TAM is often co-prescribed with SSRI antidepressants or clonidine to reduce TAM-induced hot flashes. We tested the ability of selected SSRIs and clonidine to inhibit the formation of 4-hydroxy N-desmethyltamoxifen (4-OHNDTAM) from N-desmethyltamoxifen (NDTAM) by recombinant human CYP2D6. This study is based on our observation that in plasma samples of patients who were on tamoxifen, paroxetine decreased plasma concentrations of a metabolite that has not been clinically characterized before. We subsequently confirmed the identity of this metabolite as 4-OHNDTAM and in vitro it is primarily formed from NDTAM by CYP2D6. Incubation of 10 μM clonidine, sertraline, fluoxetine, paroxetine and 1μM quinidine (positive control) inhibit the formation of 4-OHNDTAM from NDTAM by 68, 82, 83, 100 and 92% respectively. The Ki μM) values estimated from Dixon plots for fluoxetine and paroxetine were 1.07 and 1.8μM respectively. Further inhibition was observed during preincubation of fluoxetine and paroxetine with HLMs and NADPH before reaction was started with substrate probes. Treatment of TAM-induced hot flashes by SSRIs and clonidine may in part be due to inhibition of CYP2D6-mediated 4-OHNDTAM formation in vivo and it is possible that poor metabolizers of CYP2D6 are at less risk for hot flashes than extensive metabolizers.
|Original language||English (US)|
|Journal||Clinical Pharmacology and Therapeutics|
|State||Published - Dec 1 2001|
ASJC Scopus subject areas
- Pharmacology (medical)