Inhibition of prostacyclin and thromboxane biosynthesis in healthy volunteers by single and multiple doses of acetaminophen and indomethacin. Issue 5 (17th July 2015)

• Record Type: Journal Article
• Authors: Schwartz, Jules I.; Musser, Bret J.; Tanaka, Wesley K.; Taggart, William V.; Mehta, Anish; Gottesdiener, Keith M.; Greenberg, Howard E.
• Is Part Of: Clinical pharmacology in drug development. Volume 4:Issue 5(2015:Sep./Oct.)
• Page Start: 337
• Page End: 345
• Publication Date: 2015-07-17
• Subjects: Drugs -- Testing -- Periodicals; Drug development -- Periodicals; Clinical pharmacology -- Periodicals; 615.580724
• DOI: 10.1002/cpdd.194
• Languages: English
• ISSNs: 2160-7648

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <sec id="cpdd194-sec-0001" sec-type="section"> <p>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<sub>2</sub> (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 (<italic>P</italic> = .004 vs placebo). PGI‐M excretion inhibition after 1 dose was similar for indomethacin and acetaminophen, but significantly greater with indomethacin after multiple doses (<italic>P</italic> = .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 (<italic>P</italic> ≤ .003). Indomethacin reduced Tx‐M excretion significantly more than acetaminophen and placebo after single and multiple doses (<italic>P</italic> ≤ .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.</p> </sec> </abstract>