Details of Drug Interaction | MecDDI

Drug General Information (ID: DDILV4YB5W)
Drug Name			Celecoxib		Drug Info		Anisindione		Drug Info
Drug Type		Small molecule				Small molecule
Therapeutic Class		Analgesics				Anticoagulants
Structure

Mechanism of Celecoxib-Anisindione Interaction (Severity Level: Moderate)
Competitive inhibition of metabolic enzyme Click to Show/Hide Mechanism Graph

Drug Name		Celecoxib				Anisindione
Mechanism		CYP450 2C9 substrate				CYP450 2C9 substrate
Key Mechanism Factor 1
		Factor Name		Cytochrome P450 2C9				× Structure Sequence MDSLVVLVLCLSCLLLLSLWRQSSGRGKLPPGPTPLPVIGNILQIGIKDISKSLTNLSKVYGPVFTLYFGLKPIVVLHGYEAVKEALIDLGEEFSGRGIFPLAERANRGFGIVFSNGKKWKEIRRFSLMTLRNFGMGKRSIEDRVQEEARCLVEELRKTKASPCDPTFILGCAPCNVICSIIFHKRFDYKDQQFLNLMEKLNENIKILSSPWIQICNNFSPIIDYFPGTHNKLLKNVAFMKSYILEKVKEHQESMDMNNPQDFIDCFLMKMEKEKHNQPSEFTIESLENTAVDLFGAGTETTSTTLRYALLLLLKHPEVTAKVQEEIERVIGRNRSPCMQDRSHMPYTDAVVHEVQRYIDLLPTSLPHAVTCDIKFRNYLIPKGTTILISLTSVLHDNKEFPNPEMFDPHHFLDEGGNFKKSKYFMPFSAGKRICVGEALAGMELFLFLTSILQNFNLKSLVDPKNLDTTPVVNGFASVPPFYQLCFIPV
		Gene Name		CYP2C9
		Uniprot ID		CP2C9_HUMAN
		KEGG Pathway		hsa:1559
		Protein Family		Cytochrome P450 family
		Protein Function		A cytochrome P450 monooxygenase involved in the metabolism of various endogenous substrates, including fatty acids and steroids (PubMed:7574697, PubMed:9866708, PubMed:9435160, PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:7574697, PubMed:9866708, PubMed:9435160, PubMed:12865317, PubMed:15766564, PubMed:19965576, PubMed:21576599). Catalyzes the epoxidation of double bonds of polyunsaturated fatty acids (PUFA) (PubMed:7574697, PubMed:15766564, PubMed:19965576, PubMed:9866708). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes cholesterol toward 25-hydroxycholesterol, a physiological regulator of cellular cholesterol homeostasis (PubMed:21576599). Exhibits low catalytic activity for the formation of catechol estrogens from 17beta-estradiol (E2) and estrone (E1), namely 2-hydroxy E1 and E2 (PubMed:12865317). Catalyzes bisallylic hydroxylation and hydroxylation with double-bond migration of polyunsaturated fatty acids (PUFA) (PubMed:9866708, PubMed:9435160). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S-warfarin, diclofenac, phenytoin, tolbutamide and losartan (PubMed:25994031). Click to Show/Hide
Mechanism Description		Increased plasma concentrations of Celecoxib and Anisindione due to competitive inhibition of the same metabolic pathway

Recommended Action
Management		Given the potential for interaction and the high degree of interpatient variability with respect to warfarin metabolism, patients should be closely monitored during concomitant therapy with celecoxib. The INR should be checked frequently and warfarin dosage adjusted accordingly, particularly following initiation, discontinuation or change of dosage of celecoxib in patients who are stabilized on their warfarin regimen. The same precaution may be applicable during therapy with other oral anticoagulants, although clinical data are lacking. Patients should be advised to promptly report any signs of bleeding to their physician, including pain, swelling, headache, dizziness, weakness, prolonged bleeding from cuts, increased menstrual flow, vaginal bleeding, nosebleeds, bleeding of gums from brushing, unusual bleeding or bruising, red or brown urine, or red or black stools.

References
1	Haase KK, Roias-Fernandez CH "Potential interaction between celecoxib and warfarin." Ann Pharmacother 34 (2000): 666-7. [PMID: 10852097]
2	Karim A, Tolbert D, Piergies A, et al. "Celecoxib does not significantly alter the pharmacokinetics or hypoprothrombinemic effect of warfarin in healthy subjects." J Clin Pharmacol 40 (2000): 655-63. [PMID: 10868317]
3	Leese PT, Hubbard RC, Karim A, Isakson PC, Yu SS, Geis GS "Effects of celecoxib, a novel cyclooxygenase-2 inhibitor, on platelet function in healthy adults: A randomized, controlled trial." J Clin Pharmacol 40 (2000): 124-32. [PMID: 10664917]
4	Linder JD, Klaus E, Monkemuller KE, Davis JV, Wilcox CM "Cyclooxygenase-2 inhibitor celecoxib: a possible cause of gastropathy and hypoprothrombinemia." South Med J 93 (2000): 930-2. [PMID: 11005360]
5	Malhi H, Atac B, Daly AK, Gupta S "Warfarin and celecoxib interaction in the setting of cytochrome P450 (CYP2C9) polymorphism with bleeding complication." Postgrad Med J 80 (2004): 107-109. [PMID: 14970301]
6	Mersfelder TL, Stewart LR "Warfarin and celecoxib interaction." Ann Pharmacother 34 (2000): 325-7. [PMID: 10917378]
7	Product Information. Celebrex (celecoxib). Searle, Chicago, IL.
8	Stading JA, Skrabal MZ, Faulkner MA "Seven cases of interaction between warfarin and cyclooxygenase-2 inhibitors." Am J Health Syst Pharm 58 (2001): 2076-80. [PMID: 11715832]
9	Stoner SC, Lea JW, Dubisar BM, Farrar C "Possible international normalized ratio elevation associated with celecoxib and warfarin in an elderly psychiatric patient." J Am Geriatr Soc 51 (2003): 728-729. [PMID: 12752860]