Pharmacology: PHARMACODYNAMICS: Etoricoxib is an oral, selective cyclo-oxygenase-2 (COX-2) inhibitor within the clinical dose range.
Across clinical pharmacology studies, Etoricoxib produced dose-dependent inhibition of COX-2 without inhibition of COX-1 at doses up to 150 mg daily. Etoricoxib did not inhibit gastric prostaglandin synthesis and had no effect on platelet function.
Cyclooxygenase is responsible for generation of prostaglandins. Two isoforms, COX-1 and COX-2, have been identified. COX-2 is the isoform of the enzyme that has been shown to be induced by pro-inflammatory stimuli and has been postulated to be primarily responsible for the synthesis of prostanoid mediators of pain, inflammation, and fever. COX-2 is also involved in ovulation, implantation and closure of the ductus arteriosus, regulation of renal function, and central nervous system functions (fever induction, pain perception and cognitive function). It may also play a role in ulcer healing. COX-2 has been identified in tissue around gastric ulcers in man but its relevance to ulcer healing has not been established.
PHARMACOKINETICS: Etoricoxib is well absorbed from the gastrointestinal tract after oral doses. Peak plasma concentrations are reached in about 1 hour in fasted adults:
food delays absorption by about 2 hours, although it has no effect on the extent of absorption. Plasma protein binding is about 92%. At steady state the half-life of etoricoxib is about 22 hours. Etoricoxib is extensively metabolised with less than 2% of a dose recovered in the urine as the parent drug. The major route of metabolism is via cytochrome P450 isoenzymes including CYP3A4 to form the 6'-hydroxymethyl derivative of etoricoxib, which is then oxidized to the 6'-carboxylic acid derivative, the major metabolite. Both are inactive or only weak cyclo-oxygenase-2 (COX-2) inhibitors. Excretion is mainly via the urine (70%) with only 20% of a dose appearing in the faeces. Studies in animals suggest that etoricoxib may cross the placenta and that some is distributed into breast milk.