title: Pharmacokinetics of 3H-cicaprost in healthy volunteers.
abstract: Cicaprost (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, ZK 96 480) is a novel PGI2-derivative, which is chemically stable and not subject to metabolic degradation in rats and cynomolgus monkeys. The pharmacokinetics of Cicaprost were studied in six healthy volunteers (age: 54-74 y) after i.v. infusion (2.1 micrograms over 60 min) and p.o. dosage (7.6 micrograms) of the tritiated compound. All treatments were well-tolerated by the test subjects. At the end of the infusion plasma levels of approximately 100 pg/ml were reached, declining biphasically with half-lives of 3-4 min and 64 +/- 21 min. Total clearance was 3.8 +/- 0.5 ml/min/kg. The oral dosage resulted in peak plasma levels of 251 +/- 90 pg/ml occurring at 23 +/- 5 min post dose. The terminal half-life in the plasma was 115 +/- 30 min. Gastro-intestinal absorption and absolute bioavailability of Cicaprost was complete. After both routes of administration approx. 60% of dose was excreted with the urine within 24 h, whereas fecal 3H-excretion lasted for several days and accounted for approx. 35%. Radiochromatography revealed that Cicaprost was metabolically stable in plasma and urine. In the feces several degradation products were observed apart from approx. 30% of the dose fraction being excreted unchanged by that route. The present results demonstrate that Cicaprost is an orally completely bioavailable, metabolically stable PGI2-mimetic which may be an ideal candidate for oral therapy because of its pharmacokinetic characteristics.
authors.affiliation: Research Laboratories, Schering AG, Berlin, FRG.
authors.forename: M
authors.initials: M
authors.lastname: Hildebrand
authors.forename: T
authors.initials: T
authors.lastname: Staks
authors.forename: A
authors.initials: A
authors.lastname: Schütt
authors.forename: H
authors.initials: H
authors.lastname: Matthes
mesh_terms: D000284:Administration, Oral; D000368:Aged; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D011464:Epoprostenol / Q000008:administration & dosage / Q000032:analysis / Q000493:pharmacokinetics* / Q000031:analogs & derivatives; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged
chemical_list: D011464:Epoprostenol; C043867:cicaprost