Pharmacokinetics of celecoxib after oral administration in dogs and humans: effect of food and site of absorption.

Celecoxib pharmacokinetics was evaluated after single and multiple oral dosing; after dosing in a solution and as a solid; with and without food; and after administration into different sites of the GI tract using dog. After oral dosing in a solution, celecoxib was rapidly absorbed and reached maximum concentrations by 1 h; absorption was delayed another 1 to 2 h when administered as a solid. The absolute bioavailability of celecoxib was higher when given as a solution (64--88%) compared with capsule (22--40%). The absorption of celecoxib given in a capsule was delayed by food, although systemic exposure increased by 3- to 5-fold. The systemic availability of celecoxib given intragastrically in solution was similar to that obtained following direct instillation into the duodenum, jejunum, or colon through a chronic intestinal access port. Collectively, these data suggest that celecoxib is a highly permeable drug that can be absorbed throughout the GI tract and that dissolution may be a rate-limiting factor for absorption from solid dosage forms. Unlike dogs, celecoxib given to humans with a high fat meal exhibits only a slight increase in AUC(0--infinity) (11%) that is not clinically significant with regard to safety or efficacy. In humans, a lower dose and a longer GI residence time may promote the opportunity for absorption of a poorly soluble drug such as celecoxib that can be absorbed throughout the GI tract. This would minimize the effect of food on absorption; as such, patients with arthritis can be given celecoxib with or without food.

Pharmacokinetics, tissue distribution, metabolism, and excretion of celecoxib in rats.

The pharmacokinetics, tissue distribution, metabolism, and excretion of celecoxib, 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide, a cyclooxygenase-2 inhibitor, were investigated in rats. Celecoxib was metabolized extensively after i.v. administration of [(14)C]celecoxib, and elimination of unchanged compound was minor (less than 2%) in male and female rats. The only metabolism of celecoxib observed in rats was via a single oxidative pathway. The methyl group of celecoxib is first oxidized to a hydroxymethyl metabolite, followed by additional oxidation of the hydroxymethyl group to a carboxylic acid metabolite. Glucuronide conjugates of both the hydroxymethyl and carboxylic acid metabolites are formed. Total mean percent recovery of the radioactive dose was about 100% for both the male rat (9.6% in urine; 91.7% in feces) and the female rat (10.6% in urine; 91.3% in feces). After oral administration of [(14)C]celecoxib at doses of 20, 80, and 400 mg/kg, the majority of the radioactivity was excreted in the feces (88-94%) with the remainder of the dose excreted in the urine (7-10%). Both unchanged drug and the carboxylic acid metabolite of celecoxib were the major radioactive components excreted with the amount of celecoxib excreted in the feces increasing with dose. When administered orally, celecoxib was well distributed to the tissues examined with the highest concentrations of radioactivity found in the gastrointestinal tract. Maximal concentration of radioactivity was reached in most all tissues between 1 and 3 h postdose with the half-life paralleling that of plasma, with the exception of the gastrointestinal tract tissues.

Plasma protein binding of celecoxib in mice, rat, rabbit, dog and human.

The plasma protein binding of celecoxib was determined for animals and humans using in vitro and ex vivo methods. Eight, healthy, human volunteers (three male, five female, 20-39 years) received celecoxib (600 mg) BID for 7 days, blood samples were collected and concentrations of bound and unbound celecoxib determined. The fraction of bound drug in the volunteers was constant (97.4 +/- 0.1%) at total celecoxib plasma concentrations ranging from 0.01 to 4.02 microg/mL. The ex vivo plasma protein binding of celecoxib in the animals was concentration-independent up to approximately 12, 8 and 10 microg/mL for mouse, rat and dog, respectively. The plasma protein binding of celecoxib after a single oral dose of 10 and 300 mg/kg to mice was 98.3 +/- 0.2%, of 1 and 400 mg/kg to rats was 98.3 +/- 0.2% and of 1 and 100 mg/kg to dogs was 98.5 +/- 0.1%. The percent binding of celecoxib to plasma proteins in vitro was slightly lower than those values determined ex vivo. The in vitro binding of celecoxib to plasma protein was constant over the concentrations of 0.1-10 microg/mL for all species, except rat.