Biochemical selectivity of oral versus intravenous aspirin in rats. Inhibition by oral aspirin of cyclooxygenase activity in platelets and presystemic but not systemic vessels.

Abstract

In rats intravenous aspirin was only slightly more effective an inhibitor of platelet thromboxane B2 (TxB2) than of aorta 6-keto-prostaglandin (PGF)1. generation (1.9 versus 2.1 mg/kg).In contrast, oral aspirin was about five times more effective on platelet than on aorta cyclooxygenase activity. The "biochemical selectivity" of aspirin as an inhibitor of platelet and vascular cyclooxygenase thus was not apparent after intravenous administration ofthe drug. However, this could be achieved by relatively low doses of oral (or intraduodenal) aspirin, on account of "presystemic" acetylation of platelet cyclooxygenase. Even in this condition, though, aspirin selectivity was relative to "systemic" peripheral vessels but not to the vessels of the enterohepatic circulation. Indeed after an oral or intraduodenal dose of 5 mg/ kg aspirin, genertion of portal vein 6-keto-PGFI. was inhibited to much the same extent as platelet TxB2, while inferior vena cava 6-keto-PGFIa formation was spared.

Selective Inhibition of Cyclooxygenase-2 Enhances Platelet Adhesion in Hamster Arterioles In Vivo

“…It is not surprising that aspirin, when given intravenously as in our experiments, equally affected platelet and vascular Cox activities, because aspirin only becomes a rather selective platelet Cox-1 inhibitor when given orally at low doses. 21 The assumption that Cox-2 blockade exerted its proadhesive effect by decreasing endothelial prostacyclin synthesis is supported by findings showing that selective inhibitors of Cox-2 exert neither inhibitory 9,22,23 nor augmenting 24 effects on platelet aggregation ex vivo, suggesting that the enhanced platelet adhesion in our study is unlikely to be due to direct effects of NS-398 on platelets. The latter is further substantiated by a lack of NS-398 effects after pretreatment of the platelets with iloprost.…”

Pharmacokinetics and pharmacodynamics of acetylsalicylic acid after intravenous and oral administration to healthy volunteers

“…An intravenous or oral dose of ASA 5 mg/kg administered to rats resulted in comparable inhibition of portal vein 6-keto-PGF 1α and thromboxane B 2 , but formation of inferior vena cava 6-keto-PGF 1α was spared 5. In humans, administration of intravenous or oral ASA 1 g was found to completely suppress serum thromboxane B 2 , but urinary thromboxane B 2 and 6-keto-PGF 1α were also suppressed by intravenous ASA 10,17.…”

“…Thus intravenous administration likely offers a means of achieving rapid inhibition of platelet function in an emergency setting. However, there are only a few studies that have compared intravenous ASA and oral ASA, and these were performed in animal models 5,9. Human data are even more scarce and have used doses (ASA 1 g/day intravenously or orally) that are not recommended as atherothrombotic prophylaxis 10…”

Differential effect of aspirin on thromboxane and prostaglandin biosynthesis in man.

“…Following ingestion, the concentration of aspirin is therefore anticipated to be much greater in portal than in systemic blood, whereas the concentration of salicylate is much greater than that of aspirin in systemic venous blood (Seymour & Rawlins, 1982). Prolonged inhibition of platelet thromboxane production could be explained by irreversible acetylation of platelet cyclo-oxygenase by aspirin during transit of the platelets through the portal circulation (Pedersen & FitzGerald, 1984;Cerletti et al, 1986;Ritter et al, 1987b), whereas transient inhibition of bradykinin-stimulated PGI2 biosynthesis could be caused by reversible inhibition by salicylate of cyclo-oxygenase in the systemic vasculature. Recovery from such inhibition would occur as salicylate is eliminated by the kidneys.…”