Duration of activity of the acid, methyl ester and amide of an orally active platelet aggregation inhibitory prostanoid in the rat

The prostanoid 3-oxa-4,5,6-trinor-3,7-inter--phenylene PGE₁ (OI-PGE₁) has been shown to be a more potent inhibitor of ADP-induced human platelet aggregation than PGE₁. OI-PGE₁ inhibits ex vivo ADP-induced platelet aggregation for 60 minutes after an oral dose of 20 mg/kg to rats. Present studies compare duration of ex vivo inhibition to ADP-induced platelet aggregation in the rat by OI-PGE₁, its methyl ester and amide after administration by various routes. All oral (p.o.) and intraduodenal (i.d.) doses were 20 mg/kg and all intravenous (i.v.) doses were 1 mg/kg. OI-PGE₁ and its methyl ester had the same duration of activity after i.v. (60 min.) and p.o. (60 min.) administration, however, the methyl ester, when administered i.d., had a longer duration of activity than the free acid i.d. (>90 min. vs. 60 min.). OI-PGE₁-amide had significantly longer duration than the acid or methyl ester after i.v. (>120 min.), p.o. (>240 min.) or i.d. (>240 min.) administration. Present data suggest that in the rat (1) intestinal absorption of OI-PGE₁-methyl ester is more efficient than it is for the free acid and (2) due to metabolic and/or distributional differences between OI-PGE₁ and its amide, the amide has a much greater duration of activity.