engleski

The role of pharmacogenotyping in therapy optimization

Variability in the efficacy and toxicity of drug therapy in individual is often associated with polymorphisms in genes encoding drug-metabolizing enzymes, transporters, or drug targets. Pharmacogenetics studies the variations in candidate gene(s) or the network of genes that determine an individual's response to drug therapy and aims to identify individuals predisposed to high risk of toxicity from conventional doses of therapeutic agents. Genetic polymorphism based on drug metabolism ability is associated with three phenotype classes. The extensive drug me-tabolizer phenotype is characteristic of normal population. The poor metabolizer phenotype is associated with the accumulation of specific drug substrates in the body due to mutation and/or deletion of both alleles responsible for phenotypic expression. The ultrarapid metabolizer phenotype is characterized by enhanced drug metabolism due to gene amplification. Genetic variability for drug absorption forms the basis for slow and rapid drug absorption phenotypes, as well as in drug interactions with receptors result in poor or efficient receptor interaction phenotype. There are two approaches of pharmacogenetics testing in clinical use. The first approach implies making a specific hypothesis on the genes that cause therapeutic response modification and their testing in all individuals irrespective of their therapeutic response (gene candidates). The second approach implies the search for so-called SNP profile (SNP prints) associated with efficient or adverse events in a respective population (pharmacogenetic approach). Examples of SNP profiles of specific genes modifying drug response, which can currently be used in clinical practice are the genes encoding for drug metabolizing enzymes from the families CYP450, CYP2D6, 2C19 and 2C9, then phase II enzymes NAT2 and TPMT, B2-AR receptors, and some enzymes involved in the metabolism of antitumor drugs.

pharmacogenetics; drug therapy optimization

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