Introduction: Both risperidone and venlafaxine are metabolized by Cytochrome P450 2D6 (CYP2D6). Genetic polymorphism in this enzyme may contribute to the significant variation in pharmacokinetics for these substances. It has previously been shown that systemic exposure of risperidone and venlafaxine is increased in patients with homozygous mutations in CYP2D6 (poor metabolizers). The possible influence of heterozygous mutations in CYP2D6 on systemic exposure is not well investigated for these drugs.Aim: The aim of the present analysis was to investigate the importance of heterozygous mutations in CYP2D6 for serum concentrations of venlafaxine and risperidone and their main metabolites.
Method: Data were collected from a therapeutic drug monitoring database at the Department of Psychopharmacology at Diakonhjemmet Hospital. The patient samples were requested as a part of follow-ups and control of drug treatment. Steady-state serum concentrations of parent compound and metabolite as well as CYP2D6, CYP2C9 and CYP2C19 genotypes were collected for all patients. For risperidone, both tablets and long-acting injection were included in this analysis.
Result: The present analysis showed that heterozygous extensive metabolizers (n=23) had significantly higher (p<0.01) concentration/dose ratio of risperidone compared to CYP2D6 extensive metabolizers (n=42) after administration of risperidone tablets. Extensive metabilizers (n=32) on risperidone long-acting injection had significantly higher ratio of 9-hydroxyrisperidone and risperidone (p<0.03) compared to heterozygous extensive metabolizers (n=12) for 9-hydroxyrisperidone/risperidone ratio. CYP2D6 extensive metabolizers on venlafaxine (n=52) had significantly higher levels of O-desmethylvenlafaxine (p<0.02) and O-desmethylvenlafaxine/venlafaxine ratio (p<0.01) compared to CYP2D6 heterozygous extensive metabolizers (n=41). Concentration/dose ratio of N- desmethylvenlafaxine was significantly higher (9-fold higher) (p<0.01) in CYP2D6 heterozygous extensive metabolizers (n=6) compared to CYP2D6 extensive metabolizers (n=13).
Conclusion: Common for risperidone and venlafaxine is that even though the sum of the active moiety not is changed, the relative contribution of parent compund and active metabolite to the sum is altered. It is the sum of the active moiety that is determined in therapeutic drug monitoring, and patients with different CYP2D6 genotypes are therefore treated equally in clinical practice as the sum will be the same independent of genotype. This could be a problem if there is a difference in effect and/or adverse drug reactions mediated by parent drug and metabolite.