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2D6T
87966
Ereshefsy L, et al: CYP2D6 inhibition by selective serotonin reuptake inhibitors: analysis of achievable
steady-state plasma concentrations and the effect of ultrarapid metabolism at CYP2D6. Pharmacotherapy
2002;22:1001-1006
Cytochrome P450 2D6 Genotype for Tamoxifen Hormonal
Therapy
Clinical Information: Tamoxifen is a hormonal therapy used for patients with estrogen
receptor-positive breast cancer. It is a selective estrogen receptor modulator (SERM) that exerts its effect
by binding to the estrogen receptor (ER). Tamoxifen is metabolized by the cytochrome P450 enzyme
system to active metabolites. Two enzymes, cytochrome P450 3A (CYP3A) and 2D6 (CYP2D6), have
been identified that are both necessary to generate 4-hydroxy-N-desmethyl-tamoxifen, generically named
endoxifen, the most active metabolite of tamoxifen.(1) Endoxifen is approximately 100 times more potent
in ER binding than the parent drug, tamoxifen, or the metabolite N-desmethyl tamoxifen.(2) CYP2D6 is
an enzyme involved in the metabolism of many drugs including antidepressants, antihypertensive
medications, cardioactive drugs, and stimulants, as well as tamoxifen. CYP2D6-mediated drug
metabolism is highly variable. Some individuals have altered CYP2D6 gene sequences that result in
decreased enzyme production or production of enzyme with diminished catalytic activity. Furthermore,
the entire gene can be deleted in some individuals, resulting in absent enzyme activity and poor
metabolizer status. Breast cancer patients who receive tamoxifen and who are CYP2D6 poor metabolizers
produce suboptimal concentrations of endoxifen.(3) These patients have poorer outcomes, with an
increased risk of breast cancer recurrence, compared to CYP2D6 extensive (normal) metabolizers.(2)
Because tamoxifen metabolites exert their effect by binding to the ER, hot flashes are a common side
effect. However, patients who are CYP2D6 poor metabolizers appear to have a much lower incidence of
bothersome hot flashes, consistent with data demonstrating that these patients have lower concentrations
of the active tamoxifen metabolites. Polymorphisms associated with CYP2D6 poor metabolizer status are
autosomal recessive. Consequently, only individuals who are homozygous or who are compound
heterozygous for these polymorphisms are poor metabolizers. The following information outlines the
relationship between the polymorphisms detected in the CYP2D6 genotyping assay and the effect on the
activity of the enzyme produced by that allele: Allele Designation Nucleotide Change Effect on CYP2D6
mRNA or Protein Effect and Phenotype *1 No poly morphisms detected Normal mRNA and protein
Normal activity; predicted extensive metabolizer status for tamoxifen. *2A -1584C->G Increased
transcription *3 2549A->del Nonsense mutation No activity; predicted poor metabolizer status for
tamoxifen. *4 1846G->A mRNA splicing *5 gene deletion Entire gene deleted *6 1707T->del Nonsense
mutation *7 2935A->C Missense mutation *8 1758G-> Stop codon *11 883G->C mRNA splicing *12
124G->A Missense mutation *14A 100C->T 1758G->A Missense mutation *15 138insT Nonsense
mutation *2 2850C->T Missense mutation Activity with tamoxifen has not been determined; metabolizer
status for tamoxifen unknown. *9 2613AGA>del Lysine282 deletion *10 100C->T Missense mutation
*14B 1758G->A Missense mutation *17 1023C->T Missense mutation *41 2988G->A mRNA splicing
Gene duplications Whole gene duplication Depends on the allele duplicated Allele duplication may result
in no change in activity (duplication of deficient alleles) or potentially increase the metabolism of
tamoxifen (ultrarapid metabolism). A complicating factor in correlating CYP2D6 genotype with
phenotype is that many drugs or their metabolites are inhibitors of CYP2D6 catalytic activity. For
example, many antidepressants, including some of the tricyclic antidepressants and some of the selective
serotonin reuptake inhibitors, especially fluoxetine and paroxetine, are particularly inhibitory to CYP2D6
activity. Other drugs that inhibit CYP2D6 activity include some cardioactive drugs (eg, quinidine and
amiodarone), some drugs of abuse (eg, cocaine), methadone, many histamine H1 receptor antagonists (eg,
cimetidine), celecoxib, and ritonavir. Comedication with tamoxifen and inhibitory drugs may produce a
CYP2D6 poor metabolizer phenotype, even though the patient has a CYP2D6 genotype consistent with
intermediate or extensive metabolism. Consequently, it is important to interpret the results of CYP2D6
genotype testing in the context of coadministered drugs. Because antidepressants are often prescribed to
alleviate the hot flashes that accompany tamoxifen therapy, it is particularly important to utilize an
antidepressant that does not compromise CYP2D6 activity, which could reduce tamoxifenâ€s efficacy.
Useful For: Determining the CYP2D6 genotype of patients considered for tamoxifen chemotherapy
Interpretation: An interpretive report will be provided that includes assay information, genotype, and
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