SSRIs may reduce the effectiveness of tamoxifen
Newer antidepressant drugs such as paroxetine may reduce the effectiveness of tamoxifen by interfering with the breakdown of the drug into its active metabolites, suggest American researchers.
Dr Vered Stearns and colleagues from Georgetown University Medical Centre,
Washington, and Indiana University School of Medicine, Indianapolis,
point out that up to 80 per cent of women treated with tamoxifen complain
of hot flushes. Several studies have demonstrated that antidepressants
from the selective serotonin reuptake inhibitor and selective noradrenaline
reuptake inhibitor classes are effective for the treatment of hot flushes.
“Given these recent results, it is likely that the frequency of
administering tamoxifen with drugs of the SSRI and SNRI classes will
increase,” they
say.
However, the researchers note that tamoxifen and these newer antidepressants
are metabolised by a shared pathway. “Because venlafaxine, paroxetine
and fluoxetine are all metabolised by CYP2D6 and are potent inhibitors
of this enzyme, we hypothesised that SNRIs and SSRIs might alter tamoxifen
metabolism.”
The researchers examined the effect of paroxetine on levels of tamoxifen
and its metabolites in blood samples from 12 women with breast cancer
who were being treated with adjuvant tamoxifen.
The women received paroxetine for the treatment of hot flushes for four
weeks during their standard course of tamoxifen.
The researchers identified a previously uncharacterised active metabolite,
which they named endoxifen. Endoxifen was present in substantially higher
concentrations than 4-hydroxy-tamoxifen, which is thought to be the most
potent of tamoxifen’s metabolites. The researchers observed that,
after paroxetine treatment, endoxifen levels decreased, whereas levels
of 4-hydroxy-tamoxifen did not. Endoxifen concentrations decreased by
64 per cent in women with a normal CYP2D6 genotype but by only 24 per
cent in women with a variant CYP2D6 genotype.
The authors say that these findings “raise the possibility that
pharmacogenetic variation in CYP2D6 activity may influence therapeutic
outcomes from tamoxifen treatment”. However, they add: “Until
further data become available, the results of this small study should
not alter treatment recommendations.” The study is published in
the Journal of the National Cancer Institute (2003;95:1758). |
