Description
Rofecoxib ts a non-steroidal anti-inflammatory drug (NSAID) launched
in Mexico, its first market, for the management of acute pain and the treatment
of osteoarthritis (OA) and primary dysmenorrhea. Rofecoxib can be obtained by
several different ways; one example is by arylation of a 4-bromofuranone with a
phenylboronic acid under Suzuki conditions. Rofecoxib is a highly selective
inhibitor of COX-2, the inducible isoform of cyclooxygenase and therefore
exhibits a potent antiinflammatory activity without concomitant gastric or renal
toxicities linked to the non-specific COX-1/2 inhibitors. In several clinical studies
in patients with knee or hip osteoarthritis, Rofecoxib was evaluated at 12.5-50
mg doses once daily: it demonstrated efficacy for all primary and secondary endpoints at doses considerably weaker than those for classical non-specific
NSAIDs, with good tolerance and less adverse effects. Selective COX-2
inhibitors potentially have a large spectrum of activity including new indications
such as Alzheimer's disease, colorectal cancer, irritable bowel disease or
urinary incontinence.
Chemical Properties
Off-White (Pale Yellow) Crystalline Powder
Uses
Labeled Rizatriptan, intended for use as an internal standard for the quantification of Rizatriptan by GC- or LC-mass spectrometry.
Uses
A selective cyclooxygenase-2 (COX-2) inhibitor. Use as an anti-inflammatory, analgesic.
Uses
Rofecoxib has been used in high performance bioaffinity chromatography.
Definition
ChEBI: A butenolide that is furan-2(5H)-one that is substituted by a phenyl group at position 3 and by a p-(methylsulfonyl)phenyl group at position 4. A selective cyclooxygenase 2 inhibitor, it was used from 1999 to 2004 for the tr
atment of ostoarthritis, but was withdrawn following concerns about an associated increased risk of heart attack and stroke.
Indications
Rofecoxib is approved for the treatment of osteoarthritis,
dysmenorrhea, and acute pain. The most
common adverse reactions to rofecoxib are mild to
moderate GI irritation (diarrhea, nausea, vomiting, dyspepsia,
abdominal pain). Lower extremity edema and
hypertension occur relatively frequently (about 3.5%).
It is not metabolized by CYP2C9, so rofecoxib should
not be subject to some of the interactions seen with
celecoxib. However, its metabolism is increased by the
coadministration of rifampin, which acts as a nonspecific
inducer of hepatic metabolism.
brand name
Vioxx (Merck).
Biochem/physiol Actions
Rofecoxib is derived from furanone and has the ability to cross human placenta. Along with anti-inflammatory action, it possesses analgesic and antipyretic properties. Cytosolic hepatic enzymes are responsible for the metabolism of rofecoxib. It is known to cause oligohydramnios and ductus arteriosus constrictions. Rofecoxib inhibits the action of CYP1A2 (cytochrome P450 family 1 subfamily A member 2). It might be associated with aseptic meningitis. Rofecoxib is known to ameliorate the risk of colorectal adenoma, but might contribute to toxicity.
Mechanism of action
Rofecoxib is excreted primarily in the urine (72%) as metabolites. Less than 1% is excreted in the urine as
unchanged drug, whereas approximately 14% is excreted in the feces as unchanged drug. Although the metabolism
of rofecoxib has not been fully determined, the microsomal cytochrome P450 system appears to play only a minor
role—a major difference in the metabolic routes of rofecoxib and celecoxib. The major metabolic route appears to
form reduction of the dihydrofuranone ring system by cystolic enzymes to the to cis- and trans- dihydro derivatives.
Also isolated is the glucuronide of a hydroxy derivative that results from CYP2C9 oxidative metabolism. None of the
isolated metabolites of rofecoxib possess pharmacological activity as COX-1 or COX-2 inhibitors.
Pharmacokinetics
Rofecoxib has been synthesized by a number of synthetic routes that have been summarized elsewhere. It was
the second selective COX-2 inhibitor to be marketed. Rofecoxib is well absorbed from the GI tract on oral
administration, with peak plasma levels generally being attained within 2 to 3 hours of dosing. Bioavailability
averages 93% following administration of a single dose. The area under the plasma concentration–time curve is
increased in patients older than 65 years compared to younger adults and is increased slightly in black and Hispanic
patients compared with white patients, but the difference is not considered to be clinically significant.
Clinical Use
Rofecoxib was indicated for the relief of the signs and symptoms of osteoarthritis, for the management of acute pain
in adults, and for the treatment of primary
dysmenorrhea.
Side effects
Rofecoxib causes a significantly lower incidence
of upper-gastrointestinal adverse effects (perforations, ulcers, and bleeding) than conventional
NSAIDs. Most common adverse events associated with rofecoxib are diarrhoea, headache,
nausea, and upper respiratory tract infection.
Synthesis
Rofecoxib can be obtained by
different synthetic routes, e.g., by condensation of phenylacetic acid with ethyl bromoacetate to ethyl 2-phenylacetoxyacetate,
which is then cyclized to a hydroxyfuranone. Subsequently, the hydroxyfuranone reacts with trifluoromethanesulfonic (triflic) anhydride to the corresponding triflate which
reacts with LiBr to yield a bromofuranone.
The bromofuranone is condensed with 4-
(methylsulfanyl)phenylboronic acid to give
4-[4-(methylsulfanyl)phenyl]-3-phenylfuran-
2(5H)-one which is finally oxidized to rofecoxib.
IC 50
IC50 for COX-2: 1.8 × 10
?8 M
IC50 for COX-1: 1.5 × 10
?5 M
Dosage
Rofecoxib
is indicated for relief of the signs and symptoms
of osteoarthritis (recommended starting dose is
12.5 mg once daily, maximum recommended
dose is 25 mg/d), for the management of acute
pain in adults and for the treatment of primary
dysmenorrhea (recommended initial doses are
50 mg once daily, use of rofecoxib for more than 5 d in management of pain has not been studied).
References
1) Chan et al. (1999), Rofecoxib [Vioxx, MK-0966; 4-(4′-methylsulfonylphenyl)-3-phenyl-2-(5H)-furanone]: a potent and orally active cyclooxygenase-2 inhibitor. Pharmacological and biochemical profiles; J. Pharmacol. Exp. Ther., 290 551
2) Catalla-Lawson et al. (2013), Effects of specific inhibition of cyclooxygenase-2 on sodium balance, hemodynamics and vasoactive eicosanoids; J. Pharmacol. Exp. Ther., 289 735
