Pharmacogenetics: association of clinical laboratory and clinic in the optimatisation of the therapy

Field: Pharmacology, Toxicology and Pharmaceutics (Life Sciences)

Individual variation in response to drug ranges from failure to respond to drug reactions and drug to drug interactions when several drugs are taken simultaneously. The clinical consequences range from patient discomfort through serious clinical illness to the occasional fatality. Recent studies have revealed 1 out of 15 (6.7%) hospital admissions to be due to adverse drug reaction, and 1 out of 300 (0.3%) such reactions to have fatal. Thus, adverse drug reactions have been recorded as the fourth to sixth leading cause of death in hospital patients. Recently, a new field of pharmacologic sciences, pharmacogenetics investigates the linkage between an individual's genotype and that individual's ability to metabolize a therapeutic drug. Differences in metabolism of therapeutics can lead to severe toxicity or therapeutic failure by altering the relation between dose and blood concentration of pharmacologically active drug, resulting from genetic polymorphism of drug metabolizing enzymes, transporters, receptors and other drug targets. Drug metabolism in the body results in detoxification and elimination of the drug or activation of the pro-drug to the biologically active therapeutic or toxin. The enzymes responsible for the activation and metabolism of drugs show great inter-individual variations in protein expression or catalytic activity. These variations can be induced by some transient causes such as enzyme inhibition or induction, or by some permanent cause such as genetic mutation or gene deletion-polymorphism. Genetic polymorphism according to the ability to metabolize a drug has been related to three classes of phenotypes. The phenotype of extensive metabolism (EM) of drug is characteristic of the normal population. The phenotype of poor metabolism (PM) is associated with accumulation of specific drug substrates and is a typical autosomal recessive trait generated by mutation and/or deletion of both alleles responsible for phenotypic expression. The phenotype of ultra-extensive metabolism (UEM) manifests as increased drug metabolism and is an autosomal dominant trait resulting from gene amplification. These genetic polymorphism of the alleles of enzymes included in drug metabolism can be determined by the methods of molecular biology in clinical laboratories, so the clinical laboratory is the linkage between genetic and therapeutic management allowing identification of the subject� s genotype/phenotype, choice of an optimal dose of the drug and prevention of undesired reaction of therapeutic error due to an excessive or inadequate dose of the drug. Clinical application of the information obtained by genotyping and phenotyping in relation between clinical laboratory and clinical practitioners should answer the following questions: ˇ When is genotyping clinically indicated? ˇ What are the advantages of including genotyping in the process of therapeutic drug monitoring to assess the patient� s clinical status ˇ How to most efficiently apply the information obtained by genotyping to dose adjustment and/or choice of therapeutic? ˇ Do these strategies provide cost-effective health care paradigms?