Radioimmunoassay for the chemical stable prostacyclin analog, 15AU81: a preliminary pharmacokinetics study in the dog.
15AU81 is a chemically stable tricyclic benzindene analog of prostacyclin, with possible application to the treatment of congestive heart failure. Effective pharmacological doses in a dog model are in the microgram to sub-microgram/kg range, necessitating an analytical method of high sensitivity for determination of the drug in plasma. This report describes the development and validation of a radioimmunoassay for 15AU81, and its application to a pharmacokinetic study in the beagle dog. An antiserum elicited by immunization with a 15AU81-bovine thyroglobulin conjugate was employed, along with 3H-15AU81, in the radioimmunoassay. Analogs of 15AU81, as well as a glucuronide metabolite produced by a dog liver subcellular fraction in vitro, were used to demonstrate the specificity of the radioimmunoassay. Specificity was confirmed by comparative analysis by radioimmunoassay and by a quantitative GC/MS procedure of plasma samples from dogs dosed with 15AU81. The limit of quantitation in dog plasma was 1.6 ng/ml; accuracy and precision were both acceptable. The assay was applied to a study of the pharmacokinetics of 15AU81 in the beagle dog after intravenous or intratracheal administration of a single 20-micrograms/kg dose. Following intravenous dosing, 15AU81 was eliminated rapidly from plasma (t1/2, 2.8 min), while after intratracheal administration, clearance appeared to be somewhat slower and bioavailability was appreciable (mean, 46%), suggesting that this route of administration may be worthy of further evaluation.
Findlay
J W
JW
Division of Pharmacokinetics and Drug Metabolism, Wellcome Research Laboratories, Burroughs Wellcome Co., Research Triangle Park, North Carolina 27709.
McNulty
M J
MJ
Page
T L
TL
Chang
S Y
SY
Sailstad
J M
JM
D000818:Animals; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D003429:Cross Reactions; D004285:Dogs; D008401:Gas Chromatography-Mass Spectrometry; D007275:Injections, Intravenous; D008297:Male; D011453:Prostaglandins / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D011465:Prostaglandins, Synthetic; D011863:Radioimmunoassay / Q000379:methods* / Q000706:statistics & numerical data; D012680:Sensitivity and Specificity; D014132:Trachea
D002317:Cardiovascular Agents; D011453:Prostaglandins; D011465:Prostaglandins, Synthetic; C054809:U 62840