Details of Drug Interaction

Details of Drug-Drug Interaction

 Drug General Information (ID: DDI5TGJBCM)
  Drug Name Dicoumarol Drug Info Miconazole Drug Info
  Drug Type Small molecule Small molecule
  Therapeutic Class Anticoagulants Antifungal Agents
  Structure

 Mechanism of Dicoumarol-Miconazole Interaction (Severity Level: Major)
     CYP450 enzyme inhibition Click to Show/Hide Mechanism Graph
Could Not Find 2D Structure
      Drug Name Dicoumarol Miconazole
      Mechanism CYP450 2C9 substrate CYP450 2C9 inhibitor
      Key Mechanism Factor 1
Factor Name Cytochrome P450 2C9
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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 Dicoumarol caused by Miconazole mediated inhibition of CYP450 enzyme

Recommended Action
      Management Patients receiving warfarin or other oral anticoagulants should be closely monitored during concomitant therapy with miconazole. The INR should be checked frequently and anticoagulant dosage adjusted accordingly, particularly following initiation or discontinuation of miconazole therapy in patients who are stabilized on their anticoagulant regimen. 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. Some authorities consider the use of oral miconazole with warfarin to be contraindicated. Although vaginally administered miconazole is generally less than 2% absorbed in healthy women of childbearing age, increased absorption may occur in the presence of atrophic vaginal epithelium. Therefore, the same precaution is applicable when vaginal formulations of miconazole is prescribed to women receiving oral anticoagulant therapy.

References
1 Colquhoun MC, Daly M, Stewart P, Beeley L "Interaction between warfarin and miconazole oral gel." Lancet 1 (1987): 695-6. [PMID: 2882124]
2 Shenfield GM, Page M "Potentiation of warfarin action by miconazole oral gel." Aust N Z J Med 21 (1991): 928. [PMID: 1818557]
3 Watson PG, Lochan RG, Redding VJ "Drug interaction with coumarin derivative anticoagulants." Br Med J 285 (1982): 1045-6. [PMID: 6812734]