Ericox Mechanism of Action

Pharmacotherapeutic group: Anti-inflammatory and antirheumatic products, nonsteroids, coxibs. ATC code: M01AH05.
Pharmacology: Pharmacodynamics: Etoricoxib is an oral, selective cyclooxygenase-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: Absorption: Orally administered etoricoxib is well absorbed. The absolute bioavailability is approximately 100%. Following 120 mg once-daily dosing to steady-state, the peak plasma concentration (geometric mean C_max = 3.6 μg/ml) was observed at approximately 1 hour (T_max) after administration to fasted adults. The geometric mean area under the curve (AUC_0-24hr) was 37.8 μg·hr/ml. The pharmacokinetics of etoricoxib are linear across the clinical dose range.
Dosing with food (a high-fat meal) had no effect on the extent of absorption of etoricoxib after administration of a 120-mg dose. The rate of absorption was affected, resulting in a 36% decrease in C_max and an increase in T_max by 2 hours.
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 1.20 L in humans. Etoricoxib crosses the placenta in rats and rabbits, and the blood-brain barrier in rats.
Biotransformation: 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 catalyzed by CYP enzymes. CYP3A4 appears to contribute to the metabolism of etoricoxib in vivo. In vitro studies indicate that CYP2D6, CYP2C9, CYP1A2 and CYP2C19 also can catalyse the main metabolic pathway, but their quantitative roles in vivo have not been studied.
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: Following administration of a single 25-mg radiolabeled intravenous dose of etoricoxib to healthy subjects, 70% of radioactivity was recovered in urine and 20% in faeces, mostly as metabolites. Less than 2% was recovered 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.