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CYP2D6 Genotype and SSRIs Alter Tamoxifen Metabolism

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The common breast cancer drug tamoxifen may be less effective in women carrying particular alleles of CYP450 genes, as well as in women taking selective serotonin reuptake inhibitors, according to research published in the Jan. 5 issue of the Journal of the National Cancer Institute.

The researchers would not make recommendations about whether or not tamoxifen, a selective estrogen receptor modulator, should be prescribed based on genotype, said lead investigator David Flockhart, chief of the Division of Clinical Pharmacology at the Indiana University School of Medicine. But in cases involving SSRIs, Flockhart was more explicit. “Given what we know at the moment, we would recommend that clinicians not prescribe peroxitine or fluoxitine at the same time as tamoxifen,” due to the inhibition of CYP2D6 by these SSRIs.

Tamoxifen and its metabolites also compete with many SSRIs as CYP2D6 substrates, said Flockhart.

In a study of 80 tamoxifen patients, the research team found that women homozygous or heterozygous for CYP2D6 variant alleles had a statistically significant decrease in plasma levels of tamoxifen and its active metabolites after four months of treatment, as compared to women homozygous for CYP2D6 wild-type alleles.

Plasma levels of the active metabolite endoxifen are of particular interest. Identified in a previous study by the same research group, the metabolite is approximately 100 times as potent as tamoxifen in vitro. Following four months of treatment, CYP2D6 variant homozygotes and heterozygotes had average endoxifen concentrations approximately 26 percent and 55 percent of that of wild-type homozygotes, respectively.

An investigation of variant alleles of CYP2D6, CYP2C9, CYP3A5, and sulfotransferase 1A1 showed no significant link to drug levels. The researchers used a combination of restriction length polymorphism and TaqMan to genotype patients.

But the genetic component of endoxifen plasma levels falls away in the presence of SSRIs that inhibit CYP2D6. “The enzyme is pretty much wiped out by the drug interaction,” Flockhart said. The endoxifen concentration in women homozygous for wild-type CYP2D6 was 58 percent lower, on average, in those patients also taking CYP2D6 inhibitors.

Selective serotonin inhibitors are commonly prescribed to combat the hot flashes often associated with tamoxifen treatment.

“What the latest data suggest is that there is an alternative for people,” said Flockhart. “There are medications for the treatment of depression and for hot flashes that do not inhibit the enzyme, and therefore would be appropriate positive alternatives for women who need their depression or hot flashes treated,” he said.

Research presented at the 27th Annual San Antonio Breast Cancer Symposium in December by the same group of investigators complement this study, said Flockhart. The data show a link between breast cancer recurrence and CYP2D6 genotype predicts response to tamoxifen, he said.

The study, “CYP2D6 Genotype, Antidepressant Use, and Tamoxifen Metabolism During Adjuvant Breast Cancer Treatment,” was conducted by investigators from the Indiana University School of Medicine in Indianapolis; the University of Michigan, Ann Arbor; the Mayo Clinic in Rochester, Minn.; the Sidney Kimmel Comprehensive Cancer Center in San Diego, Calif.; Johns Hopkins School of Medicine in Baltimore, MD; and Fox Chase Cancer Center in Philadelphia.

— CW

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