Etoricon Mechanism of Action

Coxib.
Pharmacology: Pharmacodynamics: Etoricoxib is an oral, selective cyclo-oxygenase-2 (COX-2) inhibitor. Etoricoxib produced dose dependent inhibition of COX-2 without inhibition of COX-1 at doses up to 150 mg daily. 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 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. Etoricoxib did not inhibit gastric prostaglandin synthesis and had no effect on platelet function.
Pharmacokinetics: Absorption: Orally administered Etoricoxib is well absorbed. The absolute bioavailability approximately 100%. Following 120 mg once-daily to steady state, the peak plasma concentration (geometric mean Cmax = 3.6 μg/mL) was observed at approximately 1 hour (Tmax) after administration to fasted adults.
Dosing with food (high fat meal) had no effect on the extent of absorption of Etoricoxib after administration of 120 mg-dose. The rate of absorption was affected, resulting in a 36% decrease in Cmax and an increase in Tmax by 2 hours. These data are not considered clinically significant.
Distribution: Etoricoxib is approximately 92% bound to human plasma protein over the range of concentrations of 0.05 to 5 μg/mL. The volume of distribution at steady state (V_dss) was approximately 120 L in humans.
Metabolism: Etoricoxib is extensively metabolized with <1% of a dose recovered in urine as the parent drug. The major route of metabolism to form the 6'-hydroxymethyl derivative is catalyzed by CYP enzymes. CYP3A4 appears to contribute the metabolism of Etoricoxib in vivo. In vitro studies indicate that CYP2D6, CYP2C9, CYP1A2, and CYP2C19 also can catalyze the main metabolic pathway but their quantitative roles in vivo have not been studied.
Five metabolites have been identified for Etoricoxib in man. The principal metabolite is 6'-carboxylic acid derivative of Etoricoxib formed by further oxidation of 6'-hydroxymethyl derivative. These principal metabolites either demonstrate no measurable activity or are only weakly active as COX-2 inhibitors.
Elimination: Less than 2% remain as unchanged drug. 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 120 mg, with an accumulation ratio of approximately 2, corresponding to a half-life of approximately 22 hours. The plasma clearance after a 25 mg intravenous dose is estimated to be approximately 50 mL/min.