Celcoxx Mechanism of Action

Pharmacology: Mechanism of Action: Celecoxib is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic and antipyretic activities. The mechanism of action of celecoxib is believed to be due to inhibition of prostaglandin synthesis, primarily via inhibition of cyclooxygenase-2 (COX-2), and at therapeutic concentrations in humans, celecoxib does not inhibit the cyclooxygenase-1 (COX-1) isoenzyme.
Pharmacokinetics: Absorption: Peak plasma levels of celecoxib occur approximately 3 hrs after an oral dose. 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. With multiple dosing, steady-state conditions are reached on or before day 5.
Effect of Food and Antacid: When celecoxib was taken with a high-fat meal, C_max were delayed for about 1-2 hrs with an increase in total absorption (AUC) of 10-20%. Under fasting conditions, at doses >200 mg, there is less than a proportional increase in C_max and AUC, which is thought to be due to the low solubility of the drug in aqueous media. Co-administration of celecoxib with an aluminum- and magnesium-containing antacid resulted in a reduction in plasma celecoxib concentrations with a decrease of 37% in C_max and 10% in AUC.
Celecoxib, at doses up to 200 mg twice daily can be administered without regard to timing of meals. Higher doses (400 mg twice daily) should be administered with food to improve absorption.
Distribution: In healthy subjects, celecoxib is highly protein bound (~97%) within the clinical dose range. The apparent volume of distribution at steady-state (V_ss/F) is approximately 400 L, suggesting extensive distribution into the tissues. Celecoxib is not preferentialy bound to red blood cells.
Metabolism: Celecoxib metabolism is primarily mediated via cytochrome P-450 2C9. Three metabolites, a primary alcohol, the corresponding carboxylic acid and the glucuronide conjugate, have been identified in human plasma. These metabolites are inactive as COX-1 or COX-2 inhibitors.
Excretion: Celecoxib is eliminated predominantly by hepatic metabolism with little (<3%) unchanged drug recovered in the urine and feces. The primary metabolite in both urine and feces was the carboxylic acid metabolite (73% of dose) with low amounts of the glucuronide also appearing in the urine. The effective t_½ is approximately 11 hrs under fasting conditions. The apparent plasma clearance (CL/F) is about 500 mL/min.
Special Populations: Elderly: At steady-state, elderly subjects (>65 yrs) had a 40% higher C_max and a 50% higher AUC compared to the young subjects. In elderly females, celecoxib C_max and AUC are higher than those for elderly males, but these increases are predominantly due to lower body weight in elderly females. Dose adjustment in the elderly is not generally necessary. However, for patients <50 kg body weight, initiate therapy at the lowest recommended dose.
Children: Celecoxib has not been investigated in children <18 yrs.
Hepatic Insufficiency: Steady-state celecoxib AUC is increased about 40% and 180% in subjects with mild (Child-Pugh Class A) and moderate (Child-Pugh Class B) hepatic impairment respectively, as compared to healthy control subjects. Therefore, the daily recommended dose of celecoxib should be reduced by approximately 50% in patients with moderate (Child-Pugh Class B) hepatic impairment. Patients with severe hepatic impairment (Child-Pugh Class C) have not been studied.
Renal Insufficiency: Studies indicate that celecoxib AUC was approximately 40% lower in patients with chronic renal insufficiency (GFR 36-60 mL/min) than that seen in subjects with normal renal function. No significant relationship was found between GFR and celecoxib clearance. Patients with severe renal insufficiency have not been studied.