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 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.

Identification of the major metabolites of the prostaglandin E2-analogue sulprostone in human plasma, and isolation from urine (in vivo) and liver perfusate (in vitro) of female guinea-pigs.

After the parenteral administration of the 3H-labeled prostaglandin E2-analogue (PGE2-analogue) to three healthy women, a number of metabolites were observed in the plasma, some of them still potentially pharmacologically active. The metabolite pattern in human plasma was very similar to the one observed in the urine of female guinea pigs, which received a total dose of 0.21 mg [3H]sulprostone by repeated sc administration over a period of 5 days. In vitro perfusion of an isolated guinea pig liver with 50 mg of [3H]sulprostone, dissolved in Tyrode's solution, yielded another source for the isolation of those metabolites, which were also present in human plasma. Both urine and perfusion medium were submitted to repeated HPLC-separations and the recovery during the purification procedure was calculated for each metabolite on the basis of recovered radioactivity after each step of purification. Chromatographically pure metabolites were submitted to GC/MS analysis, 1H-NMR and IR spectroscopy for structural elucidation. Besides the unchanged parent compound, four metabolites of sulprostone could be identified in human plasma by co-chromatography with the isolated compounds. One of two major metabolites was the PGA2-analogue of the parent drug, the other was a cyclization product of the beta-side chain of sulprostone with the cyclopentenone ring, preceded by delta 13 reduction. The two minor metabolites were the free acids of sulprostone and the PGA2-analogue.