Celecoxib Pathway, Pharmacokinetics

Celecoxib is a nonsteroidal anti-inflammatory drug (NSAID) with anti-inflammatory, analgesic, and antipyretic properties. It is approved for the treatment of osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, and acute pain (PMID: 10193998; 10804043). Celecoxib has also shown promise in the prevention of cancer, and has been used as an adjunct to surgery to reduce the number of adenomatous colorectal polyps in patients with the hereditary colon cancer susceptibility syndrome, Familial Adenomatous Polyposis (FAP) (PMID: 10874062; 16943401; 16943400).

Pharmacokinetics

After oral administration, celecoxib is rapidly absorbed and achieves peak serum concentration in about 3 hours. It is extensively metabolized in the liver with very little drug (<3%) being eliminated unchanged (PMID: 10681375). The major routes of excretion for celecoxib are feces and urine (PMID: 18378608). Celecoxib is metabolized primarily through methyl hydroxylation to form hydroxycelecoxib. This reaction is largely catalyzed by CYP2C9, although CYP3A4 also plays a minor (<25%) role (PMID: 10749518; 10681375; 12392591) (Figure 1). Hydroxycelecoxib is further oxidized to form carboxycelecoxib via cytosolic alcohol dehydrogenases ADH1 and ADH2 (PMID: 12392591), then conjugated with glucuronic acid via UDP glucuronosyltransferases (UGTs) to form the 1-O-glucuronide. None of the metabolites are pharmacologically active (PMID: 10749518).

Since celecoxib metabolism is predominantly mediated via CYP2C9, polymorphisms in CYP2C9 are likely to have a direct impact on celecoxib pharmacokinetics and variability in drug responses. Individuals who are poor metabolizers of CYP2C9 substrates (eg. CYP2C9*3 allele carriers) have increased exposure to celecoxib when compared to those with normal CYP2C9 activity (PMID: 11337938; 12392591; 12893985)(see Pharmacogenomics section). Drugs that inhibit CYP2C9 should therefore be used with caution in patients taking celecoxib.

Although not a substrate of CYP2D6, celecoxib inhibits this metabolic enzyme (PMID: 12891223). Drugs that are metabolized by CYP2D6 (e.g. metoprolol, (PMID: 12891223)) should also be used with caution in patients receiving celecoxib due to a potential risk of drug interaction.