The Disposition and Metabolism of Rofecoxib, a Potent and Selective Cyclooxygenase-2 Inhibitor, in Human Subjects

Abstract

ABSTRACT:The disposition and metabolism of rofecoxib, a selective cyclooxygenase-2 inhibitor, were examined in healthy human subjects and in cholecystectomy patients. After oral administration of [ 14 C]rofecoxib (125 mg, 100 Ci) to healthy subjects, the mean concentrations of total radioactivity and rofecoxib in plasma as a function of time indicated that the t max was achieved at 9 h postdose. After t max , levels of both radioactivity and rofecoxib decreased in a parallel, exponential fashion (effective t (Prasit et al., 1999), an inducible isoform of cyclooxygenase that plays a key role in inflammatory processes. Rofecoxib has been approved for the treatment of arthritis and pain, and was developed on the premise that selective inhibition of COX-2 would result in decreased inflammation without the adverse gastrointestinal effects associated with inhibition of COX-1 (Vane and Botting, 1996; Donnelly and Hawkey, 1997; Jouzeau et al., 1997). This hypothesis has been supported by the results of recent clinical trials, including the VIGOR study, in which rheumatoid arthritis patients treated with rofecoxib displayed significantly fewer clinically important gastrointestinal events than patients treated with naproxen, a nonselective COX inhibitor (Bombardier et al., 2000).1Disposition and metabolism of rofecoxib in rats and dogs were reported recently (Halpin et al., 2000); metabolites identified in both species included 5-hydroxyrofecoxib, 5-hydroxyrofecoxib-O-␤-Dglucuronide, and trans-3,4-dihydro-rofecoxib, while additional metabolites identified in rat only were cis-3,4-dihydro-rofecoxib, rofecoxib-3Ј,4Ј-dihydrodiol, and 4Ј-hydroxyrofecoxib sulfate. Of note, following oral administration of rofecoxib to intact rats, was the appearance of a second C max which was not observed in bile duct-cannulated rats. This phenomenon was found to be due to a novel form of enterohepatic recycling, which involved reversible metabolism of rofecoxib to 5-hydroxyrofecoxib (Baillie et al., 2001).The studies presented here describe the disposition and metabolism of rofecoxib in human subjects. The specific objectives of these studies were: 1) to examine the absorption and excretion of [ 14 C]rofecoxib in healthy adult volunteers and to compare the results with those obtained from animals, 2) to identify the urinary metabolites of rofecoxib in humans, 3) to examine the extent of conversion of 5-hydroxyrofecoxib to rofecoxib following oral administration of 5-hydroxyrofecoxib to healthy subjects, and 4) to investigate the possible involvement of biliary elimination in the excretion of rofecoxib and its metabolites in humans.

Evaluation of [11C]rofecoxib as PET tracer for cyclooxygenase 2 overexpression in rat models of inflammation

“…Activated neutrophils and macrophages are known to express elevated levels of COX-2 [23,24]. In this model, the tissue distribution of a tracer dose of [ 11 C]rofecoxib (data not shown) was in good agreement with the distribution of [ 14 C]rofecoxib (2 mg/kg iv) in healthy Sprague-Dawley rats, as was described in the literature [14]. This indicates that the PET tracer [ 11 C]rofecoxib displays a similar in vivo behavior as the native drug.…”

“…The lipophilicity of rofecoxib should allow penetration of the blood-brain barrier. Ex vivo biodistribution studies in rats revealed that [ 14 C]rofecoxib was distributed rapidly to most tissues within 5 min after intravenous injection and was subsequently washed out [14]. The major elimination route of rofecoxib is by hepatic metabolism with subsequent excretion of the metabolites into the urine.…”

Parecoxib and Indomethacin Delay Early Fracture Healing: A Study in Rats

“…Due to the quick metabolism of the COX-2 inhibitors celecoxib and rofecoxib in rats [32,50], Meunier and Aspenberg [45] administered parecoxib in as high doses as 6.4 mg/kg daily using subcutaneous mini pumps with continuous release to compensate for the fast metabolism. However, to our knowledge, the half-life of parecoxib in rats is unknown.…”

“…Due to this, the blood concentration was probably too low much of the time to induce proper inhibition of the COX-2 enzyme. Additionally, male rats, in which COX-2 inhibitors have shown to have a short half-life and are quickly eliminated [32,50], were used. In Brown et al [8], there were similar findings; indomethacin delayed fracture healing at 4 weeks, but celecoxib, a specific COX-2 inhibitor, did not.…”

Involvement of 85-kd cytosolic phospholipase A2and cyclooxygenase-2 in the proliferation of human cholangiocarcinoma cells

“…[13][14][15][16][17][18] For example, COX-2 messenger RNA (mRNA) and protein expression are increased in human colon, 19,20 gastric, 21,22 breast, 23 lung, 24,25 squamous cell, 26 hepatocellular, [27][28][29] and cholangiocarcinomas. 2,30,31 Increased group II secretory phospholipase A 2 (sPLA 2 ) has been reported in hepatocellular carcinoma.…”