Torixib Mechanism of Action

Pharmacotherapeutic Group: Anti-inflammatory and antirheumatic products, non-steroids, coxibs. ATC code: M01AH05.
Pharmacology: Pharmacodynamics: Mechanism of action: Etoricoxib is an oral, selective cyclo-oxygenase-2 (COX-2) inhibitor within the clinical dose range.
Etoricoxib produced dose-dependent inhibition of COX-2 without inhibition of COX-1 at doses up to 150mg 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: Absorption: The onset of action of etoricoxib occurred as early as 24 minutes after dosing. Orally administered etoricoxib is well absorbed. The mean oral bioavailability is approximately 100%. Following 120mg once-daily dosing to steady state, the peak plasma concentration (geometric mean C_max=3.6mcg/mL) was observed at approximately 1 hour (T_max) after administration to fasted adults. The geometric mean AUC_0-24hr was 37.8mcg·hr/mL. The pharmacokinetics of etoricoxib are linear across the clinical dose range. A standard meal had no clinically meaningful effect on the extent or rate of absorption of a dose of etoricoxib 120mg. In clinical trials, etoricoxib was administered without regard to food.
Distribution: Etoricoxib is approximately 92% bound to human plasma protein over the range of concentrations of 0.05 to 5mcg/mL. The volume of distribution at steady state (V_dss) is approximately 120L in humans. Etoricoxib crosses the placenta in rats and rabbits, and the blood-brain barrier in rats.
Metabolism: Etoricoxib is extensively metabolised with <1% of a dose recovered in urine as the parent drug. The major route of metabolism to form the 6'-hydroxymethyl derivative is catalysed by cytochrome P450 (CYP) enzymes.
Five metabolites have been identified in man. The principal metabolite is the 6'-carboxylic acid derivative of etoricoxib formed by further oxidation of the 6'-hydroxymethyl derivative. These principal metabolites either demonstrate no measurable activity or are only weakly active as COX-2 inhibitors. None of these metabolites inhibit COX-1.
Elimination: Elimination of etoricoxib occurs almost exclusively through metabolism followed by renal excretion. Steady state concentrations of etoricoxib are reached within seven days of once-daily administration of 120mg, with an accumulation ratio of approximately 2, corresponding to an accumulation half-life of approximately 22 hours. The plasma clearance is estimated to be approximately 50mL/min.
Special Populations: Use in pediatric: Safety and effectiveness of etoricoxib in paediatric patients have not been established.
Use in the elderly: Pharmacokinetics in the elderly (65 years of age and older) are similar to those in the young.