Biomedical Engineering Reference
In-Depth Information
polymorphic cytochrome P450 (CYP) enzymes including CYP3A4, 3A5, 1A2, 2B6,
2 C9, 2 C19 and 2D6 catalyze, to different extents, the hepatic biotransformation of
tamoxifen into active and inactive primary and secondary metabolites [
168-
171
] .
Briefly, tamoxifen is primarily oxidized to
N
-desmethyl-tamoxifen (the most
abundant metabolite in human plasma) and 4-hydroxy-tamoxifen predominantly by
CYP3A4/5 and CYP2D6, respectively, followed by endoxifen formation from
N
-desmethyl-tamoxifen, exclusively catalyzed by CYP2D6 and from 4-hydroxy-
tamoxifen by CYP3A4/5 (Fig.
2
).
N
-desmethyl-tamoxifen is quantitatively the major metabolite found in patients'
plasma and serum. It accounts approximately for 92 % of primary tamoxifen oxidation
[
171
]. In women receiving a daily dose of 20 mg tamoxifen, steady-state plasma con-
centrations of
N
-desmethyl-tamoxifen are 1.5 to 2-fold higher than those of tamoxifen.
Plasma levels of 4-hydroxy-tamoxifen are five to tenfold lower than those of endoxifen
[
11,
165,
172,
173
]. Steady-state plasma concentration of tamoxifen is achieved after
1 month with terminal elimination half-life of about 5-7 days.
N
-desmethyl-tamoxifen
(elimination half-life of about 10-14 days), 4-hydroxy-tamoxifen, endoxifen have lon-
ger elimination half-life than tamoxifen and their steady-state plasma concentrations
are achieved 3-4 months after treatment initiation [
11,
172
] .
Tamoxifen and its metabolites undergo further glucuronidation and sulfation.
Different hepatic and extra-hepatic UDP-glucuronosyltransferases (UGTs) exhib-
ited in-vitro glucuronidation activities towards tamoxifen and its metabolites leading
to inactive metabolites [
174
] . The hepatic enzyme UGT1A4 is considered the major
UDP-glucuronosyltransferase responsible - in vitro - for the
N
-glucuronidation of
tamoxifen and 4-hydroxy-tamoxifen [
175-
178
] . Hydroxylated active tamoxifen
metabolites (i.e.,
Z
-4-hydroxy-tamoxifen and
Z
-endoxifen) equally go through
O
-glucuronidation involving mainly UGT2B7 and the extra-hepatic glucuronidat-
ing enzymes UGT1A10 and 1A8 [
179,
180
] . Typical chromatographic pro fi les of
tamoxifen phase I and phase II glucuronidated metabolites, observed in a plasma
sample from a BC patient, are depicted in Fig.
3
. Sulfotransferase (SULT) 1A1 is
the major phase II metabolizing enzyme involved in the sulfation of 4-hydroxy-
tamoxifen and endoxifen [
181-
184
]. These sulfated and glucuronidated metabolites
are further eliminated in urine and bile and undergo enterohepathic circulation
(EHC) [
185-
187
] .
As an adjuvant therapy, in pre- and post-menopausal women with ER-positive
BC, a standard 5 years treatment with tamoxifen has been demonstrated to almost
half (43 %) the rate of disease recurrence and reduce the annual breast cancer death
by a third (31 %). In the preventive setting, tamoxifen also reduces the risk of devel-
oping a new breast cancer by nearly one-half [
150,
151,
154,
157
] .
Despite the obvious benefits of this drug in the different treatment settings, the
clinical outcomes of tamoxifen treatment in terms of efficacy and side effects are
incomplete and inconstant, and almost 30-50 % of patients either fail to respond
or become resistant to tamoxifen [
188
]. One of the proposed mechanisms that
may account for the impaired response to tamoxifen therapy is an altered bioacti-
vation of the parent drug into endoxifen, either by genetic or environmental factors
[
188,
189
] .
