Genetics/genomics and drug effects.

ABSTRACT

Differences in response to medications both in terms of clinical activity and side-effects have long been recognised by physicians. Genetics has been recently considered as a potential factor to explain part of this variability. Pharmacogenetics focuses on the variants within one or more candidate genes while pharmacogenomics evaluates the entire genome for associations with pharmacologic phenotypes. Genetic variants can effect drug metabolism, drug transport or drug targets. Drug metabolism is responsible 1. for the conversion of prodrugs into active compounds or conversion of drug to toxic or inactive metabolites mostly through reactions mostly catalysed by cytochromes (CYP) P450 (phase reactions) and 2. for transforming drugs to compounds that are more water soluble and more easily excreted (phase type II reactions). Genetic polymorphisms can modify the activity of several CYPs such as CYPs, 2D6, 2C9, 2C19 with altered responses to codeine, tamoxifen, clopidogrel, warfarin, ... or of enzymes of the phase II reactions with abnormal responses to drugs like irinotecan, 5-fluorouracil, azathioprine, ... Proteins involved in the transport of drugs in or out the cells such as chemiotherapeutic agenrs, simvastatin, ... can also be affected by genetics. Genetics can also modify drug targets by mutations affecting tumour cells rending these later more or less responsive to drugs. Genetic tests have been launched for screening polymorphisms before giving drugs such as warfarin and several biomarkers are available in oncology. However, many challenges exist. For example, we need more prospective studies to have a better knowledge of the clinical impact and the cost-effectiveness of these tests. It remains that in the future pharmacogenetics/genomics will probably help to personalise medicine by conferring to the clinician the possibility of giving the right drug to the right patients and by this way improving efficacy and safety of medications.