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Inhibition of prostacyclin and thromboxane biosynthesis in healthy volunteers by single and multiple doses of acetaminophen and indomethacin
Author(s) -
Schwartz Jules I.,
Musser Bret J.,
Tanaka Wesley K.,
Taggart William V.,
Mehta Anish,
Gottesdiener Keith M.,
Greenberg Howard E.
Publication year - 2015
Publication title -
clinical pharmacology in drug development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.711
H-Index - 22
eISSN - 2160-7648
pISSN - 2160-763X
DOI - 10.1002/cpdd.194
Subject(s) - acetaminophen , medicine , excretion , prostacyclin , metabolite , pharmacology , placebo , thromboxane , crossover study , cyclooxygenase , thromboxane a2 , endocrinology , chemistry , platelet , enzyme , biochemistry , alternative medicine , pathology
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.