Influences of CYP2D6, CYP2C19 Polymorphisms on Fluoxetine pharmacokinetics and serotonin transporter Polymorphisms on clinical outcomes in Thai patients with depressive disorder

Abstract

The influence of CYP2D6 and CYP2C19 polymorphisms on steady-state normalized PK parameters of fluoxetine and norfluoxetine in 69 Thai patients with depressive disorder was performed at Srithanya hospital, Mental Health Department. The result showed that the frequency distributions of CYP2D6*10 were about 20.3%, 33.3% and 46.4% for WT, HT and MT variants, respectively. For prevalence of CYP2C19*2 genotypes and CYP2C19*3 genotypes, the frequency distributions of CYP2C19*2 were about 40.6%, 55.1% and 4.3% for WT, HT and MT variants, respectively. While the frequency distributions of CYP2C19*3 were about 87.0% and 13.0% for WT and HT variants. At steady-state condition, CYP2D6*10, CYP2C19*2 and CYP2C19*3 polymorphisms affected on PK parameters of fluoxetine especially fluoxetine clearance. Influence of study variables (age, weight, polymorphism of CYP2D6 and CYP2C19,) on fluoxetine clearance were analyzed by multiple regressions. Only CYP2C19*3 polymorphism was selected to the model. Finally, estimation equation of fluoxetine clearance was determined. The influence of the serotonin transporter polymorphisms was determined for fluoxetine PD or clinical outcome. It was found that patients with l/l genotype had a significantly better response to fluoxetine treatment when compared with s allele carriers as evaluation by the Thai HRS-D scores or psychiatist efficacy evaluation (p = 0.001). Among patients with different serotonin transporter polymorphisms, carriers with s allele had significantly higher rate of various side effects than the l/l genotype group (p = 0.002). These preliminary data could be used to reduce or prevent adverse effects and improve prescribing efficacy for depression patients with different genotypes.