title: The pharmacokinetics and pharmacodynamics of the prostacyclin analog 15AU81 in the anesthetized beagle dog.
abstract: 15AU81, a tricyclic benzindene analog of prostacyclin, is currently under preclinical evaluation as a potential treatment for congestive heart failure. The cardiovascular effects of 15AU81 were evaluated in anesthetized beagle dogs given 4-h infusions at rates of either 0.1, 0.3, 1.0, or 3.0 micrograms/kg/min. Plasma samples taken from these dogs prior to, during, and after the infusion, were analyzed for 15AU81 by a radioimmunoassay (RIA). This report integrates the vasodilatory effects and plasma concentration data from the 15AU81 infusion study. Pharmacokinetic analysis of mean data indicated a biphasic decay of 15AU81 in plasma, with an initial half-life of approximately 2 min, and a terminal half-life of approximately 20 min. Visual inspection of plots of drug effect and drug concentration against time indicated a close relationship between plasma concentration of 15AU81 and the onset of decreases in total peripheral resistance (TPR) and pulmonary vascular resistance (PVR). In general, the decreases in TPR and PVR induced by 15AU81 were maintained during infusion. Concentration-effect plots indicated some hysteresis in TPR vs plasma concentrations of 15AU81 after termination of the infusion; possible explanations for this hysteresis include the presence of saturating concentrations of 15AU81 at the effect site, with a delay in the clearance of 15AU81 from the effect site compared to its clearance from plasma, and/or the presence of active metabolites at the effect site. A fit of the TPR and PVR data to the Emax pharmacodynamic model predicted that the maximum decrease in TPR achievable with 15AU81 in anesthetized dogs was 66%, and that the concentration of 15AU81 producing 50% of the maximum effect (EC50) was 8.6 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Division of Pharmacokinetics and Drug Metabolism, Wellcome Research Laboratories, Burroughs Wellcome Co, Research Triangle Park, NC 27709.
authors.forename: M J
authors.initials: MJ
authors.lastname: McNulty
authors.forename: J M
authors.initials: JM
authors.lastname: Sailstad
authors.forename: R P
authors.initials: RP
authors.lastname: Steffen
mesh_terms: D000818:Animals; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004285:Dogs; D005260:Female; D006207:Half-Life; D007262:Infusions, Intravenous; D008297:Male; D011453:Prostaglandins / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011465:Prostaglandins, Synthetic; D011652:Pulmonary Circulation / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D002317:Cardiovascular Agents; D011453:Prostaglandins; D011465:Prostaglandins, Synthetic; C054809:U 62840