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

doi:10.1016/S0002-9343(98)00091-6

The American Journal of Medicine

Volume 104, Issue 5, May 1998, Pages 413-421

https://doi.org/10.1016/S0002-9343(98)00091-6 Get rights and content

Abstract

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.

Section snippets

Materials and methods

Prior to enrollment of study subjects, this study was approved by the Human Studies Subcommittee of the Dallas Department of Veterans Affairs Medical Center.

We enrolled 16 nonsmoking healthy volunteers (6 men and 10 nonpregnant women) between the ages of 23 and 46 years. None had a history of peptic ulcer, gastrointestinal surgery (except for appendectomy), NSAID use in the past 2 weeks, chronic upper gastrointestinal symptoms, or use of histamine H₂-receptor antagonists, proton pump

Statistical analysis

To determine correlations between drug IC₅₀s in whole blood assays and gastric mucosal assays, Spearman’s rank-correlation coefficient and Pearson’s coefficient of correlation were used (22). P values less than 0.05 were considered statistically significant.

Results

For the 25 study drugs, IC₅₀s for inhibition in the COX-1 exclusive whole blood assay (platelet-generated serum thromboxane B₂ synthesis) are ranked in Table 2. All but two of the drugs (salicylic acid and salsalate) inhibited COX-1 at the concentrations tested in this study. Ketoprofen had the lowest IC₅₀ (0.11 μM) and was thus the most potent COX-1 inhibitor in blood. The range in potency of COX-1 inhibition varied at least 1,000-fold among the 25 drugs.

All 25 drugs tested also inhibited

Discussion

We have conducted a comprehensive analysis of the COX-1 versus COX-2 effects of NSAIDs in healthy volunteers. Our results regarding COX-selectivity can be compared with those of previous reports using nonhuman cells 14., 16.. We found that two agents, indomethacin and piroxicam, that were quite COX-1 selective for murine COX, were essentially nonselective for COX in human blood (Table 3). Likewise, 6-MNA was sevenfold selective for murine COX-2, but only onefold to twofold for human COX-2.

Acknowledgements

The authors wish to thank Kristi Rushin, Libby McAllister, and Mary Walker for expert technical assistance, Vicky Robertson for help with manuscript preparation, and Dr. Stuart Spechler for thoughtful comments regarding the manuscript. Part of this work was presented at the Annual Meeting of the American Gastroenterological Association in Washington, DC, in May, 1997.

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^☆: Supported by a Merit Review Grant from the Department of Veterans Affairs and Southland Financial Corporation Distinguished Chair in Geriatrics.

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

Abstract

Section snippets

Materials and methods

Statistical analysis

Results

Discussion

Acknowledgements

J Biol Chem

J Biol Chem

Cell

Gastroenterology

Cell

J Biol Chem

Eur J Pharm

Gastroenterology

Am J Med

J Biol Chem

J Biol Chem

J Biol Chem

Gastroenterology

Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mRNA splicing

Proc Natl Acad Sci

The x-ray crystal structure of the membrane protein prostaglandin H2 synthase-1

Nature

Prostaglandin H synthase isoenzyme selectivitythe potential for safer nonsteroidal antiinflammatory drugs

Am J Med

Expression of the murine prostaglandin H synthase-1 and prostaglandin H synthase-2 isozymes in COX-1 cells

J Lipid Mediators

Prostaglandin endoperoxide synthasewhy two isoforms?

Am J Physiol

Lipopolysaccharide induces prostaglandin H synthase-2 protein and mRNA in human alveolar macrophages and blood monocytes

J Clin Invest

Expression of cyclooxygenase-2 in human gastric carcinoma

Cancer Res

Pharmacology of a selective cyclooxygenase-2 inhibitor, L-745,337a novel nonsteroidal anti-inflammatory agent with an ulcerogenic sparing effect in rat and nonhuman primate stomach

J Pharmacol Exp Ther

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

The x-ray crystal structure of the membrane protein prostaglandin H₂ synthase-1