Drug/Small Molecule:

anastrozole

Overview

Generic Names:	Anastrozol; anastrozole
IUPAC Name:	2-[3-(2-cyanopropan-2-yl)-5-(1,2,4-triazol-1-ylmethyl)phenyl]-2-methylpropanenitrile
Trade Names:	Anastrole; Arimidex
PharmGKB Accession Id:	PA448432

Description

Anastrozole is a drug indicated in the treatment of breast cancer in post-menopausal women. It is used both in adjuvant therapy (i.e. following surgery) and in metastatic breast cancer. It decreases the amount of estrogens that the body makes. Anastrozole belongs in the class of drugs known as aromatase inhibitors. It inhibits the enzyme aromatase, which is responsible for converting androgens (produced by women in the adrenal glands) to estrogens.

Indication

For treatment of breast cancer in post-menopausal women.

ATC Therapeutic Category

• L02BG:Enzyme inhibitors

Pharmacology and Interactions

Mechanism Of Action

Anastrozole selectively inhibits aromatase. The principal source of circulating estrogen (primarily estradiol) is conversion of adrenally-generated androstenedione to estrone by aromatase in peripheral tissues. Therefore, aromatase inhibition leads to a decrease in circulatin estrogen, leading to a decreased tumor mass or delayed progression of tumor growth in some women.

Pharmacology

Anastrozole is a potent and selective non-steroidal aromatase inhibitor indicated for the treatment of advanced breast cancer in post-menopausal women with disease progression following tamoxifen therapy. Many breast cancers have estrogen receptors and growth of these tumors can be stimulated by estrogens. In post-menopausal women, the principal source of circulating estrogen (primarily estradiol) is conversion of adrenally-generated androstenedione to estrone by aromatase in peripheral tissues, such as adipose tissue, with further conversion of estrone to estradiol. Many breast cancers also contain aromatase; the importance of tumor-generated estrogens is uncertain. Treatment of breast cancer has included efforts to decrease estrogen levels by ovariectomy premenopausally and by use of anti-estrogens and progestational agents both pre- and post-menopausally, and these interventions lead to decreased tumor mass or delayed progression of tumor growth in some women. Anastrozole is a potent and selective non-steroidal aromatase inhibitor. It significantly lowers serum estradiol concentrations and has no detectable effect on formation of adrenal corticosteroids or aldosterone.

Food Interactions

Food decreases the rate of absorption, but the extent of absorption is not affected.

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

Hepatic. Metabolized mainly by N-dealkylation, hydroxylation, and glucuronidation to inactive metabolites. Primary metabolite is an inactive triazole.

Protein Binding

40%

Absorption

Well absorbed into the systemic cirulation following oral administration. Food does not affect the extent of absorption.

Half Life

50 hours

Toxicity

In rats, lethality is greater than 100 mg/kg.

Chemical Properties

Chemical Formula:

C₁₇H₁₉N₅

SMILES Code:

CC(C)(C#N)c1cc(cc(c1)C(C)(C)C#N)Cn2cncn2

(Format: OpenEye Isomeric)

Molecular Weight ( average / monoisotopic )

293.3663 / 293.164

Curated Annotations ()

1. rs6493497 at chr15:49418127 in CYP19A1
   Phenotype: This SNP, along with a second one in tight LD (rs71760050) was significantly associated, in a cohort of estrogen-receptor-positive patients with primary breast cancer larger than 3 cm, with change in aromatase activity before and after aromatase inhibitor neoadjuvant treatment . It was also associated, but not significantly so after adjustment for multiple testing, with change in estrone level and with pretreatment aromatase level. Study size: 45. Study population/ethnicity: Edinburgh female ER-positive patients, primary breast cancer larger than 3 cm. Significance metric(s): nominal p = 0.0063, p = 0.039 after adjustment for multiple testing. Type of association: PD; GN;FA. Second Phenotype: In a group of 200 women with early-stage breast cancer, who were treated with 1 mg/day adjuvant anastrozole, this SNP was significantly associated with pre-drug and post-drug estradiol plasma concentrations after adjusting for plasma anastrozole concentrations. Study size: 200. Study population: women with early-stage breast cancer (Mayo Clinic-M.D. Anderson pharmacogenomic study participants) . Significance metric(s):pre-drug p = 0.028; post-drug p = 0.0002. Type of association: PD; GN;FA

   Related Drugs:

   anastrozole, exemestane, letrozole

   Related Diseases:

   Breast Neoplasms

   Evidence:

   PMID:20048079
   

2. rs7176005 at chr15:49418571 in CYP19A1
   Phenotype: This SNP, along with a second one in tight LD (rs6493497) was significantly associated, in a cohort of estrogen-receptor-positive patients with primary breast cancer larger than 3 cm, with change in aromatase activity before and after aromatase inhibitor neoadjuvant treatment . It was also associated, but not significantly so after adjustment for multiple testing, with change in estrone level and with pretreatment aromatase level. Study size: 45. Study population/ethnicity: Edinburgh female ER-positive patients, primary breast cancer larger than 3 cm. Significance metric(s): nominal p = 0.0063, p = 0.039 after adjustment for multiple testing. Type of association: PD; GN;FA. Second Phenotype: In a group of 200 women with early stage breast cancer, who were treated with 1 mg/day adjuvant anastrozole, this SNP was significantly associated with pre-drug and post-drug estradiol plasma concentrations after adjusting for plasma anastrozole concentrations. Study size: 200. Study population: women with early stage breast cancer (Mayo Clinic-M.D. Anderson pharmacogenomic study participants) . Significance metric(s):pre-drug p = 0.057; post-drug p = 0.0002. Type of association: PD; GN;FA

   Related Drugs:

   anastrozole, exemestane, letrozole

   Related Diseases:

   Breast Neoplasms

   Evidence:

   PMID:20048079
   

Curated Information

The following genes are in curated knowledge about this drug.

	Gene	Relationship	Evidence
	CYP19A1	CO PD PK FA GN	Publications, Pathways, Variants
	ESR1	PD PK	Pathways
	ESR2	PD PK	Pathways
	HSD17B1	PD PK	Pathways
	STS	PD	Pathways
	SULT1A1	PD	Pathways
	SULT1E1	PD	Pathways

Non-Curated Information

A list of non-curated publications that mention this drug along with other genes is available.

Metabolizing Enzymes

• CYP19A1

Drug Targets

• CYP19A1

PharmGKB Curated Pathways

• Anti-estrogen Pathway (Aromatase Inhibitor)
• Anti-estrogen Pathway (Summary)

Non-Curated Information

A list of non-curated publications that mention this drug along with other drugs is available.

Curated Information

The following diseases are in curated knowledge about this drug.

	Disease	Relationship	Evidence
	Breast Neoplasms	CO PD PK FA GN	Publications, Pathways, Variants
	Cardiovascular Diseases	PD PK	Pathways

Non-Curated Information

A list of non-curated publications that mention this drug along with other diseases is available.

Additional Datasets

These datasets are minimally curated and are sorted alphabetically by title.

1. A Genome-Wide Association Study in Patients Experiencing Musculoskeletal Adverse Events on Aromatase Inhibitors as Adjuvant Therapy in Early Breast Cancer.

LinkOuts

Common Searches

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Non-Curated Publications

A list of non-curated publications that mention this drug is available.