Biotransformation of the stable prostacyclin analogue, iloprost, in the rat

The metabolic pathway of the stable prostacyclin analogue, iloprost (ZK 36 374), was studied in the rat, both in vivo and in vitro by a rat liver perfusion model. Metabolites were isolated from both experiments by preparative high performance liquid chromatography and identified by GC/MS and NMR analysis. In vitro, iloprost was metabolized by consecutive beta-oxidation of the upper side chain. Both dinor- and tetranoriloprost could be isolated from the perfusion medium. The metabolic pattern in bile was similar to that in the perfusion medium. In vivo, iloprost was totally metabolized by beta-oxidation of the upper side chain and by subsequent hydroxylation and conjugation. The compounds identified in rat urine were tetranoriloprost which represented about 3/4 of all metabolites, hydroxylated tetranoriloprost with the additional hydroxyl group presumably at position 17 and a conjugate of tetranoriloprost. Dinoriloprost and unchanged drug were not observed. beta-Oxidation of the upper side chain was stereoselective to give a 6 alpha-H/6 beta-H ratio of 86:14.