Favocox Mechanism of Action

Pharmacology: Celecoxib is a new class of agent which acts through a unique mechanism as a specific cyclo-oxygenase-2 inhibitor (SCI). Cyclooxygenase-2 (COX-2) is induced in response to inflammatory stimuli. This leads to the synthesis and accumulation of inflammatory prostanoids, in particular prostaglandin E₂, causing inflammation, oedema and pain. Celecoxib acts as an anti-inflammatory, analgesic and antipyretic agent by blocking the production of inflammatory prostanoids via COX-2 inhibition. In vivo and ex vivo studies show that celecoxib has a very low affinity for the constitutively expressed cyclo-oxygenase-1 enzyme (COX-1). Consequently, at therapeutic doses, celecoxib has no effect on prostanoids synthesized by activation of COX-1 thereby not interfering with normal COX-1-related physiological processes in tissues, particularly the stomach, intestine, platelets and kidney.
Further Information from Clinical Trials: Consensus criteria for the definition, in biological terms of COX-2 specificity, have recently been agreed and include the need to demonstrate absence of COX-1 type adverse events, particularly drug-induced gastroduodenal ulceration, serious upper gastrointestinal (UGI) events (bleeds, perforation, gastric outlet obstruction) and lack of inhibition of COX-1-dependent platelet aggregatory activity.
Pharmacokinetics: Absorption: The pharmacokinetics of celecoxib have been evaluated in approximately 1500 individuals. When given under fasting conditions celecoxib is well absorbed reaching peak plasma concentrations after approximately 2-3 hours. Oral bioavailability from capsules is about 99% relative to administration in suspension (optimally available oral dosage form). Under fasting conditions, both peak plasma levels (C_max) and area under the curve (AUC) are roughly dose proportional up to 200 mg twice daily; at higher doses there are less than proportional increases in C_max and AUC.
Distribution: Plasma protein binding, which is concentration independent, is about 97% at therapeutic plasma concentrations and celecoxib is not preferentially bound to erythrocytes in the blood.
Food Effects: Dosing with food (high fat meal) delays absorption of celecoxib resulting in a T_max of about 4 hours and increases bioavailability by about 20%.
Metabolism: Celecoxib metabolism is primarily mediated via cytochrome P450 2C9. Three metabolites, inactive as COX-1 or COX-2 inhibitors, have been identified in human plasma i.e., a primary alcohol, the corresponding carboxylic acid and its glucuronide conjugate. Cytochrome P450 2C9 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity, such as those homozygous for the CYP2C9*3 polymorphism.
Excretion: Elimination of celecoxib is mostly by hepatic metabolism with less than 1% of the dose excreted unchanged in urine. After multiple dosing elimination half life is 8-12 hours and the rate of clearance is about 500 mL/min. With multiple dosing steady state plasma concentrations are reached before day 5. The intersubject variability on the main pharmacokinetic parameters (AUC, C_max, elimination half-life) is about 30%. The mean steady state volume of distribution is about 500 L/70 g in young healthy adults indicating wide distribution of celecoxib into the tissues. Preclinical studies indicate that the drug crosses the blood brain barrier.