Applications of Anastrozole

Anastrozole, chemically known as 2,2-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]bis(2-methylpropiononitrile) a derivative of benzotriazole with the CAS registry number 120511-73-1, is a non-steroidal, third-generation achiral triazole derivative marketed as ARIMIDEX® by AstraZeneca Pharmaceuticals LP1. It is one of the third-generation aromatase inhibitor which is a highly competitive and selective inhibitor of aromatase, thus blocking the conversion of testosterone into estradiol and androstenedione into estrone. Inhibition of the aromatase enzyme occurs particularly through competitive binding of aromatase to the hemegroup of cytochrome P450, decreasing estrogen biosynthesis in the peripheral tissues of the body and in the breast².

Anastrozole has significant effects on breast cancer treatment and, therefore, it is currently used as first-line treatment in estrogen receptor (ER)-positive postmenopausal women, particularly to treat locally advanced or metastatic breast cancer. Furthermore, it is also indicated for early cancer treatment, tumor chemoprevention and postmenopausal women using tamoxifen, especially 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 option³.

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 mainly through urine⁴.

Some studies showed that a daily dose of 1 mg of anastrozole was the minimum capable of consistently suppressing estrone and estradiol at the limit detectable by radioimmunoassay. However, recent studies have reported that a daily dose of 1 mg may not benefit all breast cancer patients because inter individual variability may alter the efficacy and tolerability of anastrozole, interfering in its pharmacodynamics and or pharmacokinetic properties⁵.

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%). Nevertheless, 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 osteoporosis⁶.

References

1.https://www.medicines.org.uk/emc/product/2199/smpc.
2.Sanford, M.; Plosker, G. L., Anastrozole - A review of its use in postmenopausal women with early-stage breast cancer. Drugs 2008, 68 (9), 1319-1340.
3.Kelly, C. M.; Buzdar, A. U., Anastrozole. Expert Opinion on Drug Safety 2010, 9 (6), 995-1003.
4.(a) Ingle, J. N.; Buzdar, A. U.; Schaid, D. J.; Goetz, M. P.; Batzler, A.; Robson, M. E.; Northfelt, D. W.; Olson, J. E.; Perez, E. A.; Desta, Z.; Weintraub, R. A.; Williard, C. V.; Flockhart, D. A.; Weinshilboum, R. M., Variation in anastrozole metabolism and pharmacodynamics in women with early breast cancer. Cancer research 2010, 70 (8), 3278-86; (b) Kamdem, L. K.; Liu, Y.; Stearns, V.; Kadlubar, S. A.; Ramirez, J.; Jeter, S.; Shahverdi, K.; Ward, B. A.; Ogburn, E.; Ratain, M. J.; Flockhart, D. A.; Desta, Z., In vitro and in vivo oxidative metabolism and glucuronidation of anastrozole. British journal of clinical pharmacology 2010, 70 (6), 854-69.

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