Parecoxib

The Uses of Parecoxib

3-(5-Methyl-3-phenyl-4-isoxazolyl)benzenesulfonyl Chloride is an Impurity of Parecoxib Sodium (P193275), an anti-inflammatory, analgesic.

The Uses of Parecoxib

Anti-inflammatory; analgesic (cyclooxygenase COX-2 inhibitor).

Clinical Use

Parecoxib is a pro-drug of valdecoxib administered IM or IV for perioperative analgesic and anti-inflammatory use. As a pro-drug, it undergoes rapid in vivo hydrolysis to valdecoxib.Parecoxib at greater than 20 mg has analgesic activity superior to that of placebo and similar to that of parenteral 30 or 60 mg of ketorolac in patients with postoperative dental pain. A significant adverse effect is drug hypersensitivity. Parecoxib is currently marketed worldwide but has not been approved for use in the United States.

Synthesis

The acylation of 4-(5-methyl- 3-phenylisoxazol-4-yl)benzenesulfonamide (valdecoxib), with propionic anhydride in a solution of triethanolamine (TEA) and 4-dimethylaminophenol (DMAP) in tetrahydrofuran gives N-propionamide, which is treated with NaOH in ethanol to give the sodium salt of parecoxib .

Drug interactions

Potentially hazardous interactions with other drugs
ACE inhibitors and angiotensin-II antagonists: antagonism of hypotensive effect; increased risk of nephrotoxicity and hyperkalaemia.
Analgesics: avoid concomitant use of 2 or more NSAIDs, including aspirin (increased side effects); avoid with ketorolac (increased risk of side effects and haemorrhage).
Antibacterials: possible increased risk of convulsions with quinolones.
Anticoagulants: effects of coumarins and phenindione enhanced; possibly increased risk of bleeding with heparin, dabigatran and edoxaban.
Antidepressants: increased risk of bleeding with SSRIs and venlafaxine.
Antidiabetics: possibly enhanced effect of sulphonylureas.
Antiepileptics: possibly enhanced effect of phenytoin.
Antifungals: if used with fluconazole reduce the dose of parecoxib.
Antivirals: increased risk of haematological toxicity with zidovudine; concentration possibly increased by ritonavir.
Ciclosporin: potential for increased risk of nephrotoxicity.
Cytotoxics: reduced excretion of methotrexate, (possible increased risk of toxicity); increased risk of bleeding with erlotinib.
Diuretics: increased risk of nephrotoxicity; possible antagonism of diuretic effect; increased risk of hyperkalaemia with potassium-sparing diuretics.
Lithium: reduced excretion of lithium (risk of toxicity).
Pentoxifylline: possibly increased risk of bleeding.
Tacrolimus: increased risk of nephrotoxicity.

Metabolism

Parecoxib is rapidly and almost completely converted to valdecoxib and propionic acid.
Elimination of valdecoxib is by extensive hepatic metabolism involving multiple pathways, including cytochrome P 450 (CYP) 3A4 and CYP2C9 isoenzymes and glucuronidation (about 20%) of the sulphonamide moiety. Excretion is mainly via the urine with about 70% of a dose appearing as inactive metabolites. No unchanged parecoxib is found in the urine with only trace amounts in the faeces.