Effect of CYP2D6 and CYP2C9 genotypes on fluoxetine and norfluoxetine plasma concentrations during steady-state conditions

Objectives. CYP2D6 drug-metabolising enzyme has been shown to be involved in fluoxetine metabolism in vitro and in vivo. CYP2C9 has also been shown to influence the metabolism of fluoxetine in vitro; however, this relationship has not been studied in humans. The aim of the present study was to evaluate the influence of CYP2D6 and CYP2C9 genotypes on the plasma concentration of fluoxetine and norfluoxetine in psychiatric patients during steady-state conditions. Methods. White European psychiatric patients (n=64) receiving antidepressant monotherapy with fluoxetine were studied. CYP2D6 and CYP2C9 genotypes were determined by polymerase chain reaction-specific methods. The plasma concentrations of fluoxetine and its metabolite, norfluoxetine, were measured by high-performance liquid chromatography. Results. The dose-corrected plasma concentrations of fluoxetine were related (P<0.01, r=-0.36) to CYP2D6 genotypes (number of active genes). The fluoxetine/norfluoxetine ratio also correlated (P<0.01, r=-0.39) with the number of active CYP2D6 genes. Among patients with two CYP2D6 active genes, the dose-corrected plasma concentrations of fluoxetine and active moiety (fluoxetine plus norfluoxetine) were significantly (P<0.05) higher in the CYP2C9*1/*2 and CYP2C9*1/*3 genotype groups than in CYP2C9*1/*1. However, dose-corrected (C/D) plasma concentrations of fluoxetine, active moiety and fluoxetine/norfluoxetine ratios were not highly different in the individuals with two mutated alleles as compared with those heterozygous for *2 or *3. Conclusion. The present results show that CYP2D6 and potentially CYP2C9 genotypes seem to influence fluoxetine plasma concentration during steady-state conditions in patients.