Biomedical Engineering Reference
In-Depth Information
has been recently published that sought for the association between endoxifen
concentrations and breast cancer outcomes [
173
]. This pioneering study suggested
a probable nonlinear dose-response relationship for tamoxifen effect and identified
a threshold concentration for endoxifen (of about 6 ng/ml) above which approxi-
mately 30 % reduction in disease recurrence rate was observed.
Early attempts that examined the feasibility and usefulness of tamoxifen dose-
adjustment strategy were based exclusively on CYP2D6 genotype. Genotype-guided
dose-adjustment studies have shown that tamoxifen dose increase to 30 mg or
40 mg/day significantly increases 4-hydroxy-tamoxifen and endoxifen concentra-
tions in IM and even in PM patients carrying two null alleles (reflecting metabolism
by other enzymes), without any significant difference in adverse effects. However,
an important variability is still observed in 4-hydroxy-tamoxifen and endoxifen lev-
els between the genotypic groups [
226,
227
] and this would be a strong argument
for considering TDM of tamoxifen and its active metabolites levels as a valuable
strategy for tamoxifen dose adjustment further reducing the residual variability
within CYP2D6 genotype groups.
Barginear et al. [
228
]. investigated in another prospective study the effect of
tamoxifen dose increase on the concentrations of tamoxifen, 4-hydroxy-tamoxifen,
endoxifen, and their position isomers (4¢-hydroxylated) and proposed an “antiestro-
genic activity score” (AAS) based on the concentrations of these metabolites and
their respective antiestrogenic activities. According to Barginear et al. this AAS
score would constitute a better approach to estimate the biologic effectiveness of
tamoxifen and, therefore, to guide future tamoxifen dose optimization. However,
this approach has yet to be validated by larger studies.
3.2
Tamoxifen and Metabolites Identi fi cation and Quanti fi cation
To date, several quantitative analytical methods have been developed for the moni-
toring of tamoxifen and some of its metabolites in human biological fluids and
tissues, including conventional [
229-
231
] and micellar [
232
] liquid chromatography
(LC) methods coupled to fluorescence detection, capillary electrophoresis-mass
spectrometry (CE-MS) [
233
] , gas chromatography-mass spectrometry (GC-MS)
[
234
], as well as liquid chromatography methods hyphenated with mass spectrom-
etry (LC-MS) [
195
] and tandem mass spectrometry (LC-MS/MS) [
145,
173,
193,
194,
196,
218,
226,
227,
235-
247
]. Reports have also been published describing
liquid chromatography method coupled to mass spectrometry or fluorescence detec-
tion for the study of tamoxifen metabolism in vitro and in vivo in animal models
[
185,
248-
254
]. Most of these qualitative and quantitative LC, GC, and CE methods
have already been reviewed by Teunissen et al. [
255
] .
Various hyphenated LC-MS-based assays, using either the electrospray ionization
(ESI) or the atmospheric pressure chemical ionization (APCI) interface, have been
developed and applied in the clinical setting in order to support pharmacokinetic
(PK), pharmacogenetic-pharmacokinetic (PG-PK), and pharmacokinetic-pharmaco-
dynamic (PK-PD) studies in BC patients under tamoxifen therapy (Table
3
).
