title: Inhibition of prostacyclin and thromboxane biosynthesis in healthy volunteers by single and multiple doses of acetaminophen and indomethacin.
abstract: 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.
authors.affiliation: Merck & Co., Inc., Whitehouse Station, NJ, USA.
authors.forename: Jules I
authors.initials: JI
authors.lastname: Schwartz
authors.affiliation: Merck & Co., Inc., Whitehouse Station, NJ, USA.
authors.forename: Bret J
authors.initials: BJ
authors.lastname: Musser
authors.affiliation: Merck & Co., Inc., Whitehouse Station, NJ, USA.
authors.forename: Wesley K
authors.initials: WK
authors.lastname: Tanaka
authors.affiliation: Merck & Co., Inc., Whitehouse Station, NJ, USA.
authors.forename: William V
authors.initials: WV
authors.lastname: Taggart
authors.affiliation: Merck & Co., Inc., Whitehouse Station, NJ, USA.
authors.forename: Anish
authors.initials: A
authors.lastname: Mehta
authors.affiliation: Merck & Co., Inc., Whitehouse Station, NJ, USA.
authors.forename: Keith M
authors.initials: KM
authors.lastname: Gottesdiener
authors.affiliation: Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA, USA.|Janssen Research and Development, LLC, Titusville, NJ, USA.
authors.forename: Howard E
authors.initials: HE
authors.lastname: Greenberg
mesh_terms: D015121:6-Ketoprostaglandin F1 alpha / Q000031:analogs & derivatives* / Q000652:urine; D000082:Acetaminophen / Q000008:administration & dosage* / Q000009:adverse effects; D000284:Administration, Oral; D000328:Adult; D015415:Biomarkers / Q000652:urine; D018592:Cross-Over Studies; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D007213:Indomethacin / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D015143:Philadelphia; D011446:Prospective Studies; D065667:Renal Elimination / Q000187:drug effects; D013929:Thromboxane B2 / Q000031:analogs & derivatives* / Q000652:urine; D055815:Young Adult
chemical_list: D015415:Biomarkers; D052246:Cyclooxygenase 2 Inhibitors; D000082:Acetaminophen; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; C028290:2,3-dinor-6-ketoprostaglandin F1alpha; C049235:11-dehydro-thromboxane B2; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D007213:Indomethacin
keywords: acetaminophen; clinical trial; cyclooxygenase enzymes; indomethacin; urinary prostanoids