Genetic variability of drug metabolizing enzymes

Drug metabolism is one of the key processes allowing to eliminate the administered dose. High interindividual variability of the activity of drug metabolizing enzymes is caused by many genetic and epigenetic factors. This variation can result in substantial differences in clinical response to the drug, ranging from failure of the therapy to appearance of toxic side effects or frequent onset of drug-drug interactions. The aim of the thesis was to evaluate the influence of genetically determined variability in drug metabolizing enzymes activity on the drug pharmacokinetics, pharmacodynemics and to asses whether either phenotyping or genotyping can be effectively applied under the naturalistic conditions of routine clinical practice, for e.g. as a prediction tool during to asses individual risk of development and progress of a disease or to forecast the drug response. The thesis mainly summarizes previously published articles on the topic. We have studied genetically determined variability of tramadol pharmacokinetics as well as drug-induced miosis in healthy volunteers with known CYP2D6 status. The lowest blood concentrations of principal active metabolite O-demethyltramadol accompanied by the highest levels of the parent compound at all sampling intervals up to 12 hours post-dose were found in the..