Symposium "Clinical Pharmacology Anno 2008". 10th Heymans Memorial Lecture.

Genetic factors have been suggested depending on the drug, to account for 20 to 95 % of the variability in drug disposition and effects. Pharmacogenetics is defined as the study of interindividual variations in DNA sequence related to drug disposition or drug action that can influence clinical response. In contrast, pharmacogenomics is defined more broadly as the application of genomics to elucidate disease susceptibility, drug discovery, pharmacological function, drug disposition and therapeutic response. The best recognized examples of genetic polymorphisms that influence drug response in humans are highly penetrant monogenic traits of drug metabolizing enzymes (DME). Inherited difference in a single gene of DME has such a profound effect on the pharmacokinetics of a drug resulting in more than a 100 fold difference in systemic drug exposure with clinically important effect on drug response. Loss of function or gene duplication of DME genes have been identified as mechanisms of severe and life-threatening toxicity and poor treatment response, respectively. There is a growing list of genetic polymorphisms in drug transporters and targets that have been shown to influence drug response. However, drug response involves many genes and therefore new strategies are needed to identify, for a given drug, the relevant genes and genetic polymorphisms and the pathways and processes in their interaction. These new strategies include genome-wide haplotype mapping, gene expression analyses, proteomic methods. In addition nongenetic factors will modify drug response. A major limitation in implementing pharmacogenetic testing in the clinical setting is the lack of clinical trials demonstrating that such testing can improve drug therapy by reducing toxicity and increasing efficacy.