Coprescription of paroxetine with tamoxifen to reduce hot flashes reduced plasma 4-hydroxy-N-desmethyl-tamoxifen plasma concentrations in a CYP2D6-dependent manner

Paroxetine is often prescribed to reduce hot flashes and improve compliance in patients treated with tamoxifen. To test the hypothesis that paroxetine or CYP2D6 genotype might alter tamoxifen metabolism to active metabolites we measured the drug and 3 metabolites in patients treated during chronic tamoxifen treatment. Thirteen women prescribed chronic tamoxifen (20 mg po qd) were co-prescribed paroxetine (10 mg po qd) for the treatment of hot flashes. Genotype for CYP2D6 was determined and plasma concentrations of tamoxifen and 3 metabolites: N-desmethyl-tamoxifen (X), 4-hydroxy tamoxifen (B) and 4-hydroxy-N-desmethyl tamoxifen (BX) were determined by LC with on line derivatization and fluorescence detection after 4 weeks of paroxetine treatment. Neither paroxetine administration or CYP2D6 genotype caused a significant change in the mean concentrations of tamoxifen, B or X. In contrast, the mean steady state concentration of BX dropped from 1.65±0.88 ng/ml to 0.55±0.23 ng/ml after paroxetine treatment (p<0.05). Patients with CYP2D6*1*4 genotype had lower BX concentrations (0.58±0.32ng/ml) and there was no significant effect of paroxetine in these patients (0.22±0.21 ng/ml). Paroxetine may ameliorate tamoxifen hot flashes in part by reducing the concentration of active metabolite.