Clinical Pharmacokinetics and Pharmacodynamics of Celecoxib

Abstract

Celecoxib, a nonsteroidal anti-inflammatory drug (NSAID), is the first specific inhibitor of cyclo-oxygenase-2 (COX-2) approved to treat patients with rheumatism and osteoarthritis. Preliminary data suggest that celecoxib also has analgesic and anticancer properties. The selective inhibition of COX-2 is thought to lead to a reduction in the unwanted effects of NSAIDs. Upper gastrointestinal complication rates in clinical trials are significantly lower for celecoxib than for traditional nonselective NSAIDs (e.g. naproxen, ibuprofen and diclofenac). The rate of absorption of celexocib is moderate when given orally (peak plasma drug concentration occurs after 2 to 4 hours), although the extent of absorption is not known. Celexocib is extensively protein bound, primarily to plasma albumin, and has an apparent volume of distribution of 455+/-166L in humans. The area under the plasma concentration-time curve (AUC) of celecoxib increases in proportion to increasing oral doses between 100 and 800mg. Celecoxib is eliminated following biotransformation to carboxylic acid and glucuronide metabolites that are excreted in urine and faeces, with little drug (2%) being eliminated unchanged in the urine. Celecoxib is metabolised primarily by the cytochrome P450 (CYP) 2C9 isoenzyme and has an elimination half-life of about 11 hours in healthy individuals. Racial differences in drug disposition and pharmacokinetic changes in the elderly have been reported for celecoxib. Plasma concentrations (AUC) of celecoxib appear to be 43% lower in patients with chronic renal insufficiency [glomerular filtration rate 2.1 to 3.6 L/h (35 to 60 ml/min)] compared with individuals with healthy renal function, with a 47% increase in apparent clearance. Compared with healthy controls, it has been reported that the steady-state AUC is increased by approximately 40% and 180% in patients with mild and moderate hepatic impairment, respectively. Celecoxib does not appear to interact with warfarin, ketoconazole or methotrexate; however, clinically significant drug interactions with fluconazole and lithium have been documented. As celecoxib is metabolised by CYP2C9, increased clinical vigilance is required during the coadministration of other substrates or inhibitors of this enzyme.

Altered GABAergic neurotransmission is associated with increased kainate-induced seizure in prostaglandin-endoperoxide synthase-2 deficient mice

“…The increased seizure intensity and FJB staining was associated with plasma celecoxib concentrations of 13.4 ± 2.6 μg/ml and 18.2 ± 5.8 μg/ml in mice receiving 3000 or 6000 ppm celecoxib in the diet, respectively. These plasma concentrations are within the same order of magnitude of steady state concentrations (2-3 μg/ml) observed in humans exposed chronically to 400-800 mg of celecoxib, doses normally used for the treatment of conditions such as rheumatoid arthritis and familial adenomatous polyposis [13]. Since only the unbound concentration (approximately 98%) of celecoxib is free to distribute across the blood brain barrier [14], this would place the range of brain concentrations of celecoxib in the human population and our study at approximately 160-940 nM, well above the IC 50 (39nM) of celecoxib for COX-2 [19].…”

“…For celecoxib pretreatment, PTGS-2 +/+ mice were given free access for six weeks to a diet containing 0, 3000 or 6000 ppm celecoxib. Celecoxib is a COX-2 specific inhibitor with a selectivity ratio of >375 [13]. Celebrex™ capsules (400 mg; Pfizer Inc, New York, NY) were obtained from the NIH Division of Veterinary Medicine and were incorporated into feed by Research Diets, Inc. (New Brunswick, NJ) [73].…”

Oxidation of celecoxib by polymorphic cytochrome P450 2C9 and alcohol dehydrogenase

“…Celecoxib is a potent selective COX-2 inhibitor used in the treatment of rheumatoid and ostheoarthritis [3]. Celecoxib is metabolized in the liver by methyl hydroxylation, followed by further oxidation to carboxycelecoxib, which is the major metabolite found in blood.…”

Postoperative analgesia using fentanyl plus celecoxib versus epidural anesthesia after laparoscopic colon resection

“…The combination of fentanyl and celecoxib maintained a low postoperative pain score, the effect being almost comparable to that of epidural anesthesia, except on POD 1. Moreover, the need for rescue analgesic drugs was significantly lower in group FC than in group E. In a previous report, the mean maximum drug plasma concentration of celecoxib was reached about 2-4 h after a single 200-mg oral dose [24]. Because NSAIDs exert synergistic analgesic effects when used concomitantly with opioids [20], we considered that the continuous fentanyl infusion should be stopped when the blood concentration of celecoxib had reached the therapeutic dose.…”

“…It has been suggested that NSAIDs might increase the risk of gastrointestinal ulcers, renal toxicity, or anastomotic leakage [24,28]. Although celecoxib, a selective COX-2 inhibitor, has renal toxicity equivalent to that of a non-selective COX inhibitor, it has less gastrointestinal toxicity [24].…”