Stand der Pharmakogenetik in der klinischen Arzneimitteltherapie

Abstract

Individual differences in the effect and side effect of drugs are partly due to genetic factors (genetic polymorphisms). The responsible polymorphisms lie in genes encoding for drug metabolism and transport but also in direct and indirect drug targets. While genetic variants in pharmacokinetic structures exert effects on drug efficacy via the differences in drug exposure, polymorphisms in drug targets can directly affect clinical efficacy and may lead to a broad variation spectrum between inefficacy and severe side effects. However, at present, our knowledge on genetic variants in drug targets is less detailed than the knowledge on pharmacogenetic variability within drug metabolism. A goal of pharmacogenetic diagnostics implemented in clinical practice is to better predict the individual drug effects on the basis of molecular-genetic profiles. Therapy recommendations can be given as dose adjustments, in particular in the case of polymorphisms of drug metabolizing enzymes which will lead to less variable drug concentrations. At present there are few examples of the application of pharmacogenetic tests in Germany in order to improve and individualize drug therapy. The reasons for this are multifold. On the one hand it is due to the limited awareness of pharmacogenetics; on the other hand it may be due to the lack of fast and economical availability of the appropriate laboratory tests. The most important reason, however, may be that most results of pharmacogenetic research are so far not translated into therapeutically usable conclusions and therapy recommendations. Thus, testing for a genotype without concrete consequences for the drug therapy of an individual patient does not make sense. Pharmacogenetic research, thereby, stands in many cases at the threshold to clinical applicability and in many cases, for instance for the genotyping for thiopurine methyltransferase polymorphisms prior to azathioprine therapy or of dihydropyrimidine dehydrogenase polymorphisms prior to treatment with 5-fluorouracil, as well as for diagnostics of CYP2D6 before therapy with certain tricyclic antidepressants and neuroleptics, one would ask already today whether a such drug therapy is still responsible without pharmacogenetic diagnostics.