Automated-extraction, high-performance liquid chromatographic method and pharmacokinetics in rats of a highly A2-selective adenosine agonist, CGS 21680.
CGS 21680 (2-[p-(2-carboxyethyl)phenylethylamino]-5'-N- ethylcarboxamidoadenosine, I) is a highly A2-selective (A2/A1 = 140), high-affinity adenosine agonist. A method has been devised to extract the compound from biological matrices with automated solid-phase extraction using C18 bonded silica columns. This is followed by reversed-phase, paired-ion chromatography on a Supelco LC-18-S column with fluorescence detection. The limit of quantitation is 5 ng/ml, but 1 ng/ml (five times the signal-to-noise ratio) can readily be detected. Tritium-labeled compound was used to study the pharmacokinetics in rats. After an intravenous dose of 0.3 mg/kg, biphasic elimination kinetics were observed for parent I, characterized by half-lives of 1.8 min (distribution) and 15 min (elimination). The volume of distribution in the terminal phase (V beta) was low (0.27 l/kg) and plasma clearance was moderate (0.83 l/kg/h). Although the compound was rapidly absorbed (mean Tmax = 13 min), low concentrations (mean Cmax = 94 ng/ml) were observed after an oral dose of 3.0 mg/kg, and bioavailability was only approximately 1.4%. Radioactivity persisted in plasma longer than parent compound after either dose, but levels were too low for isolation and structure identification of drug-derived compounds.
Chovan
J P
JP
Research Department, CIBA-GEIGY Corporation, Ardsley, NY 10502.
Zane
P A
PA
Greenberg
G E
GE
D000241:Adenosine / Q000031:analogs & derivatives* / Q000097:blood / Q000302:isolation & purification / Q000493:pharmacokinetics; D000818:Animals; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D008297:Male; D010627:Phenethylamines / Q000097:blood* / Q000302:isolation & purification / Q000493:pharmacokinetics; D051381:Rats; D011919:Rats, Inbred Strains; D011983:Receptors, Purinergic / Q000032:analysis* / Q000187:drug effects; D012015:Reference Standards
D010627:Phenethylamines; D011983:Receptors, Purinergic; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D000241:Adenosine