DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

of transcription factors in the two tissues and the effects of this
SERM on ER conformation. Raloxifene induces a configuration in
ERα that is distinct from that of tamoxifen-ERβ (Tamrazi et al.,
2003), suggesting that a different set of co-activators/co-repressors
may interact with ER-raloxifene compared with ER-tamoxifen.
Clomiphene increases gonadotropin secretion and stimulates
ovulation. It increases the amplitude of LH and FSH pulses without
changing pulse frequency (Kettel et al., 1993). This suggests that the
drug is acting largely at the pituitary level to block inhibitory actions of
estrogen on gonadotropin release from the gland and/or is somehow
causing the hypothalamus to release larger amounts of GnRH per pulse.
Fulvestrant binds to ERα and ERβ with a high affinity comparable
to estradiol but represses transactivation. It also increases
dramatically the intracellular proteolytic degradation of ERα while
apparently protecting ERβ from degradation (Van Den Bemd et al.,
1999). This effect on ERα protein levels may explain fulvestrant’s
efficacy in tamoxifen-resistant breast cancer.
Absorption, Fate, and Excretion
Tamoxifen is given orally, and peak plasma levels are reached within
4-7 hours after treatment. This drug displays two elimination phases
with half-lives of 7-14 hours and 4-11 days. Due to the prolonged t 1/2
,
3-4 weeks of treatment are required to reach steady-state plasma levels.
The parent drug is converted largely to metabolites within 4-6
hours after oral administration. Tamoxifen is metabolized in humans
by multiple hepatic CYPs, some of which it also induces (Sridar
et al., 2002). In humans and other species, 4-hydroxytamoxifen is
produced via hepatic metabolism, and this compound is considerably
more potent than the parent drug as an anti-estrogen. The major
route of elimination from the body involves N-demethylation and
deamination. The drug undergoes enterohepatic circulation, and
excretion is primarily in the feces as conjugates of the deaminated
metabolite. Polymorphisms affect the rate of tamoxifen metabolism
to its more potent 4-hydroxy metabolite and may impact its therapeutic
activity in breast cancer (Chapter 63).
Raloxifene is adsorbed rapidly after oral administration and
has an absolute bioavailability of ~2%. The drug has a t 1/2
of ~28 hours
and is eliminated primarily in the feces after hepatic glucuronidation;
it does not appear to undergo significant biotransformation by CYPs.
Clomiphene is well absorbed following oral administration,
and the drug and its metabolites are eliminated primarily
in the feces and to a lesser extent in the urine. The long plasma
t 1/2
(5-7 days) is due largely to plasma-protein binding, enterohepatic
circulation, and accumulation in fatty tissues. Other
active metabolites with long half-lives also may be produced.
Fulvestrant is administered monthly by intramuscular depot
injections. Plasma concentrations reach maximal levels in 7 days
and are maintained for a month. Numerous metabolites are formed
in vivo, possibly by pathways similar to endogenous estrogen metabolism,
but the drug is eliminated primarily (90%) via the feces in
humans.
Therapeutic Uses
Breast Cancer. Tamoxifen is highly efficacious in the
treatment of breast cancer. It is used alone for palliation
of advanced breast cancer in women with ER-positive
tumors, and it is now indicated as the hormonal treatment
of choice for both early and advanced breast cancer
in women of all ages (Jaiyesimi et al., 1995).
Response rates are ~50% in women with ER-positive
tumors. Tamoxifen increases disease-free survival and
overall survival; treatment for 5 years reduces cancer
recurrence by 50% and death by 27% and is more efficacious
than shorter 1- to 2-year treatment periods.
Tamoxifen reduces the risk of developing contralateral
breast cancer and is approved for primary prevention of
breast cancer in women at high risk, in whom it causes
a 50% decrease in the development of new tumors.
Prophylactic treatment should be limited to 5 years
because effectiveness decreases thereafter. The most frequent
side effect is hot flashes. Tamoxifen has estrogenic
activity in the uterus, increases the risk of endometrial
cancer by 2- to 3-fold, and also causes a comparable
increase in the risk of thromboembolic disease that leads
to serious risks for women receiving anticoagulant therapy
(Smith, 2003) and women with a history of deep
vein thrombosis or stroke.
Toremifene has therapeutic actions similar to
tamoxifen, and fulvestrant may be efficacious in
women who become resistant to tamoxifen. Untoward
effects of fulvestrant include hot flashes, GI symptoms,
headache, back pain, and pharyngitis.
Osteoporosis. Raloxifene reduces the rate of bone loss
and may increase bone mass at certain sites. In a large
clinical trial, raloxifene increased spinal bone mineral
density by >2% and reduced the rate of vertebral fractures
by 30-50% but did not significantly reduce nonvertebral
fractures (Delmas et al., 2002; Ettinger et al.,
1999). Raloxifene does not appear to increase the risk
of developing endometrial cancer. The drug has beneficial
actions on lipoprotein metabolism, reducing both
total cholesterol and LDL; however, HDL is not
increased. Adverse effects include hot flashes, deep
vein thrombosis, and leg cramps.
Infertility. Clomiphene is used primarily for treatment
of female infertility due to anovulation. By increasing
gonadotropin levels, primarily FSH, it enhances follicular
recruitment. It is relatively inexpensive, orally
active, and requires less extensive monitoring than other
treatment protocols. However, the drug may exhibit
untoward effects, including ovarian hyperstimulation,
increased incidence of multiple births, ovarian cysts,
hot flashes, and blurred vision. In addition, clomipheneinduced
cycles have a relatively high incidence of luteal
phase dysfunction due to inadequate progesterone production,
and prolonged use (e.g., ≥12 cycles) may
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CHAPTER 40
ESTROGENS AND PROGESTINS