Studies on the pharmacokinetics of ZK 96 480, a novel PGI2-mimetic, in rat and cynomolgus monkey.

ZK 96 480 (5- [(E)-(1S,5S,6S,7R)-7-Hydroxy-6-[(3S,4S)-3-hydroxy-4- methylnona-1,6-diinyl]-bicyclo [3.3.0] octan-3-yliden]-3-oxapentanoic acid) is a novel PGI2-derivative. The pharmacokinetics and biodegradation of the new drug were studied in rat and cynomolgus monkey after i.v. and i.g. administration of 3H-labelled ZK 96 480. In a rat liver perfusion experiment ZK 96 480 remained unchanged over 90 min. Following i.v. and i.g. dosing, the metabolic pattern in the urine and the methanolic extracts of homogenized, freeze-dried feces samples revealed almost exclusively unchanged compound in both animal species. After i.v. treatment, drug disposition in the plasma exhibited half-lives of 0.14 h and 4.3 h in rat and 0.07 h, 0.4 h and 2.5 h in monkey. Total clearance was 14 ml/min/kg in the latter species. Excretion of 3H-label was mainly fecal in rat, but exhibited no preferred route in monkey. On the basis of the urinary excretion of 3H-label and unchanged drug both gastro-intestinal absorption and bioavailability were complete. Whole body autoradiographs in rat demonstrated that there was no specific enrichment of radiolabel in any tissue or organ. The present results demonstrate that ZK 96 480 is an orally available and metabolically stable carbacyclin derivative in female rats and monkeys.