[Pharmacogenetics and interindividual variability in drug response: cytochrome P-450 2C9 and coumarin anticoagulants].

Pharmacogenetics, a discipline still in its infancy, is the study of genetically determined variations in how individuals respond to drugs. Mutations may affect drug metabolism, transmembrane transport into cells, or target receptors. Genetic polymorphisms affecting drug metabolism were the first to be identified. Genetic factors control the activity of phase I reactions involving cytochrome (CYP) P450 isoenzymes. Three CYP families catalyze drug metabolism in humans. Their genes have been identified and polymorphisms have been described in various populations, leading to either high activity ("extensive metabolizer" phenotype) or low activity ("poor metabolizer" phenotype). The CYP2C9 polymorphism illustrates the potential clinical importance of pharmacogenetics. This enzyme catalyzes the metabolism of the coumarinic oral anticoagulants acenocoumarol and warfarin. The homozygous mutant genotype CYP 2C9 313, present in 0, 7% of Caucasians, leads to low enzyme activity and thus to the accumulation of these drugs in the body; this in turn increases the anticoagulant activity and induces a higher risk of bleeding. In three clinical studies of patients and healthy volunteers, we found that this CYP2C9 *3 mutant allele was responsible for 14% of the variability in the response to these drugs. Then, by studying the genetic polymorphism of the receptor site of oral anticoagulants--the vitamin K epoxide reductase multiprotein complex--we showed that a combination of the two genetic variants (CYP2C9 and the receptor site) was responsible for 50% of the variability. These data suggest that patients who have both genetic polymorphisms could be at an increased risk of bleeding during oral anticoagulant therapy.