Dose-Related Kinetics of Aspirin

TLDR

Oral low‑dose aspirin has poor systemic bioavailability, which may explain its selective inhibition of thromboxane A2, while systemic absorption is required to inhibit prostacyclin synthesis and presystemic platelet inhibition can occur. The study compared plasma concentration–time curves of orally administered unlabeled aspirin and intravenously infused deuterium‑labeled aspirin in five volunteers to estimate oral bioavailability. Oral bioavailability was 46–51 % across 20–1300 mg doses, was unchanged with chronic 325 mg dosing, and thromboxane B2 was reduced 39 % before systemic aspirin appeared, supporting presystemic platelet inhibition and suggesting that slow, very low dosing enhances biochemical selectivity. N Engl J Med 1984; 311:1206–11.

Abstract

When aspirin is administered by mouth in low doses, poor systemic bioavailability may contribute to its apparent dose-related "selective inhibition" of THROMBOXANE A2 formation. Systemic bioavailability of orally administered aspirin is necessary to inhibit prostacyclin synthesis by systemic vascular endothelium, whereas cumulative inhibition of thromboxane A2 formation by platelets may occur in the presystemic (portal) circulation. We simultaneously administered unlabeled aspirin orally and deuterium-labeled aspirin intravenously in five healthy volunteers. This permitted an estimation of the bioavailability of an oral dose from the ratio of plasma drug concentration–time curves for the labeled and the unlabeled species. Systemic bioavailability ranged from 46 to 51 per cent of single oral doses of 20, 40, 325, and 1300 mg of aspirin. Bioavailability was similar after single-dose and long-term oral administration of 325 mg. Thromboxane B2 formation in serum ex vivo after oral administration of 20 mg of unlabeled aspirin was reduced 39 per cent before aspirin was detected in the systemic circulation. Furthermore, incubation of simulated peak plasma aspirin concentrations in whole blood in vitro underestimated the inhibition of thromboxane B2 ex vivo after oral administration of 20 or 40 mg of unlabeled aspirin. These data are consistent with presystemic inhibition of platelets by aspirin and suggest that biochemical "selectivity" might be enhanced by slow administration of very low doses of aspirin, thereby optimizing conditions for cumulative, presystemic acetylation of platelet cyclooxygenase and inhibition of thromboxane formation. (N Engl J Med 1984; 311:1206–11.)