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Clinical pharmacogenomics and potential application in personalized medicine

Pharmacogenetic/ pharmacogenomic research have produced many examples of the impact of inherited variability in the response to pharmacotherapy. However, these successes, have as yet failed to translate into broadly applicable strategies for the improvement of individual drug treatment. One important argument against the widespread adoption of pharmacogenetics as a clinical tool is the lack of evidence showing its impact on medical decision making and on risk benefit ratio for the patients. The final goal of association studies is to develop rational means to optimize drug therapy, with respect to the patient's genotype, to ensure maximum efficacy with minimal adverse effects. However, there are examples of succsesful translation of pharmacogenetics in clinical practice. Drug-metabolizing enzymes represent a major target of ongoing research in order to identify associations between an individual's drug response and genetic profile. Polymorphisms of the cytochrome P450 enzyme CYP2D6 influence metabolism of codeine, tramadol, hydrocodone, oxycodone, some antidepressants and antypsychotic drugs, beta-blockers and antihypertensives. For CYP2D6 polymorphisms, as predictors of outcome in breast cancer patients treated with tamoxifen, expanded polymorphism coverage is needed to improve risk stratification. Blood concentrations of some NSAIDs depend on CYP2C9 and/or CYP2C8 activity. Genomic variants of these genes associate well with NSAIDs' side effect profile. Well established examples where pharmacogenomic techniques can improve routine treatment include genotyping of TPMT variants for the prediction of thiopurine- induced bone marrow depression, VKORC1 and CYP2C9 analyses for a better control of anticoagulant administration, the SLCO1B1 variant in the context of statin-induced myopathies and DPYD analysis for better prediction of 5-FU toxicity. US FDA has recently changed clopidogrel's prescribing information to highlight the impact of CYP2C19 genotype on clopidogrel pharmacokinetics, pharmacodynamics and clinical response. Serotonin transporter polymorphism. The 5-HTTLPR variation is associated with expression of serotonin transporter protein and concentrations of extracellular serotonin. Pharmacogenomic analysis in different therapeutic areas significantly contributes to the selection of drugs and doses for the individual patient and is already recognized and recommended by scientific societies, regulatory agencies and public health organisations.

pharmacogenomics; cytochrome P450; drug transporters; serotonin transporter; drug response;

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