Parecoxib

Molecular formula CigHi8N204S Molecular weight 370.42 CAS Registry No 198470-84-7, 197502-82-2 (Na salt) 

Mobile phase MeCNilO mM pH 3.0 phosphate buffer 40 60 Flow rate 2 Injection volume 10 Detector UV 215 

Mulhern, M.G. Nema, S. Stability of reconstituted parecoxib for injection with commonly used diluents, J.Clin.Pharm.Ther., 2003, 28, 363-369. 

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It follows that drugs that selectively inhibit COX-2 should cause fewer side effects than those that inhibit both COX-1 and COX-2. At therapeutic doses, all currently available NSAIDs, with the excqrtion of celecoxib, etoricoxib, lumiracoxib and parecoxib (the prodrug of valdecoxib), are non-selective and inhibit both COX isoforms. 

The development of the COXIBs has been based on the hypothesis COX-1 is the physiological COX and COX-2, the pathophysiological isoenzyme. Inhibition of the pathophysiological COX-2 only is assumed to result in fewer side effects as compared to non-selective inhibition of both COX isoenzymes (Fig. 2). Celecoxib, etoricoxib and lumiracoxib (in some countries also parecoxib) are the only COXIBs currently approved. 

Celecoxib, rofecoxib, valdecoxib, parecoxib sodium, and etoricoxib all belong to this chemical class. 

Synthesis The acylation of 4-(5-methyl-3-phenylisoxazol-4-yl)benzenesulfonamide (valdecoxib), with propionic anhydride in a solution of TEA and DMAP in tetrahydrofurane gives A/-(4-(5-methyl-3-phenylisoxazol-4-yl)phenylsulfonyl)propionamide, which is treated with NaOH in ethanol to give parecoxib sodium salt (Talley (Parmacia Corp.), 1996 2000b Sorbera, 2001b). 

Clinical use Parecoxib (Cheer and Goa, 2001 Gotta, 2001 Sorbera et al., 2001b) is a third generation COX-2 inhibitor. Parecoxib is a prodrug of valdecoxib with aqueous solubility sufficient for the use of the substance in parenteral formulations. Valdecoxib shows about 30-fold selectivity for COX-2 in whole blood assays (see Valdecoxib Talley et al., 2000a Riendeau et al., 2001). Parecoxib shows efficacy in a variety of animal models of inflammation (Talley et al., 2000b). 

Parecoxib is rapidly hydrolyzed by the liver to its active metabolite valdecoxib. Plasma peak concentrations for valdecoxib are achieved within 1.1 to 3.5 and 0.27 to 2 h after i.m. and i.v. administration, respectively, in healthy volunteers. The elimination half-life for parecoxib is 15 to 35 min and 5 min for i.m. and i.v. administration respectively, in healthy volunteers. Metabolism of parecoxib follows the metabolism of the active metabolite valdecoxib which is a substrate for cytochrome P450 3A4 and 2C9. 

Parecoxib is used in doses of 20 and 40 mg of its sodium salt for the short-term treatment of postoperative pain. 

Talley, J. J., Bertenshaw, S. R., Brown, D. L., Carter, J. S., Graneto, M. J., Kellogg, M. S., Koboldt, C. M., Yuan. J., Zhang, Y. Y., Seibert, K. N-[[(5-methyl-3-phenylisoxazol-4-yl)-phenyl]sulfonyl]propanamide, sodium salt, parecoxib sodium A potent and selective inhibitor of COX-2 for parenteral administration, J. Med. Chem. 2000b, 43, 1661-1663. 

Similarly, the sodium salt of the poorly soluble COX-2 inhibitor pare-coxib, parecoxib sodium (Dynastat ), was designed as a parenteral analgesic for the management of acute pain to improve solubility of the parent compound. On administration, parecoxib sodium is converted rapidly and essentially completely to the pharmacologically active... 

Noveck, R. J., and Hubbard, R. C. Parecoxib sodium, an injectable COX-2-specific inhibitor, does not affect unfractionated heparin-regulated blood coagulation parameters. J. Clin. Pharmacol. 44 474—480, 2004. 

Coxibs available at present include cele-coxib (daily dosage 200-400 mg), valdecoxib (10-20 mg) (no longer available in the US) and its prodrug parecoxib (40 mg i.v.l). 

FLECAINIDE NS AIDS Parecoxib may t flecainide levels Parecoxib weakly inhibits CYP2D6-mediated metabolism of flecainide Monitor PR and BP closely. If possible, use only short courses of NSAID... 

CORTICOSTEROIDS ANALGESICS-NSAIDs 1. T risk of gastrointestinal ulceration and bleeding 2. Parecoxib levels may be 1 by dexamethasone 1. Additive effect 2. Dexamethasone induces CYP3A4-mediated metabolism of parecoxib 1. Watch for early signs of gastrointestinal upset remember that corticosteroids may mask these features 2. Watch for poor response to parecoxib... 

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