What question did this study set out to answer?

Determine how coadministration of the CYP2D6-inhibiting antidepressant paroxetine affects the plasma concentrations of active tamoxifen metabolites in breast cancer patients.

December 3, 2003JNCI Journal of the National Cancer InstituteOpen Access

Active Tamoxifen Metabolite Plasma Concentrations After Coadministration of Tamoxifen and the Selective Serotonin Reuptake Inhibitor Paroxetine

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Determine how coadministration of the CYP2D6-inhibiting antidepressant paroxetine affects the plasma concentrations of active tamoxifen metabolites in breast cancer patients.
Conducted a prospective clinical trial measuring tamoxifen and its metabolites in 12 women with breast cancer of known CYP2D6 genotype before and after 4 weeks of paroxetine coadministration.
Evaluated the potency of tamoxifen metabolites via an estradiol-stimulated MCF7 cell proliferation assay and characterized metabolic pathways using CYP-specific chemical inhibitors in vitro.
Mean plasma concentrations of endoxifen statistically significantly decreased from 12.4 ng/mL before paroxetine coadministration to 5.5 ng/mL afterward (difference = 6.9 ng/mL, 95% CI = 2.7 to 11.2 ng/mL, P = .004).
Endoxifen concentrations fell by 64% (95% CI = 39% to 89%) in women with wild-type CYP2D6 compared with 24% (95% CI = 23% to 71%) in women with variant CYP2D6 genotypes (P = .03).
In vitro assays showed endoxifen is equipotent to 4-hydroxy-tamoxifen and is synthesized via CYP3A4-mediated N-demethylation followed by CYP2D6-mediated hydroxylation.

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Implication

Prospective clinical trial reveals that paroxetine significantly reduces active endoxifen concentrations in breast cancer patients on tamoxifen, suggesting CYP2D6 inhibition impairs efficacy.

Cite This Study

Vered Stearns (2003) studied this question.

synapsesocial.com/papers/6a73081fbfabfe3aef60e4a7 https://doi.org/10.1093/jnci/djg108

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Implication

Prospective clinical trial reveals that paroxetine significantly reduces active endoxifen concentrations in breast cancer patients on tamoxifen, suggesting CYP2D6 inhibition impairs efficacy.

Active Tamoxifen Metabolite Plasma Concentrations After Coadministration of Tamoxifen and the Selective Serotonin Reuptake Inhibitor Paroxetine

Key Points

Discussion

Implication

Cite This Study

Active Tamoxifen Metabolite Plasma Concentrations After Coadministration of Tamoxifen and the Selective Serotonin Reuptake Inhibitor Paroxetine

Key Points

Discussion

Implication

Cite This Study

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