Pharmacokinetics and biotransformation of the prostacyclin analogue, ZK 36 374. III. Development of a radioimmunoassay and its application to the pharmacokinetics of ZK 36 374 in the rat

Abstract

The development of a radioimmunoassay for ZK 36 374, a chemically stable prostacyclin analogue, and its application to the pharmacokinetics of the drug in the rat is described. Antiserum against ZK 36 374 was raised in rabbits by immunization with ZK 36 374 coupled to bovine serum albumin via the carboxylic group. ZK 36 374 is extracted from plasma samples and purified from matrix constituents by means of octadecyl silyl cartridges. At a plasma concentration of 2.5 ng/ml intra- and interassay variations are 6 and 7%, respectively. The limit of detection is 0.5 ng/ml. After intravenous administration of 200 micrograms/kg to female Wistar rats a biphasic decline of the drug concentration in the plasma was observed with half-lives of 5 min and 3 h. Oral doses of 200 and 2000 micrograms/kg were very rapidly absorbed reaching maximum plasma levels of 3 and 32 ng/ml as early as 10-15 min p.admin.. Bioavailability at the two dose levels was calculated to be 8 and 13% of dose. Disposition was biphasic, as well, with a somewhat prolonged beta-phase after the highest dose.