Influence of Genetic Polymorphisms in Transporter Molecules on Drug Distribution in Humans

Genetic variability is a major factor which influences the way individuals respond to drug therapy in terms of both host toxicity and treatment efficacy and may be determined by polymorphic genes, i.e. common genetic variants that are expressed in more than 1% of a population. Polymorphisms in drug metabolizing enzymes and drug transporters frequently contribute to variable drug pharmacokinetics, whereas polymorphic drug targets are the reason for interindividual differences in drug response. Consequently, any of these proteins could be a candidate gene for genetic studies on interpatient variability in drug distribution, efficacy or toxicity. The present project aims at examining the influence of gene polymorphisms on drug distribution in humans. A candidate gene approach has been chosen to test the hypothesis that single nucleotide polymorphisms (SNPs) in transporter molecules potentially alter gene function and consequently drug distribution. Brain uptake of the 11C radiolabeled calcium channel blocker verapamil, a substrate of a polymorphic drug transporter (p-glycoprotein), will be measured by positron emission tomography (PET) in healthy volunteers and epileptic patients genotyped for the MDR-1 exon 26 C3435T polymorphism. PET allows to non-invasively quantify drug concentrations in tissues usually not accessible to standard PK analysis, e.g. the brain. Furthermore, genome-wide expression profiling will be performed to identify genetic polymorphisms in transporter molecules in subjects who experience CNS side effects after administration of fluoroquinolone antibiotics. The results of this research project could provide an explanation for therapeutic failure of drugs or might provide insight into mechanisms responsible for differences in the occurrence of side effects. The experimental approach has the potential to be employed in virtually all clinical fields to assess the influence of polymorphisms on drug pharmacokinetics and pharmacodynamics in order to allow individual drug dosing. It might furthermore be employed in drug development and evaluation.