Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs.
OBJECTIVE
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.


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 microM (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.


CONCLUSIONS
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.
Cryer
B
B
Department of Medicine, Dallas Department of Veterans Affairs Medical Center, Texas 75216, USA.
Feldman
M
M
D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000097:blood / Q000494:pharmacology*; D001706:Biopsy; D016861:Cyclooxygenase Inhibitors / Q000097:blood / Q000494:pharmacology*; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D005750:Gastric Juice / Q000737:chemistry; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007536:Isomerism; D008297:Male; D008875:Middle Aged; D010437:Peptic Ulcer / Q000139:chemically induced; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry / Q000187:drug effects*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone