Pharmacogenetics: an opportunity for a safer and more efficient pharmacotherapy.
Drug treatment is in many cases ineffective. Besides patients who do not respond to the treatment despite receiving expensive drugs, adverse drug reactions (ADRs) as a consequence of the treatment, is estimated to cost the US society 100 billion USD and over 100,000 deaths per year. Pharmacogenetics is the discipline which takes the patient's genetic information of drug transporters, drug metabolizing enzymes and drug receptors into account to allow for an individualized drug therapy leading to optimal choice and dose of the drugs in question. It is believed that much cost for the society can be saved in this manner. 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. 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 noninducible genes, has been described. Several examples exist where subjects carrying certain alleles suffer from a lack of drug efficacy because of ultrarapid metabolism caused by multiple genes or by induction of gene expression, or, alternatively, adverse effects from the drug treatment as a result of the presence of defective alleles. The information about the role of polymorphic drug receptors for efficiency of drug therapy is more scarce, although promising examples are seen in drug treatment of 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 optimization of the drug therapy. It is likely that predictive genotyping is of benefit in 10-20% of drug treatment and thereby allows for prevention of causalities as a cause of ADRs and thus improves the health for a significant fraction of the patients. In 15-40% of the cases, the penetrance of genetic polymorphism is of less importance because of the polygenic influence on the outcome of drug treatment and in 50% of the cases, pharmacogenetics would be without influence because of other more important physiological and environmental factors. In the present contribution an overview about our present knowledge how polymorphic genes can influence the drug efficacy is presented. Some emphasis will be given to different forms of cytochrome P450 which are of importance for drug metabolism.
Ingelman-Sundberg
M
M
Division of Molecular Toxicology, IMM, Karolinska Institutet, Stockholm, Sweden. maging@ki.se
D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000502:physiology; D064420:Drug-Related Side Effects and Adverse Reactions; D005544:Forecasting; D006801:Humans; D009154:Mutation / Q000235:genetics; D010597:Pharmacogenetics / Q000639:trends; D010599:Pharmacokinetics
D003577:Cytochrome P-450 Enzyme System