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Type: Journal article
Title: Pharmacogenomics of Tamoxifen Therapy
Author: Brauch, H.
Murdter, T.
Eichelbaum, M.
Schwab, M.
Citation: Clinical Chemistry (Washington, DC): international journal of molecular diagnostics and laboratory medicine, 2009; 55(10):1770-1782
Publisher: Amer Assoc Clinical Chemistry
Issue Date: 2009
ISSN: 0009-9147
Statement of
Hiltrud Brauch, Thomas E. Mürdter, Michel Eichelbaum and Matthias Schwab
Abstract: Background: Tamoxifen is a standard endocrine therapy for the prevention and treatment of steroid hormone receptor–positive breast cancer. Content: Tamoxifen requires enzymatic activation by cytochrome P450 (CYP) enzymes for the formation of active metabolites 4-hydroxytamoxifen and endoxifen. As compared with the parent drug, both metabolites have an approximately 100-fold greater affinity for the estrogen receptor and the ability to inhibit cell proliferation. The polymorphic CYP2D6 is the key enzyme in this biotransformation, and recent mechanistic, pharmacologic, and clinical evidence suggests that genetic variants and drug interaction by CYP2D6 inhibitors influence the plasma concentrations of active tamoxifen metabolites and the outcomes of tamoxifen-treated patients. In particular, nonfunctional (poor metabolizer) and severely impaired (intermediate metabolizer) CYP2D6 alleles are associated with higher recurrence rates. Summary: Accordingly, CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) genotyping before treatment to predict metabolizer status may open new avenues for individualizing endocrine treatment, with the maximum benefit being expected for extensive metabolizers. Moreover, strong CYP2D6 inhibitors such as the selective serotonin reuptake inhibitors paroxetine and fluoxetine, which are used to treat hot flashes, should be avoided because they severely impair formation of the active metabolites.
Keywords: Humans
Breast Neoplasms
Neoplasms, Hormone-Dependent
Aryl Hydrocarbon Hydroxylases
Cytochrome P-450 CYP2D6
Oxidoreductases, N-Demethylating
Antineoplastic Agents, Hormonal
Cytochrome P-450 CYP3A
Genetic Variation
Cytochrome P-450 CYP2B6
Cytochrome P-450 CYP2C9
Cytochrome P-450 CYP2C19
Rights: © 2009 American Association for Clinical Chemistry, Inc.
DOI: 10.1373/clinchem.2008.121756
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Pharmacology publications

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