RT Journal Article
SR Electronic
T1 Selectivity of oral aspirin as an inhibitor of platelet vs. vascular cyclooxygenase activity is reduced by portacaval shunt in rats.
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 287
OP 290
VO 245
IS 1
A1 M C Gambino
A1 S Passaghe
A1 Z M Chen
A1 F Bucchi
A1 G Gori
A1 R Latini
A1 G de Gaetano
A1 C Cerletti
YR 1988
UL http://jpet.aspetjournals.org/content/245/1/287.abstract
AB Oral aspirin can be extensively hydrolyzed to salicylate in the stomach and liver before it enters the systemic circulation. "Presystemic" acetylation of platelets may thus occur during aspirin absorption. This may result in concomitant sparing of peripheral vascular cyclooxygenase mainly exposed to salicylate. We tested whether the "biochemical selectivity" of p.o. aspirin as an inhibitor of platelet rather than vascular cyclooxygenase was reduced by elimination of the "first-pass" hepatic metabolism. A portacaval shunt was inserted in anesthetized rats by connecting the portal vein to the inferior vena cava through a heparinized polyethylene "Y" cannula. Sham-operated rats acted as controls. Ninety minutes after recovery from anesthesia rats were given aspirin p.o. (10 mg/kg) and 45 min later serum thromboxane B2 and 6-keto-prostaglandin F1 alpha formation by vascular rings was evaluated by radioimmunoassay. Serum thromboxane B2 was almost suppressed completely in all animals; vascular 6-ketoprostaglandin F1 alpha was reduced significantly (by 40-60% in aorta and vena cava) in rats with the portacaval shunt but not in sham-operated animals. The results in rats with the shunt were similar to those obtained previously after i.v. aspirin. Fifteen minutes after aspirin, plasma levels of unmetabolized drug measured by high-pressure liquid chromatography were significantly higher in rats with portacaval shunt (0.56 +/- 0.16 micrograms/ml; n = 5) than in sham-operated controls (0.16 +/- 0.02 micrograms/ml; n = 5). These findings support directly the role of first-pass hepatic metabolism in the "biochemical selectivity" of p.o. aspirin.