Oral presentations O11.1 Pharmacogenetics: an opportunity for a safer and more efficient pharmacotherapy

The inter-individual variability of drug response is a major problem in clinical practice. It can lead to therapeutic failure or adverse effects of drugs (ADRs) in individuals or subpopulations of patients. Potential risk factors for drug inefficacy or toxicity include drug-drug interactions , the patient's age, renal and liver functions or other disease factors, and lifestyle variables such as smoking and alcohol consumption. All these factors should be evident for the physicians. In addition, it has become clear in recent years that genetic factors may also significantly modify drug responses or increase the risk for ADRs. New methods and techniques as well as increased knowledge in the field of pharmacogenetics are applied to identify inter-individual variation in drug responses. Single-nucleotide polymorphisms (SNPs) account for over 99% of genetic variation in the human genome. The remainder of variation is caused by insertions, deletions and tandem repeats. Most drug effects are determined by the interplay of several gene products that influence the pharma-cokinetics and pharmacodynamics of medications, including inherited differences in drug targets (e.g. genetic polymorphism of receptors) and drug dispositions (e.g. genetic polymorphism of drug metabolizing enzymes and transporters for drugs). A critical factor in the drug response such as in ADRs could be the inter-patient differences in plasma concentrations arising from the same drug regimen. Many drugs are substrates for cytochrome P450 (CYP450) isoforms and of ATP-binding cassette (ABC) membrane transporter proteins. Several polymor-phisms that effect CYP genes and ABC genes (e.g. ABCB1) have been described to alter the protein product function influencing metabolism, absorption, distribution and excretion of many drugs. Oxidation polymorphism related to CYP450 isoenzymes such as CYP2C9, CYP2C19, CYP2D6 or CYP3A4 is one of the most thoroughly studied and clinically important, especially in case of psychiatric and cardiovascular drugs. Polymorphisms of thi-opurine methyltransferase (TPMT), dihydropyrimidine dehydrogenase (DPD), UDP-glucuronysyltransferase 1A1 (UGT1A1), thymidylate synthase (TS) enzymes play an important role for commonly used chemotherapy drugs such as mercaptopurine, 5-fluorouracil, cyclo-phosphamide, camptothecins and methotrexate. Phar-macodynamic consequences of genetic polymorphism has been explored less than pharmacokinetic changes. Genetic variation of adrenergic, dopamine and serotonin receptors as well as serotonin transporters and histamine have been examined and linked to therapy response in both schizophrenia and depression. Others examples of polymorphisms of drug targets, possibly playing a role in therapy response, include beta-adrenergic receptors and response to beta-agonists in asthmatics, sensitivity to ACE inhibitors and responsiveness to sulfonylurea hy-poglycaemic drugs. Pharmacogenetics blends important …