METABOLISM OF THE STEROIDAL AROMATASE INHIBITOR ATAMESTANE IN RATS, CYNOMOLGUS MONKEYS AND HUMANS - ISOLATION AND IDENTIFICATION OF THE MAJOR METABOLITES

The metabolism of the steroidal aromatase inhibitor atamestane was stu died in the rat, the cynomolgus monkey and in the human. Metabolite pa tterns were recorded in plasma, urine and bile (rat only) before and a fter enzymatic cleavage of sulfate and glucuronide conjugates. Atamest ane was rapidly and extensively metabolized by all three species. Majo r 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 H-1-NMR analysis. The metabolite patterns observed in the animals and in the human were sim ilar, although some species- and sex-related differences were observed . There seem to be two principal routes by which atamestane is metabol ized: one route is characterized by the attack of 17 beta-hydroxystero id dehydrogenase, the other route includes hydroxylation of the 1-meth yl group with subsequent attack by 5 beta-reductase, followed by a hyd roxylation at position C-6. Some of the metabolites which were identif ied still had some pharmacological activity, although less marked than the parent compound.