Inhibition of prostacyclin and thromboxane biosynthesis in healthy volunteers by single and multiple doses of acetaminophen and indomethacin

This double-blind, randomized crossover study assessed the effect of acetaminophen (1000 mg every 8 hours) versus indomethacin (50 mg every 8 hours) versus placebo on cyclooxygenase enzymes (COX-1 and COX-2). Urinary excretion of 2,3-dinor-6-keto-PGF1α, (prostacyclin metabolite, PGI-M; COX-2 inhibition) and 11-dehydro thromboxane B2 (thromboxane metabolite, Tx-M; COX-1 inhibition) were measured after 1 dose and 5 days of dosing. Peak inhibition of urinary metabolite excretion across 8 hours following dosing was the primary end point. Mean PGI-M excretion was 33.7%, 55.9%, and 64.6% on day 1 and 49.4%, 65.1%, and 80.3% on day 5 (placebo, acetaminophen, and indomethacin, respectively). Acetaminophen and indomethacin inhibited PGI-M excretion following single and multiple doses (P = .004 vs placebo). PGI-M excretion inhibition after 1 dose was similar for indomethacin and acetaminophen, but significantly greater with indomethacin after multiple doses (P = .006). Mean Tx-M excretion was 16.2%, 45.2%, and 86.6% on day 1 and 46.2%, 58.4%, and 92.6% on day 5 (placebo, acetaminophen, and indomethacin, respectively). Tx-M excretion inhibition following 1 dose was reduced by acetaminophen (P ≤ .003). Indomethacin reduced Tx-M excretion significantly more than acetaminophen and placebo after single and multiple doses (P ≤ .001). Acetaminophen and indomethacin inhibited COX-1 and COX-2 following a single dose, but acetaminophen was a less potent COX-1 inhibitor than indomethacin.