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Pharmacogenetic testing in therapy optimization

Variation in drug metabolism and drug response among individuals of the same body weight and on the same drug dose can be due temporary causes such as transient enzyme inhibition and induction, or permanent causes such as genetic mutation, gene deletion or amplification. A genetic mutation frequency exceeding 1% of a population is considered as a genetic polymorphism. Pharmacogenetic polymorphisms can manifest at the pharmacokinetic and pharmacodynamic levels. The pharmacokinetic level deals with gene polymorphisms that modify the concentrations of drug and its metabolites at the sites of their molecular action (polymorphisms of drug metabolism enzymes, drug transporters), whereas the pharmacodynamic level deals with polymorphisms of the genes associated with drug effect and mechanism of action not related to its concentration (receptors, ion channels). Pharmacogenetics explores the connection between genetic predisposition and drug efficacy, thus allowing for the specific phenotypes to identify. According to drug metabolizing ability, genetic polymorphism is related to three phenotype classes. The extensive drug metabolizer phenotype is characteristic of the normal population ; the poor drug metabolizer phenotype is a consequence of mutation and/or deletion of both alleles and is associated with accumulation of specific drug substrates ; the ultraextensive drug metabolizer phenotype is a consequence of gene amplification and results in enhanced drug metabolism. Genetic polymorphism of a drug transporter and receptor results in a phenotype characterized by slow and fast drug absorption, and by poor or efficient interaction with receptors. Examples of specific genes that modify drug response and can presently be used in clinical practice are those encoding for metabolic enzymes of the cytochrome P-450 family: CYP2D6, 2C19 and 2C9 ; the enzymes N-acetyltransferase 2 (NAT2) and thiopurine methyltransferase (TPMT) ; and  2-adrenoceptors (B2-AR) among receptors. The pharmacogenetic screening approach in phenotype prediction is based on the identification of alleles showing diagnostic sensitivity greater than 95%, and is performed by PCR amplification, usually followed by restriction endonuclease digestion, or some other identification method, of single nucleotide polymorphism (SNP). The result of this pharmacogenetic study can be used to identify those from a group of patients with the same diagnosis who require higher or lower drug doses, or those who need another drug of the same action which is not the polymorphic gene substrate. The ultimate goal of the pharmacogenetic polymorphism research is development of a pharmacogenetic identity card which, however, requires indepth understanding of the mechanisms of genetic predisposition to undesired reactions, sophisticated SNP mapping technologies, less expensive genotyping methods, and elaboration of appropriate ethics criteria.

Pharmacogenetic profile; CYP2D6; CYP2C9; CYP2C19;

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