ABSTRACT:Rofecoxib is a cyclooxygenase-2 (COX-2) inhibitor that has been withdrawn from the market because of an increased risk of cardiovascular (CV) events. With a special focus on the arteries, the distribution profiles of radioactivity in rats orally administered Rofecoxib (VIOXX) is a potent and highly selective cyclooxygenase-2 (COX-2) inhibitor that has been widely used as a nonsteroidal anti-inflammatory drug (NSAID). However, this drug was withdrawn from the worldwide market because of an increased risk of cardiovascular (CV) events found in the Adenomatous Polyp Prevention on VIOXX (APPROVe) trial, which was conducted for the prevention of the recurrence of colorectal polyps and included 2600 patients with no history of CV disease before enrollment (Merck, 2004). The study had originally been intended to last for 3 years but was halted in midcourse because of the increased CV risks among patients in the group that was taking 25 mg of rofecoxib, in which the incidence of risk was more than twice that in the group taking the placebo.In the last few years, it has been reported that other selective COX-2 inhibitors (e.g., etoricoxib, parecoxib/valdecoxib, and celecoxib) and nonselective NSAIDs (e.g., naproxen) may also have a potential for increased CV risk (Bombardier et al., 2000;Ott et al., 2003; FDA, 2004; FDA Advisory Committee.com, 2004; NIH, 2004;Aldington et al., 2005;Krotz et al., 2005;Nussmeier et al., 2005). However, rofecoxib differs in the following ways: 1) a significantly greater frequency and higher odds of CV events (Mamdani et al., 2004;Solomon et al., 2004a;Graham et al., 2005;Kimmel et al., 2005); 2) a shorter period and a lower dose (even at the clinical dose) leading to the incidence of CV events; and 3) an earlier onset and a greater hypertensive effect correlating closely with CV risk (Brinker et al., 2004;Solomon et al., 2004b;Wolfe et al., 2004;Fredy et al., 2005). Therefore, it is suggested that rofecoxib could have distinctive mechanisms or more potent toxic activity leading to CV risks, in comparison with other selective COX-2 inhibitors or nonselective NSAIDs. Consequently, it is vital to investigate rofecoxib by comparing it with other selective COX-2 inhibitors to clarify its relevance to increased CV events.Several hypotheses have been proposed to explain the mechanism for the increased risk of CV events with rofecoxib. McAdam et al. (1999) suggested the endothelial prostacyclin (PGI 2 )/thromboxane A 2 (TxA 2 ) imbalance theory, whereby the CV complications caused by selective COX-2 inhibitors might be partially due to an imbalance of the concentration ratio of two prostanoids with major CV actions: PGI 2 , a vasodilator and inhibitor of platelet aggregation, and TxA 2 , a vasoconstrictor and promotor of platelet aggregation. That is, selective COX-2 inhibitors diminish the production of PGI 2 in the endothelium, but not TxA 2 in the platelets, so that the relative concentration of TxA 2 increases around the affected area, which might increase the risks. Walter et al. (200...

A technique utilizing simultaneous intravenous microdosing of (14)C-labeled drug with oral dosing of non-labeled drug for measurement of absolute bioavailability was evaluated using R-142086 in male dogs. Plasma concentrations of R-142086 were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and those of (14)C-R-142086 were measured by accelerator mass spectrometry (AMS). The absence of metabolites in the plasma and urine was confirmed by a single radioactive peak of the parent compound in the chromatogram after intravenous microdosing of (14)C-R-142086 (1.5 microg/kg). Although plasma concentrations of R-142086 determined by LC-MS/MS were approximately 20% higher than those of (14)C-R-142086 as determined by AMS, there was excellent correlation (r=0.994) between both concentrations after intravenous dosing of (14)C-R-142086 (0.3 mg/kg). The oral bioavailability of R-142086 at 1 mg/kg obtained by simultaneous intravenous microdosing of (14)C-R-142086 was 16.1%, this being slightly higher than the value (12.5%) obtained by separate intravenous dosing of R-142086 (0.3 mg/kg). In conclusion, on utilizing simultaneous intravenous microdosing of (14)C-labeled drug in conjunction with AMS analysis, absolute bioavailability could be approximately measured in dogs, but without total accuracy. Bioavailability in humans may possibly be approximately measured at an earlier stage and at a lower cost.