Bioactivation of eptaloprost in animals and man.

Eptaloprost is a novel concept PGI2-mimetic, which is designed to be activated to the pharmacologically potent cicaprost via beta-oxidation. By pro-drug formation advantages in terms of sustained delivery of prostacyclin-mimetic activity were envisaged. The active metabolite is known to be metabolically stable and highly pharmacologically potent. In the present set of experiments the pharmacokinetics of eptaloprost was studied in rat, monkey and man by i.v. and ig administration of tritiated compound. Eptaloprost was completely and rapidly absorbed in all three species. Peak plasma levels of the parent compound were observed within 30 min postdose. Total clearance of the pro-drug accounted for 170, 62 and 66 ml/min/kg in rat, monkey and man. Disposition of eptaloprost exhibited half-lives of 0.1 to 0.5 h and mean residence times accounted for 0.15, 0.4 and 0.6 h in the three species. The active metabolite cicaprost was present in the central compartment with a slight delay as compared to eptaloprost. Its peak plasma levels were found within 0.25 to 0.5 h postdose. Disposition of radiolabel in plasma and 3H-excretion with the urine and feces was determined by the pharmacokinetic behaviour of cicaprost. In rats excretion was mainly biliary while monkeys and man excreted almost unchanged cicaprost in equal portions with urine and feces. Half-lives of renal excretion were in the range of terminal half-lives in the central compartment. Neither in animals nor in man eptaloprost administration resulted in an advantageous systemic profile of cicaprost. On the contrary the bioavailable dose fraction of cicaprost was lower as compared to cicaprost administration. A delay or an extension of cicaprost plasma levels was not observed. The present pharmacokinetic data of eptaloprost studied in three species demonstrated that a pro-drug concept based on simple beta-oxidative bioactivation could be successfully realized for a special PGI2-mimetic. An advantage resulting from oral pro-drug administration as compared to direct treatment with the active metabolite could not be shown. For long-lasting plasma levels of cicaprost a chemically determined retardation might require a more sophisticated pro-drug concept or alternatively pharmaceutical technology is required.