Pathway Celecoxib Pathway, Pharmacodynamics

Stylized cell depicting the mechanism of action of celecoxib and candidate genes interacting with celecoxib and involved in the regulation of cell cycle, apoptosis and angiogenesis by celecoxib.
Celecoxib Pathway, Pharmacodynamics
pla2g2a pla2g4a nsaids ptgs2 ptgs1 ptgis akr1c3 pgds ptges tbxas1 celecoxib vegfa mmp9 igfbp3 cdkn1a cdkn1B pparg ctnnb1 pdk1 akt1 casp9 bcar1 casp3 ddit3 ca9 ca12 ptgfr ptgdr ptgir tbxa2r ptger serca cacn kcnq
clickable pathway icons

Description

Celecoxib (Celebrex) is a selective cycloxygenase-2 (PTGS2/ COX-2) inhibitor used for treatment of osteoarthritis and rheumatoid arthritis. It acts by reducing prostaglandin synthesis through inhibition of COX-2. Selective COX-2 inhibitors appear to provide comparable anti-inflammatory effects to conventional non-steroidal anti-inflammatory agents (NSAIDs), while avoiding serious adverse reactions, in particular, gastrointestinal toxicity observed with chronic use of NSAIDs due to COX-1(PTGS1) inhibition.

PK: 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 (eg. Metoprolol, (PMID: 12891223)) should also be used with caution in patients receiving celecoxib due to a potential risk of drug interaction.

PD: Celecoxib acts by inhibiting prostaglandin synthesis via inhibition of COX2 (PTGS2). Cox enzymes (PTGS1 and PTGS2) catalyze the committed step that leads to production of prostaglandins (PGH2) from arachidonic acid. PGH2s are then converted into active metabolites (prostaglandin E2 (PGE2), prostacyclin (PGI2), thromboxane (TXA2), prostaglandin D2 (PGD2), prostaglandin F2 (PGF2)) that mediate various physiological responses such as inflammation, fever, blood pressure regulation and clotting. PTGS1/COX-1 is constitutively expressed in many cell types, while PTGS2/COX-2 expression is negligible but can be induced by growth factors, cytokines and stress in many tissues. PTGS2 level is increased in inflammatory diseases such as arthritis and in cancer cells. Most of the NSAIDs inhibit both PTGS1 and PTGS2, Selected PTGS2/COX-2 inhibitors such as celecoxib (Celebrex) and rofecoxib (Vioxx) have been developed to treat information and provide pain relief. Celecoxib is the only NSAID approved to treat Familial Adenomatous Polyposis (FAP), a genetic condition that often leads to colorectal cancer. The use of celecoxib as a possible cancer treatment is currently being explored. The exact mechanisms for its anti-cancer activity are not clear, but they most likely involve both COX-dependent and COX-independent mechanisms. The anticarcinogenic mechanisms of celecoxib generally involve induction of apoptosis, cell cycle arrest, and regulation of angiogenesis. Inhibition of cell cycle progression mediated by celecoxib is observed along with increased expression of cell cycle inhibitors CDKN1A/p21, and CDKN1B/p27 and/or decreased expression of cyclins such CCNA1, CCNB1 and CCND1. Extensive degradation of CTNNB1 (beta-catenin, which promote cell proliferation) was also observed in celecoxib treated human colon cancer cells. Induction of apoptosis by celecoxib is associated with either activation of pro-apotosis molecules such as CASP3, CASP9 and DDIT3, and/or inhibition of anti-apoptosis molecules such as PDK1 and its downstream target AKT1. Celecoxib treatment also leads to decreased expression of VEGFA and inhibition of MMP9 in cancer cells suggesting a possible mechanism for inhibition of angiogenesis and decreased tumor growth.

Authors: Li Gong..
Citation:
Gong Li, Thorn Caroline F, Bertagnolli Monica M, Grosser Tilo, Altman Russ B, Klein Teri E. "Celecoxib pathways: pharmacokinetics and pharmacodynamics" Pharmacogenetics and genomics (2012).
If you would like to reproduce this PharmGKB pathway diagram, please acknowledge the copyright to PharmGKB and state that permission has been given by PharmGKB and Stanford University. Also, please send a brief email to feedback@pharmgkb.org to inform us of which pathway diagram you are using and for what purpose.
History:
Therapeutic Categories:
  • Pain, anti-inflammatory and immunomodulating agents
  • Musculoskeletal agents

Entities in the Pathway

Genes (58)

Drugs/Drug Classes (2)

Relationships in the Pathway

Arrow FromArrow ToControllersPMID
AKT1 AKT1 PDK1 12000750
arachidonic acid PGH2 PTGS1, PTGS2 8969167
BCAR1 BCAR1 celecoxib 16353145
CACNA1A, CACNA1B, CACNA1C, CACNA1D, CACNA1E, CACNA1F, CACNA1G, CACNA1H, CACNA1I, CACNA1S, CACNA2D1, CACNA2D2, CACNA2D3, CACNA2D4, CACNB1, CACNB2, CACNB3, CACNB4 CACNA1A, CACNA1B, CACNA1C, CACNA1D, CACNA1E, CACNA1F, CACNA1G, CACNA1H, CACNA1I, CACNA1S, CACNA2D1, CACNA2D2, CACNA2D3, CACNA2D4, CACNB1, CACNB2, CACNB3, CACNB4 celecoxib 17719233, 20689646
CA12, CA9 CA12, CA9 celecoxib 16134002, 16772765, 17955049
CASP3 CASP3 celecoxib 12824303, 16550520
CASP9 CASP9 celecoxib 12824303
CDKN1A CDKN1A celecoxib 11606477, 12800245, 14973068
CDKN1B CDKN1B celecoxib 12800245, 14973068
CTNNB1 CTNNB1 celecoxib 15946992
DDIT3 DDIT3 celecoxib 17166886
IGFBP3 IGFBP3 celecoxib 15020235
KCNQ1, KCNQ2, KCNQ3, KCNQ4, KCNQ5 KCNQ1, KCNQ2, KCNQ3, KCNQ4, KCNQ5 celecoxib 19605525, 19654224, 20858500
MMP9 MMP9 celecoxib 18080123, 19218449
PDK1 PDK1 celecoxib 12000750
PGH2 PGD2 HPGDS 11729303
PGH2 PGE2 PTGES 10869354
PGH2 PGF2 AKR1C3 11729303
PGH2 PGI2 PTGIS 11729303
PGH2 TXA2 TBXAS1 11729303
Phospholipid arachidonic acid PLA2G2A, PLA2G4A 15007070, 16603549
PPARG PPARG celecoxib 16299255
PTGDR PTGDR PGD2 11729303
PTGER1, PTGER2, PTGER3, PTGER4 PTGER1, PTGER2, PTGER3, PTGER4 PGE2 11729303
PTGFR PTGFR PGF2 11729303
PTGIR PTGIR PGI2 11729303
PTGS1 PTGS1 antiinflammatory and antirheumatic products, non-steroids 8969167
PTGS2 PTGS2 antiinflammatory and antirheumatic products, non-steroids, celecoxib 10193998, 8969167
ATP2A1, ATP2A2, ATP2A3 ATP2A1, ATP2A2, ATP2A3 celecoxib 12076251
TBXA2R TBXA2R TXA2 11729303
VEGFA VEGFA celecoxib 15026340

Download data in TSV format. Other formats are available on the Downloads/LinkOuts tab.