Metabolism of the steroidal aromatase inhibitor atamestane in rats, cynomolgus monkeys and humans

Abstract

The metabolism of the steroidal aromatase inhibitor atamestane was studied in the rat, the cynomolgus monkey and in the human. Metabolite patterns were recorded in plasma, urine and bile (rat only) before and after enzymatic cleavage of sulfate and glucuronide conjugates. Atamestane was rapidly and extensively metabolized by all three species. Major metabolites which were observed in the human, could be isolated from urine pools of treated monkeys by preparative high performance liquid chromatography and were identified by GC/MS and 1H-NMR analysis. The metabolite patterns observed in the animals and in the human were similar, although some species- and sex-related differences were observed. There seem to be two principal routes by which atamestane is metabolized: one route is characterized by the attack of 17 beta-hydroxysteroid dehydrogenase, the other route includes hydroxylation of the 1-methyl group with subsequent attack by 5 beta-reductase, followed by a hydroxylation at position C-6. Some of the metabolites which were identified still had some pharmacological activity, although less marked than the parent compound.

Metabolic studies of formestane in horses

“…[8] Similarly, because of their potential abuse or misuse, this class of compounds is also banned in horseracing and equestrian sports. [13] However, very limited information about the metabolism of aromatase inhibitors in horses is available. [13] However, very limited information about the metabolism of aromatase inhibitors in horses is available.…”

“…A number of publications have been reported on the metabolic studies of aromatase inhibitors in human [9][10][11][12] and other animals such as rats and monkeys. [13] However, very limited information about the metabolism of aromatase inhibitors in horses is available. To the best of our knowledge, there is a study reporting the observation of a number of reduced metabolites from the equine in vitro experiments of formestane by liquid chromatography-high resolution accurate mass spectrometry and gas chromatographymass spectrometry (GC-MS), [14] but their identities have yet to be confirmed.…”

Comparing the effects of atamestane, toremifene and tamoxifen alone and in combination, on bone, serum lipids and uterus in ovariectomized rats

“…Atamestane (ATA) is a third generation orally bioavailable steroidal aromatase inhibitor (AI) [1][2][3][4][5]. Both selective estrogen receptor modulators (SERMs), tamoxifen (TAM) and toremifene (TOR) are oral, non-steroidal anti-estrogens which compete with estrogen for the estrogen receptors in breast tissue and are used for first-line treatment of hormone dependent advanced breast cancer in patients [6,7].…”

The effects of atamestane and toremifene alone and in combination compared with letrozole on bone, serum lipids and the uterus in an ovariectomized rat model

“…Atamestane (ATA) is a third generation orally bioavailable steroidal aromatase inhibitor with potential use in the treatment of breast cancer [1][2][3][4]. Atamestane in combination with toremifene entered Phase 3 clinical testing in a large multicenter study in the United States and Europe in 2002.…”