Abril - 2017

anastrozole

the

chemoprevention

and

treatment

breast

cancer

: A

literature

review

ssoc

ras

2017; 63(4):371-378

373

zole, is the one with the most widely recommended drugs,

due to their high specificity for the aromatase enzyme

and less adverse effects compared with the previous gen-

erations of AI drugs (Figure 3). Exemestane is a steroidal

compound that forms covalent bonds with aromatase,

and this type of inhibition is irreversible and can only be

overcome by the synthesis of a new enzyme. Letrozol and

anastrozole are nonsteroidal compounds with reversible

action and are competitive AIs.

11,12

Anastrozole and all third-generation compounds have

become endocrine drugs of choice for postmenopausal

breast cancer patients, as they are associated with a stron-

ger activity and better general tolerability compared with

tamoxifen (TAM), a first-generation selective estrogen

receptor modulator (SERM)

that has been associated

with potentially fatal adverse effects such as an increased

incidence of endometrial cancer, thromboembolism and

cerebrovascular event.

However, there are few studies

particularly on the pharmacodynamic and pharmacoki-

netic properties of anastrozole and its use in the chemo-

prevention and treatment of breast cancer.

In this review, we will discuss the pharmacodynam-

ic and pharmacokinetic properties of anastrozole, as

well as its use in the chemoprevention and treatment of

breast cancer.

harmacodynamic

properties

anastrozole

Anastrozole is a derivative of benzotriazole marketed as

ARIMIDEX

by AstraZeneca Pharmaceuticals LP. Simi-

larly to other AIs, it has an inhibitory action on aromatase,

thus blocking the conversion of testosterone into estra-

diol and androstenedione into estrone (Figure 4).

15-18

In-

hibition of the aromatase enzyme occurs particularly

through competitive binding of aromatase to the heme

group of cytochrome P450, decreasing estrogen biosynthe-

sis in the peripheral tissues of the body and in the breast.

Anastrozole has significant effects on breast can-

cer treatment and, therefore, it is currently used as first-

-line treatment in estrogen receptor (ER)-positive post-

menopausal women, particularly to treat locally advanced

or metastatic breast cancer. Furthermore, it is also indi-

cated for early cancer treatment, tumor chemopreven-

tion and postmenopausal women using TAM, especial-

ly if the drug is used during a prolonged period of time

and has been indicated in the disease’s recurrence, i.e.,

as another therapeutic endocrine option.

9,10

Prolonged use of anastrozole has no effects on the

concentrations of steroid hormones cortisol, aldosterone,

androstenedione and 16-hydroxyprogesterone, confirm-

ing that it is highly selective for the inhibition of aroma-

tase without interfering in other pathways of adrenal

stereoidogenesis. The lack of alterations in luteinizing

hormone and folllicle-stimulating hormone demonstrates

that anastrozole has no estrogenic, progestational or

androgenic activity, and it does not affect the synthesis

of gonadotropins.

8,20

harmacokinetic

properties

anastrozole

Some studies were conducted in an attempt to identify the

daily dose required for anastrozole to promote aromatase

inhibition and decrease estrogen synthesis. The results

showed that a daily dose of 1 mg of anastrozole was the

minimum capable of consistently supressing estrone and

estradiol at the limit detectable by radioimmunoassay.

18,21

However, recent studies have reported that a daily dose of

1 mg may not benefit all breast cancer patients because

interindividual variability may alter the efficacy and toler-

ability of anastrozole,

22,23

interfering in its pharmacody-

namic and or pharmacokinetic properties.

Administered orally during fasting, anastrozole is rap-

idly absorbed. After meals, however, it has a slower absorp-

tion rate. In the recommended dose of 1 mg, anastrozole

achieves maximum plasma concentrations within 2 hours

after its administration and, after seven days, approxi-

mately 90 to 95% of its plasma concentrations are obtained.

Less than 10% of anastrozole is excreted in the form of un-

altered drug, while 60% are excreted as metabolites.

17,18

Anastrozole is metabolized in the liver, involving

N-dealkylation, hydroxylation and glucuronidation

reactions, leading to a mean plasmatic half-life of 50

hours, which indicates that the administration of a

single daily dose of the drug is adequate. The three main

metabolites of anastrozole observed in the plasma and

urine of human patients are: triazol, hydroxy-anastrozole

glucuronide and anastrozole glucuronide. Triazole is

the main metabolite; however, it is inactive and does not

suppress, along with two other metabolites, the activity

of aromatase. The excretion of these metabolites is main-

ly through urine.

22,25

The main side effects of anastrozole use include hot

flashes (35%), asthenia (17%), headache (13%) and edema

(10%). Nausea is the most common gastrointestinal side

effect (19%), while diarrhea, constipation, abdominal pain

and anorexia are less frequently reported (8%).

Neverthe-

less, in addition to these effects, studies have recently

identified the presence of muscle and joint pain, as well

as a significant increase in the loss of bone mass, leading

to increased incidence of osteopenia and osteoporosis.

23,27