Cytochrome P450 2C9, 2C19 and 2D6 genetic polymorphisms : Evaluation of genotyping as a tool for individualised treatment

Sammanfattning: Recent advances in the understanding of drug metabolism and the molecular biology of CYPs have generated great expectations regarding the use of pharmacogenetic testing as a tool to individualize drug treatment. The individual pharmacogenetic constitution might in principle predict the response to drugs, hormones and toxins. Therefore, a simple phenotyping or genotyping test before treatment with a compound subject to polymorphic metabolism could be of value in selecting the dosage schedule, thus enhancing therapeutic efficacy and preventing toxicity. Many antipsychotics and antidepressants are mainly metabolised through CYP2D6. CYP2C9 and CYP2C19 are involved in the metabolism of warfarin, phenytoin and fluoxetine. All these three enzymes are highly polymorphic. The general aims of this thesis were to elucidate the impact of polymorphic CYP isoenzymes on the metabolism of psychoactive drugs (risperidone, fluoxetine) and anticoagulants (warfarin), characterised by a narrow therapeutic range and the potential risk for drug-drug interactions, to investigate the role of CYP polymorphism as a risk factor for the appearance of psychoactive drug- induced side-effects, and to evaluate the potential usefulness of genotyping as a tool for individualising the therapy. CYP2D6 genotype appears to partially explain the broad variability in the steady state plasma levels of risperidone and fluoxetine, but its usefulness in predicting clinical effects remains to be clarified. A significant relationship has been found in our studies between CYP2C9 genotype and warfarin dose requirement and clearance, as well as between CYP2C9 genotype and fluoxetine active moiety. Furthermore, our findings suggest that PMs of CYP2D6 are more prone to EPS during treatment with classical antipsychotics. Similarly, CYP2C9 and CYP2C19 genetically impaired metabolic activity seems to represent a predisposing factor for phenytoin toxicity. CYP2D6 genotyping can today be recommended as a complement to the determination of plasma concentrations when aberrant metabolic capacity (poor or ultrarapid) is suspected, while its usefulness in predicting clinical effects must be further explored. Therapeutic drug monitoring still represents a better tool for individualization of dosage of CYP2D6 substrates. On the other hand CYP2C9 genotype may be of value in choosing the right dose, andlor avoiding potentially harmful drugs in selected subgroups of patients with genetically impaired metabolic activity. The next step should involve prospective studies of impotant drugs to establish the clinical utility of genotype specific dosage-schedules.