentially sensitive, subpopulation within the general population, which must be taken into account when performing risk assessments including determining an acceptable daily exposure (ADE) for the purpose of a cleaning validation. Known differences in the pharmacokinetics of drugs between young adults (who are typically the subjects recruited into clinical trials) and the elderly are potential contributors affecting the interindividual uncertainty factor (UFH) component of the ADE calculation...
March 20, 2017: International Journal of Hygiene and Environmental Health
https://www.readbyqxmd.com/read/28395507/pantoprazole-does-not-reduce-the-antiplatelet-effect-of-clopidogrel-a-randomized-controlled-trial-in-korea
#12
Yoon Jin Choi, Nayoung Kim, In-Jin Jang, Joo-Youn Cho, Ryoung Hee Nam, Ji Hyun Park, Hyun Jin Jo, Hyuk Yoon, Cheol Min Shin, Young Soo Park, Dong Ho Lee, Hyun Chae Jung
Background/Aims: Concerns that proton pump inhibitors (PPIs) diminish the efficacy of clopidogrel could hamper the appropriate prescription of PPIs. We evaluated the influence of pantoprazole on the antiplatelet effect of clopidogrel compared with ranitidine, which is regarded as safe, after stratification of the population according to the presence of a cytochrome (CYP) 2C19 polymorphism in Korea. Methods: Forty patients who underwent dual antiplatelet therapy were randomized to receive pantoprazole (n=20) or ranitidine (n=20)...
April 11, 2017: Gut and Liver
https://www.readbyqxmd.com/read/28391407/influence-of-genetic-and-non-genetic-factors-on-phenytoin-induced-severe-cutaneous-adverse-drug-reactions
#13
Kittika Yampayon, Chonlaphat Sukasem, Chanin Limwongse, Yotin Chinvarun, Therdpong Tempark, Ticha Rerkpattanapipat, Pornpimol Kijsanayotin
PURPOSE: The purpose of this study was to investigate the association of genetic factors including variants in HLA-B and CYP2C genes and non-genetic factors with phenotype-specific phenytoin (PHT)-induced severe cutaneous adverse reactions (SCARs) in Thai patients. METHODS: Thirty-six PHT-induced SCAR cases (15 Stevens-Johnson syndrome (SJS) and 21 drug rash with eosinophilia and systemic symptoms (DRESS)/drug hypersensitivity syndrome (DHS)) and 100 PHT-tolerant controls were studied...
April 8, 2017: European Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28378544/effects-of-cyp2c19-genetic-polymorphisms-on-pk-pd-responses-of-omeprazole-in-korean-healthy-volunteers
#14
Sunny Park, Yang Jin Hyun, Yu Ran Kim, Ju Hyun Lee, Sunae Ryu, Jeong Mi Kim, Woo Yong Oh, Han Sung Na, Jong Gu Lee, Doo Won Seo, In Yeong Hwang, Zewon Park, In Jin Jang, Jaeseong Oh, Seung Eun Choi
The aim of this study was to examine the effects of CYP2C19*2 and *3 genetic polymorphisms on omeprazole pharmacokinetic (PK) and pharmacodynamic (PD) responses. Twenty-four healthy Korean volunteers were enrolled and given 20 mg omeprazole orally once daily for 8 days. The genotypes of CYP2C19 single nucleotide polymorphisms (SNPs) (*2, *3, and *17) were screened. The plasma concentrations of omeprazole, omeprazole sulfone, and 5-hydroxy (5-OH) omeprazole were determined by liquid chromatography with tandem mass spectrometry (LC-MS/MS)...
May 2017: Journal of Korean Medical Science
https://www.readbyqxmd.com/read/28377187/gene-variants-in-responsiveness-to-clopidogrel-have-no-impact-on-clinical-outcomes-in-chinese-patients-undergoing-percutaneous-coronary-intervention-a-multicenter-study
#15
Chenze Li, Lina Zhang, Haoran Wang, Sha Li, Yan Zhang, Ling You, Yang Sun, Dong Wang, Jun Yang, Yinghua Cui, Yanyan Cao, Xiaoqing Shen, Yan Wang, Wei Cui, Jiangtao Yan, Hesong Zeng, Xiaomei Guo, Jianjun Li, Dao Wen Wang
BACKGROUND: Gene variants contribute to variability in individual responsiveness to clopidogrel and influence cardiovascular outcomes in Caucasian patients with acute coronary syndrome (ACS). However, limited data is available in Asian populations. METHODS: We resequenced 14 genes in metabolizing and activity pathway of clopidogrel in 138 patients with ACS and prospectively assessed the modulating effects of 13 variants possibly related to clopidogrel efficacy on one-year cardiovascular event occurrence in 5820 ACS patients after percutaneous coronary intervention (PCI)...
March 8, 2017: International Journal of Cardiology
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
#16
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/28373773/factors-associated-with-residual-gastroesophageal-reflux-disease-symptoms-in-patients-receiving-proton-pump-inhibitor-maintenance-therapy
#17
Fumiaki Kawara, Tsuyoshi Fujita, Yoshinori Morita, Atsushi Uda, Atsuhiro Masuda, Masaya Saito, Makoto Ooi, Tsukasa Ishida, Yasuyuki Kondo, Shiei Yoshida, Tatsuya Okuno, Yoshihiko Yano, Masaru Yoshida, Hiromu Kutsumi, Takanobu Hayakumo, Kazuhiko Yamashita, Takeshi Hirano, Midori Hirai, Takeshi Azuma
AIM: To elucidate the factors associated with residual gastroesophageal reflux disease (GERD) symptoms in patients receiving proton pump inhibitor (PPI) maintenance therapy in clinical practice. METHODS: The study included 39 GERD patients receiving maintenance PPI therapy. Residual symptoms were assessed using the Frequency Scale for Symptoms of GERD (FSSG) questionnaire and the Gastrointestinal Symptom Rating Scale (GSRS). The relationships between the FSSG score and patient background factors, including the CYP2C19 genotype, were analyzed...
March 21, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/28370390/auto-inhibitory-properties-of-the-parent-but-not-of-the-n-oxide-metabolite-contribute-to-infusion-rate-dependent-voriconazole-pharmacokinetics
#18
Nicolas Hohmann, Rebecca Kreuter, Antje Blank, Johanna Weiss, Jürgen Burhenne, Walter E Haefeli, Gerd Mikus
PURPOSE: The pharmacokinetics of voriconazole show a non-linear dose-exposure relationship caused by inhibition of its own CYP3A-dependent metabolism. Because the magnitude of auto-inhibition also depends on voriconazole concentrations, infusion rate might modulate voriconazole exposure. The impact of four different infusion rates on voriconazole pharmacokinetics was investigated. METHODS: Twelve healthy participants received 100 mg voriconazole i.v. over 4 h, 400 mg over 6 h, 4 h, and 2 h in a crossover design...
March 29, 2017: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28368717/association-of-genetic-variants-of-cyp2c19-and-cyp2d6-with-esophageal-squamous-cell-carcinoma-risk-in-northern-india-kashmir
#19
Gulzar Ahmad Bhat, Arshid Bashir Bhat, Mohd Maqbool Lone, Nazir Ahmad Dar
Genetic polymorphism in xenobiotic metabolizing enzymes (XMEs) is associated with various malignancies. However, the association of esophageal cancer with XMEs is mixed. The current study was aimed to explore the association of genetic polymorphisms of cytochrome (CYP) 2C19 and CYP2D6 genotypes with esophageal squamous cell carcinoma (ESCC) risk in Kashmir, India. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and sequencing methods were used for genotyping of 492 ESCC cases and equal number of individually matched controls...
April 3, 2017: Nutrition and Cancer
https://www.readbyqxmd.com/read/28346068/institutional-profile-university-of-florida-health-personalized-medicine-program
#20
Larisa H Cavallari, Kristin W Weitzel, Amanda R Elsey, Xinyue Liu, Scott A Mosley, Donald M Smith, Benjamin J Staley, Almut G Winterstein, Carol A Mathews, Francesco Franchi, Fabiana Rollini, Dominick J Angiolillo, Petr Starostik, Michael J Clare-Salzler, David R Nelson, Julie A Johnson
The University of Florida (UF) Health Personalized Medicine Program launched in 2012 with CYP2C19 genotyping for clopidogrel response at UF Health Shands Hospital. We have since expanded CYP2C19 genotyping to UF Health Jacksonville and established the infrastructure at UF Health to support clinical implementation for five additional gene-drug pairs: TPMT-thiopurines, IFNL3 (IL28B)-PEG IFN-α-based regimens, CYP2D6-opioids, CYP2D6/CYP2C19-antidepressants and CYP2C19-proton pump inhibitors. We are contributing to the evidence based on outcomes with genotype-guided therapy through pragmatic studies of our clinical implementations...
April 2017: Pharmacogenomics
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