Pharmacogenetics: The State of the Art and How to Proceed

Currently, pharmacogenetics is at the stage of translational research, between basic research and clinical application and, as the authors conclude, there is an important role to play for physicianscientists. Wilkinson, in his article on ‘Drug Metabolism and Variability among Patients in Drug Response’, also focuses on ADRs, taking, however, drug interactions as a starting point. Cytochrome P-450 enzymes (CYPs) play a key role in the metabolism of drugs and chemicals from the diet and the environment. Inhibition or induction of CYP3A4, the major P-450 enzyme through drug interactions, may have enormous clinical consequences, in particular in the form of ADRs. For example, blood concentrations of cyclosporine may almost double by the regular intake by patients of normal quantities of grapefruit juice. These CYP3A4 effects are independent from the individual genotype. For other CYP enzymes, in particular CYP2D6, CYP2C19, and CYP2C9, common polymorphisms are clinically relevant, as they determine the metabolizer type of an individual. Knowledge about drug interactions and scientifi c evidence for the clinical consequences of CYP polymorphisms have been available for many years. However, as stated by Wilkinson, there have not yet been clinical trials showing that knowledge of a patient’s genotype before prescribing either increases drug effi cacy, prevents ADRs, or lowers the costs of therapy. For the time being, according to Wilkinson, the individual patient is best served by an alert physician.