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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.

The pharmacokinetics and absolute bioavailability of nocloprost, a synthetic PGE2-analogue with cytoprotective properties, was investigated in human volunteers as a function of the dose. Ten young male volunteers received nocloprost 5 micrograms i.v. and 100, 200 and 400 micrograms p.o. in random order at weekly intervals. Serum nocloprost levels were monitored for up to 12 h after each dose, using a specific, validated assay. After nocloprost 5 micrograms i.v. the highest serum level of 373 pg.ml-1 was found in the first sample 5 min after injection, and the subsequent decline showed one or two phases, with half-lives of 4 and 49 min. The AUC was 89 pg.h.ml-1, the total plasma clearance was 13.2 ml.min-1.kg-1, and the volume of distribution at steady state was 0.16 l.kg-1. After oral administration the maximum serum level and AUC increased in proportion to the dose. tmax showed a wide scatter, with an average value of about 30 min independent of the dose. Although not detectable in every subject, post maximum serum levels declined biphasically, with half-lives of ca 10 and 35-40 min. The absolute bioavailability after oral administration averaged about 2% and was independent of the dose.