CYP2D6 Genotype, Antidepressant Use, and Tamoxifen Metabolism During Adjuvant Breast Cancer Treatment

Abstract

Interactions between CYP2D6 polymorphisms and coadministered antidepressants and other drugs that are CYP2D6 inhibitors may be associated with altered tamoxifen activity.

Efficacy of tamoxifen based on cytochrome P450 2D6, CYP2C19 and SULT1A1 genotype in the Italian Tamoxifen Prevention Trial

“…Antidepressants, in particular paroxetine and fluoxetine, known to be potent CYP2D6 inhibitors, are commonly prescribed with tamoxifen in the treatment of hot flashes or depression. 15 However, in Italy, antidepressants are not commonly prescribed for management of hot flashes, and our data show that the overall prevalence of these drugs in the trial was below 1% (data on file). Nevertheless, the effect of CYP2D6 inhibitors on the clinical outcomes cannot specifically be addressed in this study.…”

“…It has also been reported that SULT1A1 may influence tamoxifen metabolites' concentration. 29,42,43 However, previous studies 15,29 have not shown significant associations between SULT1A1 genotypes and the serum levels of 4OH-tamoxifen or endoxifen per se. Our results did not show any differences between SULT1A1 genotype and BC risk, suggesting that SULT1A1 may not be important in explaining tamoxifen preventive efficacy.…”

“…13,14 They both have a 30-to 100-fold higher affinity to ER receptors compared to tamoxifen, respectively. Because endoxifen reaches a steady-state plasma concentration 6-to 10-fold higher than 4-OH-tamoxifen, 10,14,15 it is considered the most relevant metabolite in determining the parent drug's clinical efficacy. CYP2D6 is one of the most significant enzymes that modulates plasma endoxifen concentration.…”

“…Genotypically, PM patients or patients receiving CYP2D6-inhibiting drugs have reduced plasma concentrations of endoxifen. 14,15,21 At the clinical level, PM subjects with BC on adjuvant tamoxifen tend to have a higher risk of relapse. 22,23 This worse clinical outcome has been associated with a decreased prevalence of hot flashes, a putative marker of tamoxifen activity.…”

Coffee prevents early events in tamoxifen-treated breast cancer patients and modulates hormone receptor status

“…CYP2D6 is the key enzyme metabolizing the pro-drug tamoxifen into its metabolites 4-hydroxy tamoxifen, 4-desmetyl tamoxifen and its most active metabolite, endoxifen [13,14]. The CYP1A2 and CYP2C8 enzymes also contribute to tamoxifen metabolism [15,16] as well as the metabolism of caffeine [17], while SULT1A1 has been proposed to be involved in sulfation of 4-hydroxytamoxifen and may also play a role in endoxifen clearance [13].…”