Drug treatment is in many cases ineffective. Besides patients who do not respond to the treatment despite receiving expensive drugs, adverse drug reactions as a consequence of the treatment, is estimated to cost the US society 100 billion USD and over 100,000 deaths per year. Many drug transporters are polymorphic. In addition, the majority of phase I and phase II dependent drug metabolism is carried out by polymorphic enzymes which can cause abolished, quantitatively or qualitatively altered or enhanced drug metabolism. Pharmacogenetics aims at taking the patients genetic constitution into account to increase the number of responders and decrease the adverse drug reactions.
Stable duplication, multiduplication or amplification of active genes, most likely in response to dietary components that have resulted in a selection of alleles with multiple non-inducible genes, has been described. Several examples exist where subjects carrying certain alleles suffer from a lack of drug efficacy due to ultrarapid metabolism caused by multiple genes or by induction of gene expression, or, alternatively, adverse effects from the drug treatment due to the presence of defective alleles. The evolutionary aspect of the genetic polymorphism in these genes includes genetic drift but also selection because of environmental stress.
Pharmacogenetics is of particular importance for determination of the outcome of therapy with antidepressants and neuroleptics, drugs that are high affinity substrates for the highly polymorphic CYP2D6. Clinical investigations have shown that non response is very often caused by the Ultrarapid Metabolizer phenotype where multiple active genes are present on the same allele. Millions of people in e.g the Mediterranean area do not respond to such treatment because of this genotype. Furthermore, adverse drug reactions are much more commonly seen among subjects who lack functional CYP2D6 due to the presence of inactive CYP2D6 genes. Predictive genotyping is in these cases of high value. Today pharmacogenetics can also be used beneficially to predict the outcome of treatment with e.g analgesics, anticoagulants, proton pump inhibitors and anticancer drugs.
The information about the role of polymorphic drug transporters and drug receptors for efficiency of drug therapy is scarcer, although promising examples are seen in drug treatment of e.g. asthma where the efficiency can be severely enhanced by predictive genotyping of the drug targets. In addition, certain polymorphic genes can be used as markers for optimisation of the drug therapy. Besides the genetic aspects, environmental factors, and drug-drug interactions are of critical importance for optimisation of the drug therapy and these aspects will be addressed in the lecture.
In conclusion, it can be anticipated that predictive genotyping in the future will be of great benefit in 15-30 % of all drug treatment and thereby allows for prevention of causalities as a cause of ADRs, increase in drug response and thus improves the health for a significant fraction of the patients. For certain specific drug therapies pharmacogenetics will be of critical importance and an unavoidable tool.
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