Hydrolysis of an orally active platelet inhibitory prostanoid amide in the plasma of several species.
The prostanoid 3-oxa-4,5,6-trinor-3,7-inter-m-phenylene-PGE1-amide (OI-PGE1-amide) has a prolonged duration of oral platelet aggregation inhibitory activity when compared to the parent free acid (OI-PGE1) in the rat. When incubated in rat plasma at 1 microgram/ml for 30 seconds prior to addition of ADP, OI-PGE1-amide inhibits in vitro rat platelet aggregation approximately 50%. OI-PGE1 inhibits at 1 ng/ml. Inhibition of platelet aggregation by plasma incubated with OI-PGE1-amide (1 microgram/ml) increases with time and the rate of this increase differs with species. Incubation of OI-PGE1 in plasma does not result in an increase of platelet inhibitory activity with time. The increase of platelet inhibitory activity was assumed to indicate hydrolysis of OI-PGE1-amide to the more active OI-PGE1. A compound, different from OI-PGE1-amide, was isolated by an ion exchange/silica gel separation sequence from an incubation of OI-PGE1-amide in rat plasma. It had potent platelet aggregation inhibitory activity. This material was shown to be OI-PGE1 by thin-layer chromatography, gas chromatography and mass spectral analysis. Studies with [3H]-OI-PGE1-amide confirmed the formation of OI-PGE1 in plasma incubations. Amide hydrolytic activity was significantly different between species, the rank order being: rat greater than guine pig greater than monkey = human greater than dog. This relationship corresponded with that determined by measuring the increase in platelet inhibitory activity with time in plasma incubations of OI-PGE1-amide reported above. Present data indicate that (a) OI-PGE1-amide is hydrolyzed to the parent acid by plasma enzymes of several species and (b) hydrolytic activity of plasma varies widely between species.
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000527:Alprostadil / Q000031:analogs & derivatives*; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D002855:Chromatography, Thin Layer; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D000882:Haplorhini; D006801:Humans; D006868:Hydrolysis; D008252:Macaca fascicularis / Q000097:blood; D008253:Macaca mulatta / Q000097:blood; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects*; D011458:Prostaglandins E / Q000138:chemical synthesis; D011459:Prostaglandins E, Synthetic / Q000097:blood / Q000494:pharmacology*; D051381:Rats; D013045:Species Specificity
C025014:3-oxa-4,5,6-nor-(3,7-inter)-3-phenyleneprostaglandin E1 methyl ester; C025013:3-oxa-4,5,6-nor-3,7-inter-3-phenyleneprostaglandin E1; C025007:3-oxa-4,5,6-trinor-3,7-inter-3-phenyleneprostaglandin E1 amide; D011458:Prostaglandins E; D011459:Prostaglandins E, Synthetic; D000244:Adenosine Diphosphate; D000527:Alprostadil