Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.1.1.67 (thiopurine methyltransferase)
551 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The application of pharmacogenetics holds great promise for individualized therapy. However, it has little clinical reality at present, despite many claims. The main problem is that the evidence base supporting genetic testing before therapy is weak. The pharmacology of the drugs subject to inherited variability in metabolism is often complex. Few have simple or single pathways of elimination. Some have active metabolites or enantiomers with different activities and pathways of elimination. Drug dosing is likely to be influenced only if the aggregate molar activity of all active moieties at the site of action is predictably affected by genotype or phenotype. Variation in drug concentration must be significant enough to provide "signal" over and above normal variation, and there must be a genuine concentration-effect relationship. The therapeutic index of the drug will also influence test utility. After considering all of these factors, the benefits of prospective testing need to be weighed against the costs and against other endpoints of effect. It is not surprising that few drugs satisfy these requirements. Drugs (and enzymes) for which there is a reasonable evidence base supporting genotyping or phenotyping include suxamethonium/mivacurium (butyrylcholinesterase), and azathioprine/6-mercaptopurine (thiopurine methyltransferase). Drugs for which there is a potential case for prospective testing include warfarin (CYP2C9), perhexiline (CYP2D6), and perhaps the proton pump inhibitors (CYP2C19). No other drugs have an evidence base that is sufficient to justify prospective testing at present, although some warrant further evaluation. In this review we summarize the current evidence base for pharmacogenetics in relation to drug-metabolizing enzymes.
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PMID:Pharmacogenetics, drug-metabolizing enzymes, and clinical practice. 1696 50

The pharmacogenetics of either individual patients or tumors has been used to aid the progress of personalized medicine to generate antitumor drugs (eg, trastuzamab and erlotinib) that are active against tumors expressing particular growth factor receptors. Outside the field of cancer therapeutics, pharmacogenetic tests have been introduced to detect patient genotypes with the aim of individualizing existing treatments. For example, the analysis of thiopurine S-methyltransferase genotypes enables the prediction of toxicity in patients to be treated with either 6-mercaptopurine or azathioprine, while the uridine 5'-diphosphoglucuronosyl-transferase 1A1 genotype may predict irinotecan toxicity. There is a large body of information concerning cytochrome P450 (CYP) polymorphisms and their relationship with drug toxicity and response; however, currently, there is limited use of CYP genotypes to individualize treatments. It is now well recognized that the CYP2C9 genotype, when combined with the genotype for vitamin K epoxide reductase complex subunit 1, is predictive of dose requirement for oral anticoagulants, a fact that is likely to have clinical utility. There is also potential to individualize treatments with certain drugs on the basis of CYP2D6, CYP2C19 and CYP3A5 genotypes. Studies on genes encoding drug receptors in relation to individualized prescription have been limited but there is increasing information on the relationship between response to beta2-adrenoceptor agonists and the genotype for the beta2-adrenoceptor gene. The introduction of pharmacogenetic tests into routine healthcare requires both a demonstration of cost-effectiveness and the availability of appropriate accessible testing systems.
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PMID:Individualized drug therapy. 1726 38

Variation in the human genome is a most important cause of variable response to drugs and other xenobiotics. Susceptibility to almost all diseases is determined to some extent by genetic variation. Driven by the advances in molecular biology, pharmacogenetics has evolved within the past 40 years from a niche discipline to a major driving force of clinical pharmacology, and it is currently one of the most actively pursued disciplines in applied biomedical research in general. Nowadays we can assess more than 1,000,000 polymorphisms or the expression of more than 25,000 genes in each participant of a clinical study -- at affordable costs. This has not yet significantly changed common therapeutic practices, but a number of physicians are starting to consider polymorphisms, such as those in CYP2C9, CYP2C19, CYP2D6, TPMT and VKORC1, in daily medical practice. More obviously, pharmacogenetics has changed the practices and requirements in preclinical and clinical drug research; large clinical trials without a pharmacogenomic add-on appear to have become the minority. This review is about how the discipline of pharmacogenetics has evolved from the analysis of single proteins to current approaches involving the broad analyses of the entire genome and of all mRNA species or all metabolites and other approaches aimed at trying to understand the entire biological system. Pharmacogenetics and genomics are becoming substantially integrated fields of the profession of clinical pharmacology, and education in the relevant methods, knowledge and concepts form an indispensable part of the clinical pharmacology curriculum and the professional life of pharmacologists from early drug discovery to pharmacovigilance.
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PMID:Pharmacogenetics: data, concepts and tools to improve drug discovery and drug treatment. 1822 12

Serious adverse drug reactions represent the sixth major cause of death in the USA, are the main reason for postmarketing drug withdrawal and represent billions of US dollars in costs every year in all developed countries. Some of these serious adverse drug reactions might be avoided by systematically screening for pharmacogenomic risk factors. During the last few years, regulatory agencies introduced pharmacogenomics labels for several drugs, but although a priori genetic testing remains advised or recommended, it is seldom compulsory due to poor evidence-based medicine knowledge. Recently published pharmacogenomic randomized, controlled and ongoing trials will progressively make genotyping tests, such as those for HLA-B*5701 (abacavir), TPMT (6-mercaptopurine), CYP2C9 plus VKORC1 (warfarin) and CYP3A5 (tacrolimus), mandatory. Parallel development of pharmacogenomic bed tests will certainly establish genetically-based prescriptions in routine medical practice.
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PMID:Pharmacogenomics of adverse drug reactions: practical applications and perspectives. 1953 Sep 63

Pharmacogenomics investigates inherited differences in drug responses including beneficial and adverse reactions. While a considerable amount of evidence for genetic influences on drug responses has been accumulated within the last decade, predominantly in small studies, its value in routine therapy is still a matter of debate. The aim of this review is to discuss well established examples where pharmacogenomic techniques can improve routine treatment. Examples include genotyping of CYP2D6 in the context of antidepressant therapy, analysis of TPMT variants for the prediction of mercaptopurine-induced bone marrow depression, VKORC1 and CYP2C9 analyses for a better control of anticoagulant administration and the SLCO1B1 variant in the context of statin-induced myopathies.
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PMID:[Pharmacogenomics in routine medical care]. 2010 57

Pharmacogenomics strives to explain the interindividual variability in response to drugs due to genetic variation. Although technological advances have provided us with relatively easy and cheap methods for genotyping, promises about personalised medicine have not yet met our high expectations. Successful results that have been achieved within the field of pharmacogenomics so far are, to name a few, HLA-B*5701 screening to avoid hypersensitivity to the antiretroviral abacavir, thiopurine S-methyltransferase (TPMT) genotyping to avoid thiopurine toxicity, and CYP2C9 and VKORC1 genotyping for better dosing of the anticoagulant warfarin. However, few pharmacogenetic examples have made it into clinical practice in the treatment of complex diseases. Unfortunately, lack of reproducibility of results from observational studies involving many genes and diseases seems to be a common pattern in pharmacogenomic studies. In this article we address some of the methodological and statistical issues within study design, gene and single nucleotide polymorphism (SNP) selection and data analysis that should be considered in future pharmacogenomic research. First, we discuss some of the issues related to the design of epidemiological studies, specific to pharmacogenomic research. Second, we describe some of the pros and cons of a candidate gene approach (including gene and SNP selection) and a genome-wide scan approach. Finally, conventional as well as several innovative approaches to the analysis of large pharmacogenomic datasets are proposed that deal with the issues of multiple testing and systems biology in different ways.
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PMID:Methodological and statistical issues in pharmacogenomics. 2048 94

Pharmacogenetic testing is becoming more common; however, very few quality control and other reference materials that cover alleles commonly included in such assays are currently available. To address these needs, the Centers for Disease Control and Prevention's Genetic Testing Reference Material Coordination Program, in collaboration with members of the pharmacogenetic testing community and the Coriell Cell Repositories, have characterized a panel of 107 genomic DNA reference materials for five loci (CYP2D6, CYP2C19, CYP2C9, VKORC1, and UGT1A1) that are commonly included in pharmacogenetic testing panels and proficiency testing surveys. Genomic DNA from publicly available cell lines was sent to volunteer laboratories for genotyping. Each sample was tested in three to six laboratories using a variety of commercially available or laboratory-developed platforms. The results were consistent among laboratories, with differences in allele assignments largely related to the manufacturer's assay design and variable nomenclature, especially for CYP2D6. The alleles included in the assay platforms varied, but most were identified in the set of 107 DNA samples. Nine additional pharmacogenetic loci (CYP4F2, EPHX1, ABCB1, HLAB, KIF6, CYP3A4, CYP3A5, TPMT, and DPD) were also tested. These samples are publicly available from Coriell and will be useful for quality assurance, proficiency testing, test development, and research.
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PMID:Characterization of 107 genomic DNA reference materials for CYP2D6, CYP2C19, CYP2C9, VKORC1, and UGT1A1: a GeT-RM and Association for Molecular Pathology collaborative project. 2088 55

The present article summarizes the discussions of the 3rd European Science Foundation-University of Barcelona (ESF-UB) Conference in Biomedicine on Pharmacogenetics and Pharmacogenomics, which was held in June 2010 in Spain. It was focused on practical applications in routine medical practice. We provide practical recommendations for ten different clinical situations, that have either been approved or not approved by regulatory agencies. We propose some comments that might accompany the results of these tests, indicating the best drug and doses to be prescribed. The discussed examples include KRAS, cetuximab, panitumumab, EGFR-gefitinib, CYP2D6-tamoxifen, TPMT-azathioprine-6-mercaptopurine, VKORC1/CYP2C9-warfarin, CYP2C19-clopidogrel, HLA-B*5701-abacavir, HLA-B*5701-flucloxacillin, SLCO1B1-statins and CYP3A5-tacrolimus. We hope that these practical recommendations will help physicians, biologists, scientists and other healthcare professionals to prescribe, perform and interpret these genetic tests.
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PMID:Practical recommendations for pharmacogenomics-based prescription: 2010 ESF-UB Conference on Pharmacogenetics and Pharmacogenomics. 2117 26

Different clinical response of different patients to the same medicine has been recognised and documented since the 1950's. Variability in response of individuals to standard doses of drug therapy is important in clinical practice and can lead to therapeutic failures or adverse drug reactions. Pharmacogenetics seeks to identify individual genetic differences (polymorphisms) in drug absorption, metabolism, distribution and excretion that can affect the activity of a particular drug with the view of improving efficacy and reducing toxicity. Although knowledge of pharmacogenetics is being translated into clinical practice in the developed world, its applicability in the developing countries is low. Several factors account for this including the fact that there is very little pharmacogenetic information available in many indigenous African populations including Ghanaians. A number of genes including Cytochrome P450 (CYP) 2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, MDR1 and TPMT have been genotyped in the Ghanaian population since the completion of the Human genome project. There is however, an urgent need to increase pharmacogenetic research in Ghana to increase availability of data. Introducing Pharmacogenetics into the curriculum of Medical and Pharmacy training institutions will influence translating knowledge of pharmacogenetics into clinical practice. This will also equip health professionals with the skill to integrate genetic information into public health decision making.
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PMID:Pharmacogenetics in Ghana: reviewing the evidence. 2185 25

Pharmacogenetics has substantially added to our understanding of the variability of drug response. A number of single gene markers have been established and are ready to use in clinical practice. Here we review the validity and utility of markers in a number of genes (CYP2D6, CYP2C19, CYP2C9, VKORC1, TPMT, UGT1A1, OATP1B1, KRAS and HLA locus) for therapy decisions. As drug response is a complex trait in the majority of cases, most of the identified functional variants will only explain a limited part of the variability of drug response. In this sense, a phenotype is the product of many low-penetrance variations. Technical progress has not only improved the cost-effectiveness of screening for single gene markers, but offers the possibility of generating vast amounts of genome-wide single nucleotide polymorphism (SNP) or sequence data for each patient. The latest challenge is to incorporate these amounts of data into pharmacogenetic decision support. We discuss here the challenges associated with choosing the correct therapy for patients who present to their physicians with personal genome data.
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PMID:Pharmacogenetic screening for drug therapy: from single gene markers to decision making in the next generation sequencing era. 2222 55


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