Rabirox Mechanism of Action

Pharmacotherapeutic group: M01AH Coxibs.
Pharmacology: Pharmacodynamics: The mechanism of action of celecoxib is via inhibition of prostaglandin synthesis primarily by inhibition of cyclooxygenase 2 (COX-2). At therapeutic concentrations in humans, celecoxib does not inhibit cyclooxygenase 1 (COX-1). 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, edema and pain. Celecoxib acts as an anti-inflammatory, analgesic, and antipyretic agent by blocking the production of inflammatory prostanoids via COX-2 inhibition. Celecoxib also reduced the incidence and multiplicity of tumors.
Celecoxib has a very low affinity for the constitutively expressed COX-1 enzyme. 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 process in tissues, particularly the stomach, intestine and platelets.
Pharmacokinetics: Absorption: 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 concentration and the drug is not preferential bound to erythrocytes in the blood.
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: 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.
Patients who are known, or suspected to be CYP2C9 poor metabolizers based on previous history/experience with other CYP2C9 substrates should be administered celecoxib with caution.
Elimination: Elimination of celecoxib is mostly by hepatic metabolism with less than 1% of the dose excreted unchanged in urine. Elimination half-life is 8-12 hours and the rate of clearance is about 500ml/min. Steady-state plasma concentrations are reached before day 5 of treatment. The inter-subject 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 kg in young healthy adults indicating wide distribution of celecoxib into tissue. Celecoxib crosses the blood/brain barrier.
Food Effects: Dosing with food (high fat meal) delays absorption of celecoxib resulting in a T_max of about 4 hours and increases bioavailability about 20%.