Drug Insight: Cyclo-Oxygenase-2 Inhibitors--A Critical Appraisal

Burkhard Hinz; Bertold Renner; Kay Brune


Nat Clin Pract Rheumatol. 2007;3(10):552-560. 

In This Article

Pharmacokinetics of COX2 Inhibitors

COX2 inhibitors currently in use are the sulfonamide celecoxib, the methylsulfone etoricoxib and the phenylacetic acid derivative lumiracoxib. Of these, celecoxib is the only COX2 inhibitor available in the US. Another COX2 inhibitor, marketed in the European Union for treatment of postoperative pain, is parecoxib, an injectable prodrug of valdecoxib.

Pharmacological data of COX2 inhibitors used for oral treatment of arthritic pain are compiled in Table 1 . Differences in physicochemical characteristics are reflected in different pharmacokinetic behavior. Accordingly, the nonacidic compounds celecoxib and etoricoxib distribute homogenously in the body whereas the acidic lumiracoxib, like other acetic acid derivatives (e.g., diclofenac), distributes unequally to concentrate in blood, inflamed tissue, kidney and liver.[12] Owing to its very high lipophilicity, the absorption of celecoxib is relatively slow and incomplete; this compound undergoes considerable first pass metabolization (20–60% oral bioavailability) and its rate of elimination (t1/2 = 6–12 h approx.) seems to be highly variable.[13,14,15] Etoricoxib is eliminated from the body slowly (t1/2 = 20–26 h approx.) and is absorbed at a fast rate, which seems to cause its fast onset of action.[16]

Of the COX2 inhibitors, lumiracoxib has peculiar pharmacodynamic and pharmacokinetic features, which include having the highest selectivity towards COX2 in vitro and the shortest pharmacological half life (t1/2 = 2–6 h approx.). Lumiracoxib, being an amphiphilic molecule, persists for a long time in the synovial fluid, which might explain the long-lasting efficacy of this drug; patients with rheumatoid arthritis treated with lumiracoxib at 400 mg once daily for 7 days had approximately 3-fold higher steady-state concentrations of lumiracoxib in synovial fluid as compared with plasma.[17] As these kinetics of distribution are likely to extend the therapeutic action of lumiracoxib beyond that expected from plasma pharmacokinetics, the data support the use of lumiracoxib in a once-daily regimen for the treatment of rheumatoid arthritis. Administering lumiracoxib at 400 mg, however, exceeds considerably the dose necessary to inhibit COX2 at the time of maximal plasma concentration, implying that the long-lasting analgesic effect of lumiracoxib at therapeutic doses, administered once a day, might also be because administration of the drug at high doses translates into extended pharmacodynamic half life.

All COX2 inhibitors undergo oxidative drug metabolism by cytochrome P450 (CYP) enzymes. Celecoxib has been shown to inhibit the metabolism of the CYP2D6 substrate metoprolol, a widely used β-blocker.[14] This interaction might also interfere with the elimination of other CYP2D6 substrates, including sedatives, serotonin reuptake inhibitors, tricyclic antidepressants, and some neuroleptics. For lumiracoxib the major metabolic pathways involve oxidation of the 5-methyl group, or hydroxylation of its dihaloaromatic ring, or both. Major metabolites of lumiracoxib in plasma are the 5-carboxy, 4'-hydroxy and 4'-hydroxy-5-carboxy derivatives, of which only the 4'-hydroxy derivative is active and COX2 selective (about one third of its parent compound).[18]

On the basis of their diverse pharmacokinetics, use of different COX2 inhibitors in different clinical settings is recommended. Accordingly, the slow absorption and variable first pass metabolization of celecoxib limits its utility for treatment of acute pain. By contrast, etoricoxib seems promising for this indication particularly when prolonged action is required as in gouty arthritis and rheumatoid arthritis. Lumiracoxib seems promising for the treatment of acute osteoarthritic pain.


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