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 B 2 (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.