Background: Fluoxetine, a widely prescribed selective serotonin reuptake inhibitor, exhibits significant interindividual variability in pharmacokinetics, largely attributed to pharmacogenomic factors. Objectives: The study aimed to evaluate the impact of pharmacogenetics and clinical determinants on the dose-normalized fluoxetine/norfluoxetine metabolic ratio in patients undergoing fluoxetine therapy in routine clinical settings. Methods: Genotypes for CYP2D6, CYP2C9, and CYP2C19 genotypes were determined in 47 patients receiving fluoxetine therapy using TaqMan^® assays. Steady-state trough plasma concentrations of fluoxetine and norfluoxetine were measured using validated high-performance liquid chromatography methods. Log₁₀-transformed dose-normalized fluoxetine/norfluoxetine metabolic ratio (logMR) was compared across CYP2D6, CYP2C9, and CYP2C19 genotype-predicted metabolizer groups. Multivariate generalized linear modeling (GLM) was used to evaluate the independent effects of CYP genotypes and clinical covariates on the logMR. Results: The logMR differed significantly among the CYP2D6 genotype-predicted metabolizer groups (p < 0.003). CYP2D6 poor metabolizers exhibited significantly higher logMR than normal metabolizers (p < 0.004). The GLM analysis confirmed that CYP2D6 genotype was the only significant predictor of the logMR independent of all clinical covariates. No significant effects of CYP2C9, CYP2C19 genotypes, or clinical variables on the logMR were observed. Conclusions: These findings highlight CYP2D6 genotype as a key determinant of fluoxetine metabolism during standard treatment. No associations were observed with CYP2C9 or CYP2C19 genotypes or clinical factors.

Background/Objectives: Venlafaxine has been reported to exhibit significant interindividual pharmacokinetic heterogeneity across populations, which has been linked to cytochrome P450 polymorphisms and clinical factors. This study aimed to assess the impact of pharmacogenetic (PGx) and clinical determinants on the dose-normalized venlafaxine/O-desmethylvenlafaxine (ODV) metabolic ratios (MRs) in routine clinical settings in Spain. Methods: 29 adult patients receiving venlafaxine were prospectively recruited through the MedeA PGx Implementation Strategy into clinical practice (Extremadura, Spain). CYP2D6, CYP2C19, and CYP2C9 genotypes were determined using TaqMan^® assays, and CYP2D6 activity scores were assigned based on allele functionality. Steady-state trough plasma concentration of venlafaxine and ODV were measured using a validated high-performance liquid chromatography method. Dose-normalized venlafaxine/ODV MRs were compared across CYP2D6-, CYP2C19-, and CYP2C9-genotype-predicted metabolizer groups. The influence of demographic and clinical variables on dose-normalized venlafaxine/ODV MR was also assessed. Results: Significant variability in dose-normalized venlafaxine/ODV MRs was observed across CYP2D6 (p = 0.019) and CYP2C19 (p = 0.008) metabolizer groups. Among clinical variables, sex was significantly associated with differences in dose-normalized venlafaxine/ODV MR (p = 0.0006). Conclusions: CYP2D6 and CYP2C19 genotypes and sex significantly contribute to variability in venlafaxine metabolism in patients treated in routine clinical settings. These results highlight the value of combining PGx and clinical data with drug plasma concentration measurement to optimize venlafaxine therapy within PGx implementation programs.