Details of Drug Interaction

Details of Drug-Drug Interaction

 Drug General Information (ID: DDILQE8XN5)
  Drug Name Sulfasalazine Drug Info Anisindione Drug Info
  Drug Type Small molecule Small molecule
  Therapeutic Class Antiinflammatory Agents Anticoagulants
  Structure

 Mechanism of Sulfasalazine-Anisindione Interaction (Severity Level: Major)
     Competitive binding of plasma proteins Click to Show/Hide Mechanism Graph
Could Not Find 2D Structure
      Drug Name Sulfasalazine Anisindione
      Mechanism 1 Competition for plasma protein binding sites Competition for plasma protein binding sites
      Key Mechanism Factor 1
Factor Name Plasma protein binding
Factor Description Plasma protein binding refers to the degree of binding of a drug to proteins in the blood, and the lower the degree of binding, the more efficiently the drug can cross cell membranes or diffuse. Plasma protein binding alters the distribution and therapeutic characteristics of the drugs.
      Mechanism Description
  • Increased plasma concentration of Anisindione and Sulfasalazine due to competitive binding of plasma proteins
     CYP450 enzyme inhibition Click to Show/Hide Mechanism Graph
Could Not Find 2D Structure
      Drug Name Sulfasalazine Anisindione
      Mechanism 2 CYP450 2C9 inhibitor CYP450 2C9 substrate
      Key Mechanism Factor 2
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
  • Decreased metabolism of Anisindione caused by Sulfasalazine mediated inhibition of CYP450 enzyme

Recommended Action
      Management Patients receiving coumarin anticoagulants should be closely monitored during concomitant therapy with sulfonamides. The INR should be checked frequently and coumarin dosage adjusted accordingly, particularly following initiation or discontinuation of sulfonamide therapy in patients who are stabilized on their anticoagulant regimen. The same precaution may be applicable during therapy with other oral anticoagulants (e.g., indandiones), 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 Cook DE, Ponte CD "Suspected trimethoprim sulfamethoxazole induced hypoprothrombinemia." J Fam Pract 39 (1994): 589-91. [PMID: 7798864]
2 Fischer HD, Juurlink DN, Mamdani MM, Kopp A, Laupacis A "Hemorrhage during warfarin therapy associated with cotrimoxazole and other urinary tract anti-infective agents: a population-based study." Arch Intern Med 170 (2010): 617-21. [PMID: 20386005]
3 Glasheen JJ, Fugit RV, Prochazka AV "The risk of overanticoagulation with antibiotic use in outpatients on stable warfarin regimens." J Gen Intern Med 20 (2005): 653-6. [PMID: 16050864]
4 Hermans JJ, Thijssen HH "Human liver microsomal metabolism of the enantiomers of warfarin and acenocoumarol: P450 isozyme diversity determines the differences in their pharmacokinetics." Br J Pharmacol 110 (1993): 482-90. [PMID: 8220911]
5 Hermida J, Zarza J, Alberca I, et al. "Differential effects of 2C9*3 and 2C9*2 variants of cytochrome P-450 CYP2C9 on sensitivity to acenocoumarol." Blood 99 (2002): 4237-9. [PMID: 12010835]
6 Kelly JG, O'Malley K "Clinical pharmacokinetics of oral anticoagulants." Clin Pharmacokinet 4 (1979): 1-15. [PMID: 369763]
7 Lumholtz B, Siersbaek-Nielsen K, Skovsted L, Kampmann J, Hansen JM "Sulfamethizole-induced inhibition of diphenylhydantoin, tolbutamide, and warfarin metabolism." Clin Pharmacol Ther 17 (1975): 731-4. [PMID: 1139863]
8 Miners JO, Birkett DJ "Cytochrome P4502C9: an enzyme of major importance in human drug metabolism." Br J Clin Pharmacol 45 (1998): 525-38. [PMID: 9663807]
9 O'Donnell D "Antibiotic-induced potentiation of oral anticoagulant agents." Med J Aust 150 (1989): 163-4. [PMID: 2716588]
10 O'Reilly RA "Stereoselective interaction of trimethoprim-sulfamethaxazole with the separated enantiomorphs of racemic warfarin in man." N Engl J Med 302 (1980): 33-5. [PMID: 7350395]
11 O'Reilly RA, Motley CH "Racemic warfarin and trimethoprim-sulfamethoxazole interaction in humans." Ann Intern Med 91 (1979): 34-6. [PMID: 464451]
12 Penning-van Beest F, Erkens J, Petersen KU, Koelz HR, Herings R "Main comedications associated with major bleeding during anticoagulant therapy with coumarins." Eur J Clin Pharmacol 61 (2005): 439-44. [PMID: 15947920]
13 Penning-van Beest FJ, van Meegen E, Rosendaal FR, Stricker BH "Drug interactions as a cause of overanticoagulation on phenprocoumon or acenocoumarol predominantly concern antibacterial drugs." Clin Pharmacol Ther 69 (2001): 451-7. [PMID: 11406743]
14 Self TH, Evans W, Ferguson T "Interaction of sulfisoxizole and warfarin." Circulation 52 (1975): 528. [PMID: 1157265]
15 Serlin MJ, Breckenridge AM "Drug interactions with warfarin." Drugs 25 (1983): 610-20. [PMID: 6347619]
16 Sioris LJ, Weibert RT, Pentel PR "Potentiation of warfarin anaticoagulation by sulfisoxazole." Arch Intern Med 140 (1980): 546-7. [PMID: 7362390]
17 Takahashi H, Wilkinson GR, Caraco Y, et al. "Population differences in S-warfarin metabolism between CYP2C9 genotype-matched Caucasian and Japanese patients." Clin Pharmacol Ther 73 (2003): 253-63. [PMID: 12621390]
18 Thijssen HH, Flinois JP, Beaune PH "Cytochrome P4502C9 is the principal catalyst of racemic acenocoumarol hydroxylation reactions in human liver microsomes." Drug Metab Disposition 28 (2000): 1284-90. [PMID: 11038154]
19 Venkatakrishnan K, vonMoltke LL, Greenblatt DJ "Effects of the antifungal agents on oxidative drug metabolism - Clinical relevance." Clin Pharmacokinet 38 (2000): 111-80. [PMID: 10709776]
20 Visser LE, Penning-Van Bees FJ, Harrie Kasbergen AA, et al. "Overanticoagulation associated with combined use of antibacterial drugs and acenocoumarol or phenprocoumon anticoagulants." Thromb Haemost 88 (2002): 705-10. [PMID: 12428081]
21 Wells PS, Holbrook AM, Crowther NR, Hirsh J "Interactions of warfarin with drugs and food." Ann Intern Med 121 (1994): 676-83. [PMID: 7944078]