Impact of P450 genetic polymorphism on the first-pass extraction of cardiovascular and neuroactive drugs.

This review highlights the present knowledge on the CYP2D6 (sparteine/debrisoquine) and the CYP2C19 (mephenytoin) polymorphisms. The relevant mutations at genomic level affecting protein expression and function and consequences for first-pass metabolism and effects of cardiovascular and neuroactive drugs are highlighted. In vitro techniques for identification of metabolic steps catalyzed by polymorphic enzymes will be discussed as well as drug-drug interactions related to CYP2D6 and CYP2C19. The importance of the CYP2D6 polymorphism arises from the fact that this enzyme, which is involved in metabolism of more than 50 drugs, is not active in about 8% of a Caucasian population. This group is named poor metabolizers in contrast to the remainder of the population called extensive metabolizers. Depending on the pharmacokinetic and pharmacodynamic properties of the administered drug and its metabolites elevated concentrations of the parent compound can result in an increased risk of toxicity or loss of therapeutic effects in poor metabolizers. On the other hand ultrarapid metabolizers of CYP2D6 might require higher doses than recommended in order to achieve therapeutic drug levels. Moreover, consequences of polymorphic CYP2C19 expression, which is not active in 20% of Orientals and 3% of Caucasians, for drug disposition will be outlined.