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9 AnalgesicsKinetics
Celecoxib reaches peak plasma concentration after 2–3 hours and has an elimination
half-life of 8–12 hours. It is 97% protein bound and has a volume of distribution of
5.7 l.kg. It is metabolized by hepatic CYP2C9 to inactive metabolites so that only a
small amount appears unchanged in the urine. Drugs that inhibit (omeprazole) or
induce (carbamazepine) CYP2C9 will increase or decrease plasma concentrations.
Ithas a sulphonamide group and therefore should not be used in patients with a
sulphonamide allergy.Valdecoxib and parecoxib
Parecoxib is a prodrug, which is converted to the active moiety valdecoxib. Its half-life
is 45 minutes and has no actions of its own. Valdecoxib has been withdrawn (April
2005) due to serious dermatological side effects (see below). At the time of writing
paracoxib remains in use and has not been associated with similar dermatological
side effects probably due to its short-term use. It has a COX-1:COX-2 inhibitory ratio
of 1:61.
Parecoxib is a parenteral COX-2 antagonist and should be reconsituted with 0.9%
saline prior to administration. The initial dose is 40 mg (i.m. or i.v.) followed by 20–40
mg 6–12 hourly up to a maximum dose of 80 mg per day.Kinetics
Parecoxib is converted to valdecoxib by enzymatic hydrolysis in the liver. Valdecoxib
undergoes hepatic metabolism by CYP2C9, CYP3A4 and glucuronidation to many
metabolites, one of which antagonizes COX-2. Due to its hepatic elimination, renal
impairment does not influence its kinetics, but it is not recommended in severe
hepatic impairment.
The dose should be reduced when coadministered with fluconazole due to inhi-
bition of CYP2C9, although no adjustment is necessary when coadministered with
ketoconazole or midazolam which is metabolized by CYP3A4. Valdecoxib appears to
inhibit other cytochrome P450 enzymes and may increase the plasma concentration
of flecanide and metoprolol (CYP2D6 inhibition), and omeprazole, phenytoin and
diazepam (CYP2C19 inhibition).
Parecoxib has a plasma half-life of 20 minutes while valdecoxib has an elimination
half-life of 8 hours.
Hypersensitivity reactions including exfoliative dermatitis, Stevens–Johnson syn-
drome, toxic dermal necrolysis and angiodema have been reported following valde-
coxib in those who also have sulphonamide sensitivity. The overall reporting rate is
in the order of 8 per million patients. It is, therefore, contraindicated in this group.
However, parecoxib has a non-aromatic sulphonamide group similar to frusemide
and tolbutamide, neither of which is contraindicated in sulphonamide sensitivity.