Biomedical Engineering Reference
In-Depth Information
2
LC-MS/MS to Support Clinical Pharmacogenomics
2.1
Tamoxifen
2.1.1
Pharmacology and Pharmacogenetics
Tamoxifen is a widely available hormonal adjuvant therapy for women with breast
cancer, and is most effective on tumors that are positive for estrogen and progesterone
receptors. While alternative drugs are available, such as the aromatase inhibitors,
tamoxifen remains the drug of choice for premenopausal breast cancer patients.
Tamoxifen exists as a prodrug that must be converted to endoxifen, the metabolite that
has about 100-fold higher activity in blocking estrogen receptors than the parent drug
[ 1 ]. The conversion of tamoxifen to endoxifen occurs through two metabolic path-
ways. The major pathway is catalyzed principally by CYP 3A4/5 and first to
N -desmethyltamoxifen which has minimal biologic activity, and then to endoxifen by
CYP 2D6. The minor pathway is conversion by CYP 2D6 to 4-hydroxytamoxifen,
which has significant biologic activity but is present in low blood concentrations, and
then to endoxifen by CYP 3A4/5 [ 2 ]. The rate-limiting step in either pathway is the
enzyme CYP 2D6. Individuals who have CYP 2D6 genotypes that encode a null
enzyme (e.g., 2D6 *3 through *8 ) have reduced concentrations of endoxifen relative
to wild-type individuals. Those who have a reduce enzyme activity genotypes (e.g.,
2D6 *9, *10, *17, and *29 ) also have lower endoxifen concentrations. Retrospective
clinical trials involving tamoxifen have shown that patients who are poor (2D6 *4/*4 )
or intermediate (2D6 *10/*10 ) have significantly shorter time to breast cancer recur-
rence and worse relapse-free survival [ 3, 4 ]. Other researchers have shown that there
is a trend towards reduced endoxifen concentrations, with the highest concentrations
seen in ultra (2D6 gene duplication) and extensive metabolizers ( *1/*1 ), successively
lower levels with one or more copies of the reduced activity genes ( *10 ), and lowest
concentrations with one or more copies of the null genes ( *10 ). The hypothesis is that
worsening clinical outcomes are associated with decreasing endoxifen concentrations.
Madlensky et al. recently showed that when patients are divided into quintiles, there
is a threshold effect, i.e., only in the lowest endoxifen quintile of values was associated
with poor outcomes [ 5 ]. As such, there are no consequences of having an excess
endoxifen concentration, such as expected for individuals who have more than two
copies of the 2D6 wild-type gene and are ultrarapid drug metabolizers.
2.1.2
Nongenetic Factors
While genotyping is an important first step in predicting individuals who will not
benefit from tamoxifen treatment, there are nongenetic factors that also result in
lowering of tamoxifen concentrations. The most widely studied are the class of
drugs that are serotonin selective reuptake inhibitors (SSRI) such as paroxetine and
fl uoxetine [ 6 ]. These drugs are used to treat depression, hot flashes, and vaginal
dryness and are potent inhibitors of CYP2D6 enzyme activity. Borges et al. showed
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