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Christina Mitropoulou, Vasilios Fragoulakis, Ljiljana B Rakicevic, Mirjana M Novkovic, Athanassios Vozikis, Dragan M Matic, Nebojsa M Antonijevic, Dragica P Radojkovic, Ron H van Schaik, George P Patrinos
INTRODUCTION: Clopidogrel, which is activated by the CYP2C19 enzyme, is among the drugs for which all major regulatory agencies recommend genetic testing to be performed to identify a patient's CYP2C19 genotype in order to determine the optimal antiplatelet therapeutic scheme. The CYP2C19*2 and CYP2C19*3 variants are loss-of-function alleles, leading to abolished CYP2C19 function and thus have the risk of thrombotic events for carriers of these alleles on standard dosages, while the CYP2C19*17 allele results in CYP2C19 hyperactivity...
October 21, 2016: Pharmacogenomics
Laureen A Lammers, Roos Achterbergh, Marcel C M Pistorius, Yuma Bijleveld, Emmely M de Vries, Anita Boelen, Heinz-Josef Klümpen, Johannes A Romijn, RonA A Mathôt
BACKGROUND: The metabolic activity of P450 enzymes in vivo can be determined by using selective probe drugs. The simultaneous administration of multiple CYP-specific probe drugs is commonly referred to as the "cocktail approach." Disadvantages of a cocktail are large volumes of samples required for analysis and time-consuming analyses. The aim of this study was to develop and validate a simplified but sensitive method for the simultaneous quantification of five probe drugs (caffeine (CYP1A2), metoprolol (CYP2D6), midazolam (CYP3A4), omeprazole (CYP2C19), and S-warfarin (CYP2C9)) in a previously validated cocktail using an LC-MS/MS method...
October 19, 2016: Therapeutic Drug Monitoring
Kannan Sridharan, Rachna Kataria, Drishti Tolani, Shital Bendkhale, Nithya J Gogtay, Urmila M Thatte
INTRODUCTION: CYP2C19 and P2Y12 polymorphisms have been claimed to alter the pharmacodynamic response to clopidogrel. ABCB1 polymorphism has been associated with the efflux of clopidogrel resulting in decreased bioavailability. Due to paucity of data from Indian population, the present study was undertaken to evaluate the association of genetic polymorphisms of CYP2C19, P2Y12, and ABCB1 with inhibition of platelet aggregation (IPA) by clopidogrel. METHODS: Healthy adults (n = 90) of either gender were administered single dose of 300 mg clopidogrel...
July 2016: Indian Journal of Pharmacology
Dal-Sik Kim, Yunjeong Kim, Ji-Young Jeon, Min-Gul Kim
BACKGROUND: We evaluated the drug interaction profile of Red Ginseng (RG) with respect to the activities of major cytochrome P450 (CYP) enzymes and the drug transporter P-glycoprotein (P-gp) in healthy Korean volunteers. METHODS: This article describes an open-label, crossover study. CYP probe cocktail drugs, caffeine, losartan, dextromethorphan, omeprazole, midazolam, and fexofenadine were administered before and after RG supplementation for 2 wk. Plasma samples were collected, and tolerability was assessed...
October 2016: Journal of Ginseng Research
Jesús Sánchez-Ramos, Cristina Lucía Dávila-Fajardo, Pablo Toledo Frías, Xando Díaz Villamarín, Luis Javier Martínez-González, Susana Martínez Huertas, Francisco Burillo Gómez, Juan Caballero Borrego, Alicia Bautista Pavés, Mª Carmen Marín Guzmán, José Antonio Ramirez Hernández, Concepción Correa Vilches, Jose Cabeza Barrera
BACKGROUND: Clopidogrel has provided beneficial effects in acute coronary syndrome and percutaneous coronary intervention. Different polymorphisms have been associated with differences in clopidogrel response. The aim of this study was to check if CYP2C19/ABCB1-genotype-guided strategy reduces the rates of cardiovascular events and bleeding. METHODS: This experimental study included patients undergoing percutaneous coronary intervention with stent. The prospective genotype-guided strategy (intervention group) was compared against a retrospective non-tailored strategy (control group)...
September 26, 2016: International Journal of Cardiology
Koroush Khalighi, Gang Cheng, Seyedabbas Mirabbasi, Bahar Khalighi, Yin Wu, Wuqiang Fan
Warfarin therapy is complicated by its large inter-individual and intra-individual variability. Both genetic and non-genetic factors can affect warfarin therapy. This study aims to investigate the allele distribution of VKORC1, CYP2C9 and CYP2C19, contribution of different allele variants and possible gene-gene interaction on warfarin therapy. Four hundreds and ninety-two patients were enrolled and single nucleotide polymorphisms for vitamin K epoxide reductase complex subunit 1 (VKORC1), cytochrome P450 CYP2C9 and cytochrome P450 CYP2C19 were genotyped...
October 14, 2016: Journal of Thrombosis and Thrombolysis
Elena Puris, Markku Pasanen, Mikko Gynther, Merja R Häkkinen, Jussi Pihlajamäki, Tapani Keränen, Paavo Honkakoski, Hannu Raunio, Aleksanteri Petsalo
Cocktail phenotyping using specific probe drugs for cytochrome P450 (CYP) enzymes provides information on the real-time activity of multiple CYPs. We investigated different sample preparation techniques and validated a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method with simple protein precipitation for the analysis of nine CYP probe drugs and their metabolites in human serum and urine. Specific CYP probe drugs (melatonin, CYP1A2; nicotine, CYP2A6; bupropion, CYP2B6; repaglinide, CYP2C8; losartan, CYP2C9; omeprazole, CYP2C19 and CYP3A4; dextromethorphan, CYP2D6; chlorzoxazone, CYP2E; midazolam, CYP3A4) and their main metabolites, with the exception of 3'-hydroxyrepaglinide, were quantified in human serum and urine using the developed LC-MS/MS method...
October 12, 2016: Analytical and Bioanalytical Chemistry
Allison B Chambliss, Molly Resnick, Athena K Petrides, William A Clarke, Mark A Marzinke
BACKGROUND: Current methods for the detection of single nucleotide polymorphisms (SNPs) associated with aberrant drug-metabolizing enzyme function are hindered by long turnaround times and specialized techniques and instrumentation. In this study, we describe the development and validation of a high-resolution melting (HRM) curve assay for the rapid screening of variant genotypes for targeted genetic polymorphisms in the cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP3A5. METHODS: Sequence-specific primers were custom-designed to flank nine SNPs within the genetic regions of aforementioned drug metabolizing enzymes...
October 12, 2016: Clinical Chemistry and Laboratory Medicine: CCLM
Xiao-Fang Tang, Ya-Ling Han, Jia-Hui Zhang, Jing Wang, Yi Yao, Chen He, Bo Xu, Zhan Gao, Shu-Bin Qiao, Jue Chen, Yuan Wu, Ji-Lin Chen, Run-Lin Gao, Yue-Jin Yang, Jin-Qing Yuan
INTRODUCTION: Both CYP2C19 genotyping and platelet function testing are used to predict major adverse cardiac events (MACEs) in Chinese patients treated with clopidogrel and undergoing stent implantation, but the most accurate prognostic technique is still debated. Here, we combine both techniques, to determine if a more accurate prognosis is possible. METHODS: Patients undergoing stent implantation (1104) were genotyped and assessed for platelet reactivity, with a 12-month follow-up...
October 7, 2016: Thrombosis Research
Soo Min Han, Joonhee Park, Ji Hyun Lee, Sang Seop Lee, Hyoki Kim, Hyojun Han, Yuhnam Kim, Sojeong Yi, Joo-Youn Cho, In-Jin Jang, Min Goo Lee
Phenotypic differences in drug responses have been associated with known pharmacogenomic loci, but many remain to be characterized. We therefore developed next-generation sequencing (NGS) panels to enable broad and unbiased inspection of genes that are involved in pharmacokinetics (PK) and pharmacodynamics (PD). These panels feature repetitively optimized probes to capture up to 114 PK/PD-related genes with high coverage (99.6%) and accuracy (99.9%). Sequencing of a Korean cohort (n = 376) with the panels enabled profiling of actionable variants as well as rare variants of unknown functional consequences...
October 11, 2016: Clinical Pharmacology and Therapeutics
İbrahim Ömer Barlas, Orhan Sezgin, Collet Dandara, Gözde Türköz, Emre Yengel, Zinhle Cindi, Handan Ankaralı, Semra Şardaş
Pharmacogenomics harnesses the utility of a patient's genome (n = 1) in decisions on which therapeutic drugs and in what amounts should be administered. Often, patients with shared ancestry present with comparable genetic profiles that predict drug response. However, populations are not static, thus, often, population mobility through migration, especially enmasse as is seen for refugees, changes the pharmacogenetic profiles of resultant populations and therefore observed responses to commonly used therapeutic drugs...
October 2016: Omics: a Journal of Integrative Biology
Olufunmilayo E Adejumo, Taiwo R Kotila, Adeyinka G Falusi, Boladale O Silva, Jacinta N Nwogu, Pius S Fasinu, Chinedum P Babalola
Polymorphic expression of metabolic enzymes have been identified as one of the key factors responsible for the interindividual/ethnic/racial variability in drug metabolism and effect. In Nigeria, there is a disproportionately high incidence of sickle-cell disease (SCD), a condition characterized by painful crisis frequently triggered by malaria. Proguanil, a substrate of the polymorphic CYP2C19, is a chemoprophylactic antimalarial drug widely used among SCD patients in Nigeria. This study aimed to conduct a comparative CYP2C19 phenotyping among SCD patients and healthy controls and to compare the results with those previously reported...
October 2016: Pharmacology Research & Perspectives
D D Nabinger, L E Mazzoleni, G B Sander, F Mazzoleni, M C Osório, M G Klein, T F Rech, L Basso da Silva, G S de Moraes, R A Cristovam, E F Nardelli, C F M Francesconi, D Simon
The aim of this study was to examine the effect of polymorphisms in the cytochrome P450 (CYP) 2C19 gene (CYP2C19) on the Helicobacter pylori eradication rate in Brazilian patients with functional dyspepsia. Adults diagnosed with functional dyspepsia based on the ROME III criteria and infected with H. pylori were recruited to this study. The patients were subjected to gastrointestinal endoscopy and the H. pylori status was defined when both urease test and histopathology results were negative or positive. The patients were treated with proton pump inhibitor-based triple therapy (omeprazole, amoxicillin, and clarithromycin)...
September 16, 2016: Genetics and Molecular Research: GMR
Xianbao Shi, Brianna Mackie, Gang Zhang, Shuman Yang, Yonggui Song, Dan Su, Yali Liu, Lina Shan
Morusin, the important active component of a traditional Chinese medicine, Morus alba L., has been shown to exhibit many vital pharmacological activities. In this study, six recombinant CYP450 supersomes and liver microsomes were used to perform metabolic studies. Chemical inhibition studies and screening assays with recombinant human cytochrome P450s were also used to characterize the CYP450 isoforms involved in morusin metabolism. The morusin metabolites identified varied greatly among different species. Eight metabolites of morusin were detected in the liver microsomes from pigs (PLMs), rats (RLMs), and monkeys (MLMs) by LC-MS/MS and six metabolites were detected in the liver microsomes from humans (HLMs), rabbits (RAMs), and dogs (DLMs)...
2016: Evidence-based Complementary and Alternative Medicine: ECAM
Tadayoshi Okimoto, Kazuhiro Mizukami, Ryo Ogawa, Kazuhisa Okamoto, Mitsutaka Shuto, Kensuke Fukuda, Masaaki Kodama, Kazunari Murakami
The aim of this study was to assess the efficacy of esomeprazole-based triple therapy compared with rabeprazole-based triple therapy according to CYP2C19 genotype and clarithromycin susceptibility status for first-line eradication therapy of Helicobacter pylori (H. pylori) in Japan. We enrolled 219 H. pylori-infected patients, and randomly allocated patients to the EAC group (esomeprazole 20 mg, clarithromycin 200 mg, amoxicillin 750 mg for one week, with all drugs given twice daily) or RAC group (rabeprazole 10 mg, clarithromycin 200 mg, amoxicillin 750 mg for one week, with all drugs given twice daily)...
September 2016: Journal of Clinical Biochemistry and Nutrition
Kamini Vasudev, Yun-Hee Choi, Ross Norman, Richard B Kim, Ute I Schwarz
OBJECTIVE: Atypical antipychotics are linked to a higher incidence of metabolic side effects, including weight gain, dyslipidemia, and diabetes. In this study, we examined the prevalence and potential genetic predictors of metabolic side effects in 60 adult patients on clozapine. METHOD: Genetic variants of relevance to clozapine metabolism, clearance, and response were assessed through targeted genotyping of cytochrome P450 enzymes CYP1A2 and CYP2C19, the efflux transporter ABCB1, the serotonin receptor (HTR2C), leptin (LEP), and leptin receptor (LEPR)...
September 28, 2016: Canadian Journal of Psychiatry. Revue Canadienne de Psychiatrie
V Barysheva, G Ketova
No abstract text is available yet for this article.
October 6, 2016: Clinical Therapeutics
J Y Byeon, C M Lee, H J Lim, Y H Kim, D H Kim, S Y Lee
No abstract text is available yet for this article.
October 6, 2016: Clinical Therapeutics
Chieri Fujino, Yuki Tamura, Satoko Tange, Hiroyuki Nakajima, Seigo Sanoh, Yoko Watanabe, Naoto Uramaru, Hiroyuki Kojima, Kouichi Yoshinari, Shigeru Ohta, Shigeyuki Kitamura
The oxidative, reductive, and hydrolytic metabolism of methiocarb and the hydrolytic metabolism of carbaryl by liver microsomes and plasma of rats or humans were examined. The effects of the metabolism of methiocarb and carbaryl on their nuclear receptor activities were also examined. When methiocarb was incubated with rat liver microsomes in the presence of NADPH, methiocarb sulfoxide, and a novel metabolite, methiocarb sulfone were detected. Methiocarb sulfoxide was oxidized to the sulfone by liver microsomes and reduced back to methiocarb by liver cytosol...
2016: Journal of Toxicological Sciences
Bruce Green, Herta Crauwels, Thomas N Kakuda, Simon Vanveggel, Anne Brochot
BACKGROUND: Etravirine is a non-nucleoside reverse transcriptase inhibitor indicated in combination with other antiretrovirals for treatment-experienced HIV patients ≥6 years of age. Etravirine is primarily metabolized by cytochrome P450 (CYP) 2C9, CYP2C19, and CYP3A. This analysis determined the impact of concomitant antiretrovirals and CYP2C9/CYP2C19 phenotype on the pharmacokinetics of etravirine. METHODS: We used 4728 plasma concentrations from 817 adult subjects collected from four clinical studies to develop the population pharmacokinetic model...
September 24, 2016: Clinical Pharmacokinetics
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