COX-2 Selectivity - Part 5: Cyclooxygenase-2-Selective Inhibitors: Translating Pharmacology into Clinical Utility

Coxibs spare the beneficial activity of COX-1, that is, its role in the synthesis of prostaglandins important to the GI mucosa. This led to the idea that COX-1-sparing drugs are likely to be less ulcerogenic. Assays were developed in order to delineate the degree of selectivity a given NSAID may have for COX-1 or COX-2. This determination has become especially important for the newer coxibs.

There are in vitro as well as ex vivo methods to determine the 50% inhibitory concentration (IC50) of various NSAIDs and coxibs for each enzyme (Figure 3).(30) The results of in vitro assays, which rely on recombinant enzymes, are useful for drug screening but are difficult to interpret and are sometimes contradictory. This may be due to factors like enzyme and substrate used, incubation periods, and other experimental variables. Whole-blood assays (ex vivo), which use whole blood from healthy adults, are the most widely accepted for the determination of COX selectivity.

Activity of COX-1 is determined by measuring thromboxane B2 synthesis by platelets in whole blood. For COX-2, activity is measured as the synthesis of PGE2 in whole blood. The use of ex vivo assays is most successful when tests are highly standardized and results are based on large numbers of subjects, as variation between individuals may be as high as 20%.(31) In addition, membrane effects and biotransformation may influence results. Another limitation of this approach is that selectivity in blood may not reflect selectivity at the mucosa. For example, whole-blood assays showed that diclofenac, the most effective COX-2 inhibitor among traditional NSAIDs, remained a potent inhibitor of prostaglandin production in gastric mucosal biopsies.(32) Use of biopsies, however, is not necessarily representative of the in vivo events, and COX enzymes may be differentially expressed in patients with ulcers compared with healthy donors used in these experiments. Although ex vivo assays identify inhibition of COX enzymes at therapeutic plasma levels, COX selectivity at the concentrations seen in the tissues remains unknown.

The IC50 values obtained using in vitro or ex vivo assays are expressed as a ratio of COX-1 to COX-2 inhibition. As a more selective drug requires a lower concentration (IC50) to be effective, the ratio for a COX-2-selective agent will be higher than 1. These pharmacologic methods have potential drawbacks that necessitate careful interpretation of the data.

Figure 3.

Several important considerations should not be overlooked in the discussion of the pharmacology of COX inhibitors. First, the relation between the relative inhibition of COX-1 and COX-2 and alteration of prostaglandin-mediated biologic functions is not linear.(33) As pharmacologic targets, the dose-effect thresholds of efficacy and safety for COX-1 and COX-2 inhibition are probably undefinable. Even if it were possible to accurately predict the relative selectivity of COX inhibitors in vivo, it is still not known to what extent, and for how long, COX-1 can be inhibited without an increased risk of GI toxicity. Conversely, the degree of COX-2 inhibition needed to produce anti-inflammatory responses in vivo also is unknown.(31) There are currently insufficient data to accurately correlate biochemical and pharmacologic measures of COX selectivity with clinical efficacy and safety, and the question of how to determine the clinically measurable benefit of selective COX-2 inhibition remains.(3)

Cronstein BN. Cyclooxygenase-2-selective inhibitors: translating pharmacology into clinical utility. Cleve Clin J Med 2002;69:SI13-19.

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