Half-Lives of Agents

The three agents that have demonstrated an increased CV risk—rofecoxib, and valdecoxib—have half-lives ranging from six to 18 hours (Table 1). In contrast, the two agents without a demonstrated increased CV risk—lumira-coxib and etoricoxib—have half-lives of two to six hours and 20 to 26 hours, respectively. Thus, the coxibs with the shortest and longest half-lives have not shown an increased CV risk, whereas those with moderate half-lives have shown this risk.

In view of these conflicting data, the half-life of this class of drugs cannot exclusively account for the development of CV events. The data for lumiracoxib and are scant, and this limitation may offset the lack of CV endpoint differences that have been demonstrated to date.

COX-2 Selectivity

COX-2 selectivity (i.e., the agent’s specificity and affinity for the COX-2 enzyme over the COX-1 enzyme) may also be a factor in the relationship of coxibs to the risk of CV events. Clearly, rofecoxib has demonstrated the greatest risk, whereas celecoxib has shown an increased risk only sporadically. In assessments of COX-2 selectivity, rofecoxib has a higher selectivity (with a COX-2 : COX-1 ratio of 272 to 1) than celecoxib (with a ratio of 30 to 1) (see Table 1). However, etoricoxib and lumiracoxib are the most COX-2 selective (with ratios of 344 to 1 and 700 to 1, respectively); neither agent has shown a comparable increased CV risk, as with rofecoxib and celecoxib.

We emphasize that the classification of nonselective NSAIDS and coxibs on the basis of their COX enzyme selectivity is controversial. Some nonselective NSAIDS, such as (Mobic canadian, Boehringer Ingelheim) and potassium (Novartis), have a COX-2 selectivity that is comparable to that of celecoxib.

Renovascular Effects

Coxibs cause various renovascular effects, including volume retention and increases in blood pressure (BP). Reports of changes in BP and edema involving coxibs have provided conflicting results.

Patients taking rofecoxib showed an increased risk for edema and hypertension, when compared with users of cele-coxib, nonselective NSAIDs, and non-NSAIDs in multiple stud-ies. Valdecoxib has had this effect, when compared with placebo, in a pooled analysis of five clinical trials. Conversely, lumiracoxib and etoricoxib had similar effects on BP and edema, when compared with nonselective NSAIDs.

A meta-analysis of more than 45,000 patients showed that coxibs cause elevations of systolic and diastolic BP when compared with NSAIDs and placebo. Within this analysis, rofecoxib showed an even greater risk of BP elevations than celecoxib. Reasons for these differences are not clearly understood, but the unique pharmacokinetics of each coxib may play a role. More details are presented next under the heading “Metabolism and Chemical Structure.”

Thus, even though rofecoxib and valdecoxib have been associated with the greatest risk of CV events and appear to have the greatest chance of causing renovascular events, no firm correlation in clinical trials has been shown.

Metabolism and Chemical Structure

All coxibs have similar mechanisms of action for COX-2 inhibition, but each one has a unique pharmacokinetic profile. Only rofecoxib does not undergo extensive metabolism via a cytochrome P450 (CYP 450) system. Instead, its metabolism is mediated through the reduction of cytosolic enzymes, with less than 1% of the drug being recovered unchanged in the urine. All other coxibs are eliminated predominantly by the CYP 450 system, either 3A4 (valdecoxib, etoricoxib canadian) or 2C9 (celecoxib, valdecoxib, and lumiracoxib). In addition, enterohepatic recirculation is unique to rofecoxib and has been reported in both rat and human studies, with resultant biphasic serum peaks of drug.

Although the clinical significance of these differences inmetabolism is unclear, these disparities might contribute to the variations in renal and cardiovascular effects. For instance, after cytosol reductase metabolism, rofecoxib may compete for the metabolism of aldosterone, with resulting increases in both sodium and fluid retention as well as the promotion of vascular remodeling. The consequences include an increased risk of edema, hypertension, and acute decompensation of chronic heart failure.

Alternatively, canadian celecoxib does not compete for cytosol reductase; instead, it works as a carbonic anhydrase inhibitor and provides a diuretic effect in the kidney that counteracts potential increases in hypertension and edema.54 It is noteworthy that these renovascular outcomes that have been reported in multiple studies and analyses occur more often with rofecoxib than with any other coxib.

The chemical structure of each coxib, excluding lumira-coxib, is classified as either a sulfone or a sulfonamide (Table 1). Lumiracoxib is classified as an arylacetic acid derivative. Its unique structure contributes to its very short half-life (two to six hours), compared with the other coxibs. The shorter half-life may decrease the overall exposure time of this drug in circulation and may potentially reduce thrombo-embolic risk. To gain a better understanding of their role in the development of these adverse effects, we need further investigations into the relevance of these differences in phar-macokinetic parameters and chemical structures.