Cyclooxygenase-1 and Cyclooxygenase-2 Selectivity of Widely Used Nonsteroidal Anti-Inflammatory Drugs

  • Byron Cryer
    Requests for reprints should be addressed to Byron Cryer, MD, Gastroenterology (111B1), Dallas VA Medical Center, 4500 S. Lancaster Rd., Dallas, Texas 75216
    Department of Medicine, Dallas Department of Veterans Affairs Medical Center and University of Texas Southwestern Medical School, Dallas, Texas, USA
    Search for articles by this author
  • Mark Feldman
    Department of Medicine, Dallas Department of Veterans Affairs Medical Center and University of Texas Southwestern Medical School, Dallas, Texas, USA
    Search for articles by this author


      Purpose: Both isoforms of cyclo-oxygenase, COX-1 and COX-2, are inhibited to varying degrees by all of the available nonsteroidal anti-inflammatory drugs (NSAIDs). Because inhibition of COX-1 by NSAIDs is linked to gastrointestinal ulcer formation, those drugs that selectively inhibit COX-2 may have less gastrointestinal toxicity. We measured the extent to which NSAIDs and other anti-inflammatory or analgesic drugs inhibit COX-1 and COX-2 in humans.
      Subjects and Methods: Aliquots of whole blood from 16 healthy volunteers were incubated ex vivo with 25 antiinflammatory or analgesic drugs at six concentrations ranging from 0 (control) to 100 μM (n = 5 for each). Blood was assayed for serum-generated thromboxane B2 synthesis (COX-1 assay) and for lipopolysaccharide-stimulated prostaglandin E2 synthesis (COX-2 assay). In addition, gastric biopsies from the same volunteers were incubated with each drug ex vivo and mucosal prostaglandin E2 synthesis measured.
      Results: Inhibitory potency and selectivity of NSAIDs for COX-1 and COX-2 activity in blood varied greatly. Some NSAIDs (eg, flurbiprofen, ketoprofen) were COX-1 selective, some (eg, ibuprofen, naproxen) were essentially nonselective, while others (eg, diclofenac, mefenamic acid) were COX-2 selective. Inhibitory effects of NSAIDs on gastric prostaglandin E2 synthesis correlated with COX-1 inhibitory potency in blood (P <0.001) and with COX-1 selectivity (P <0.01), but not with COX-2 inhibitory potency. Even COX-2 “selective” NSAIDs still had sufficient COX-1 activity to cause potent inhibitory effects on gastric prostaglandin E2 synthesis at concentrations achieved in vivo.
      Conclusion: No currently marketed NSAID, even those that are COX-2 selective, spare gastric COX activity at therapeutic concentrations. Thus, all NSAIDs should be used cautiously until safer agents are developed.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to The American Journal of Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Xie W.
        • Chipman J.G.
        • Robertson D.L.
        • et al.
        Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing.
        Proc Natl Acad Sci. 1991; 88: 2692-2696
        • Kujubu D.A.
        • Fletcher B.S.
        • Varnum B.C.
        • et al.
        TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue.
        J Biol Chem. 1991; 266: 12866-12872
        • Picot D.
        • Loll P.J.
        • Garavito R.M.
        The x-ray crystal structure of the membrane protein prostaglandin H2 synthase-1.
        Nature. 1994; 367: 243-249
        • DeWitt D.L.
        • Meade E.A.
        • Smith W.L.
        Prostaglandin H synthase isoenzyme selectivity.
        Am J Med. 1993; 95: 40S-46S
        • Meade E.A.
        • Smith W.L.
        • DeWitt D.L.
        Expression of the murine prostaglandin H synthase-1 and prostaglandin H synthase-2 isozymes in COX-1 cells.
        J Lipid Mediators. 1993; 6: 119-129
        • Williams C.S.
        • Dubois R.N.
        Prostaglandin endoperoxide synthase.
        Am J Physiol. 1996; 270: G393-G400
        • Morita I.
        • Schindler M.
        • Reginaler M.K.
        • et al.
        Different intracellular locations for prostaglandin endoperoxide H synthase-1 and -2.
        J Biol Chem. 1995; 270: 10902-10908
        • Morham S.G.
        • Langenbach R.
        • Loftin C.D.
        • et al.
        Prostaglandin synthase-2 gene disruption causes severe renal pathology in the mouse.
        Cell. 1995; 83: 473-482
        • Hempel S.L.
        • Monick M.M.
        • Hunninghake G.W.
        Lipopolysaccharide induces prostaglandin H synthase-2 protein and mRNA in human alveolar macrophages and blood monocytes.
        J Clin Invest. 1994; 93: 391-396
        • Kargman S.
        • Charleson S.
        • Cartwright M.
        • et al.
        Characterization of prostaglandin G/H synthase 1 and 2 in rat, dog, monkey, and human gastrointestinal tracts.
        Gastroenterology. 1996; 111: 445-454
        • Ristimaki A.
        • Honkanen N.
        • Jankala H.
        • et al.
        Expression of cyclooxygenase-2 in human gastric carcinoma.
        Cancer Res. 1997; 57: 1276-1280
        • Chan C.
        • Boyce S.
        • Brideau C.
        • et al.
        Pharmacology of a selective cyclooxygenase-2 inhibitor, L-745,337.
        J Pharmacol Exp Ther. 1995; 274: 1531-1537
        • Langenbach R.
        • Morham S.G.
        • Tiano H.F.
        • et al.
        Prostaglandin synthase 1 gene disruption in mice reduces arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration.
        Cell. 1995; 83: 483-492
        • Meade E.A.
        • Smith W.L.
        • DeWitt D.L.
        Differential inhibition of prostaglandin endoperoxide synthase (cyclooxygenase) isozymes by aspirin and other non-steroidal anti-inflammatory drugs.
        J Biol Chem. 1993; 268: 6610-6614
        • Glaser K.
        • Sung M.
        • O’Neil K.
        Etodolac selectively inhibits human prostaglandin G/H synthase 2 (prostaglandin HS-2) versus human prostaglandin HS-1.
        Eur J Pharm. 1995; 281: 107-111
        • Mitchell J.A.
        • Akarasereenont P.
        • Thiemermann C.
        • et al.
        Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase.
        Proc Natl Acad Sci. 1994; 90: 11693-11697
        • Laneuville O.
        • Breuer D.K.
        • DeWitt D.L.
        • et al.
        Differential inhibition of human prostaglandin endoperoxide H synthase-1 and -2 by nonsteroidal anti-inflammatory drugs.
        J Pharmacol Exp Ther. 1994; 271: 927-934
        • Patrignani P.
        • Panara M.R.
        • Greco A.
        • et al.
        Biochemical and pharmacological characterization of the cyclooxygenase activity of human blood prostaglandin endoperoxide synthases.
        J Pharmacol Exp Ther. 1994; 271: 1705-1712
        • Brideau C.
        • Kargman S.
        • Liu S.
        • Dallob A.L.
        A human whole blood assay for clinical evaluation of biochemical efficacy of cyclooxygenase inhibitors.
        Inflamm Res. 1996; 45: 68-74
        • Lee M.
        • Feldman M.
        Nonessential role of leukotrienes as mediators of acute gastric mucosal injury induced by aspirin in rats.
        Dig Dis Sci. 1992; 37: 1282-1287
        • Redfern J.S.
        • Lee E.
        • Feldman M.
        Effect of indomethacin on gastric mucosal prostaglandins in humans. Correlation with mucosal damage.
        Gastroenterology. 1987; 92: 969-977
      1. Colton T. Statistics in Medicine. Boston, Mass: Little, Brown and Co.; 1974.

        • Piper R.M.
        • Ray W.A.
        • Daugherty J.R.
        • Griffin M.R.
        Corticosteroid use and peptic ulcer disease.
        Ann Intern Med. 1991; 114: 735-740
      2. Physicians’ Desk Reference. 51st ed. Montvale, NJ: Medical Economics Co. 1997.

        • Insel P.A.
        Analgesic-antipyretics and antiinflammatory agents.
        in: Gillman A.G. Rall T.W. Nies A.S. Taylor P. Goodman and Gillman’s The Pharmacological Basis of Therapeutics. 8th ed. Pergamon Press, New York1990: 638-681
        • Crook P.R.
        • Willis J.V.
        • Kendall M.J.
        • et al.
        The pharmacokinetics of diclofenac sodium in patients with active rheumatoid disease.
        Eur J Clin Pharmacol. 1982; 21: 331-334
        • Small R.E.
        • Cox S.R.
        • Adams W.J.
        Influence of H2 receptor antagonists on the disposition of flurbiprofen enantiomers.
        J Clin Pharmacol. 1990; 30: 660-664
        • Davies E.F.
        • Avery G.S.
        Drugs. 1971; 2: 416-446
        • Hundal O.
        • Rugstad H.E.
        • Husby G.
        Naproxen free plasma concentrations and unbound fractions in patients with osteoarthritis.
        Therapeut Drug Monitor. 1991; 13: 478-484
        • Olive G.
        • Rey E.
        Effect of age and disease on the pharmacokinetics of nimesulide.
        Drugs. 1993; 46: 73-78
        • Duggan D.E.
        • Hare L.E.
        • Ditzler C.A.
        The disposition of sulindac.
        Clin Pharmacol Ther. 1977; 21: 326-335
        • Friedel H.A.
        • Todd P.A.
        Drugs. 1988; 35: 504-524
        • McMahon F.G.
        • Vargas R.
        • Ryan J.R.
        • Fitts D.A.
        Nabumetone kinetics in the young and elderly.
        Am J Med. 1987; 83: 92-95
        • DeWitt D.L.
        • El-Harith A.
        • Kraemer S.A.
        • et al.
        The aspirin and heme-binding sites of ovine and murine prostaglandin endoperoxide synthases.
        J Biol Chem. 1990; 265: 5192-5198
        • Shimokawa T.
        • Smith W.L.
        Prostaglandin endoperoxide synthase. The aspirin acetylation regastrointestinalon.
        J Biol Chem. 1992; 267: 12387-12392
        • Lecomte M.
        • Laneuville O.
        • Ji C.
        • et al.
        Acetylation of human prostaglandin endoperoxide synthase-2 (cyclooxygenase-2) by aspirin.
        J Biol Chem. 1994; 269: 13207-13215
        • Cryer B.
        • Goldschmiedt M.
        • Redfern J.S.
        • Feldman M.
        Comparison of salsalate and aspirin on mucosal injury and gastroduodenal mucosal prostaglandins.
        Gastroenterology. 1990; 99: 1616-1621
        • Graham D.Y.
        • Smith J.L.
        • Holmes G.I.
        • Davies R.O.
        Nonsteroidal anti-inflammatory effect of sulindac sulfoxide and sulfide on gastric mucosa.
        Clin Pharmacol Ther. 1985; 38: 65-70
        • Henry D.
        • Lim L.L.
        • Garcia-Rodriguez L.A.
        • et al.
        Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs.
        BMJ. 1996; 312: 1563-1566
        • Willkens R.F.
        An overview of the long-term safety experience of nabumetone.
        Drugs. 1990; 40: 34-37
        • Lanza F.
        • Simon T.
        • Quan H.
        • et al.
        Selective inhibition of cyclooxygenase-2 (COX-2) with MK-0966 (250 mg q.d.) is associated with less gastroduodenal damage than aspirin (ASA) 650 mg q.i.d. or ibuprofen (IBU) 800 mg t.i.d.
        Gastroenterology. 1997; 112: A194
        • Lanza F.L.
        • Rack M.F.
        • Callison D.A.
        • et al.
        A pilot endoscopic study of the gastroduodenal effects of SC-5835, a novel COX-2-selective inhibitor.
        Gastroenterology. 1997; 112: A194