Details of Drug Interaction

Details of Drug-Drug Interaction

 Drug General Information (ID: DDIS7HV4RN)
  Drug Name Fluconazole Drug Info Ethotoin Drug Info
  Drug Type Small molecule Small molecule
  Therapeutic Class Antifungal Agents Anticonvulsants
  Structure

 Mechanism of Fluconazole-Ethotoin Interaction (Severity Level: Major)
     CYP450 enzyme inhibition Click to Show/Hide Mechanism Graph
Could Not Find 2D Structure
      Drug Name Fluconazole Ethotoin
      Mechanism 1 CYP450 2C19 inhibitor CYP450 2C19 substrate
      Key Mechanism Factor 1
Factor Name Cytochrome P450 2C19
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Structure Sequence
MDPFVVLVLCLSCLLLLSIWRQSSGRGKLPPGPTPLPVIGNILQIDIKDVSKSLTNLSKIYGPVFTLYFGLERMVVLHGYEVVKEALIDLGEEFSGRGHFPLAERANRGFGIVFSNGKRWKEIRRFSLMTLRNFGMGKRSIEDRVQEEARCLVEELRKTKASPCDPTFILGCAPCNVICSIIFQKRFDYKDQQFLNLMEKLNENIRIVSTPWIQICNNFPTIIDYFPGTHNKLLKNLAFMESDILEKVKEHQESMDINNPRDFIDCFLIKMEKEKQNQQSEFTIENLVITAADLLGAGTETTSTTLRYALLLLLKHPEVTAKVQEEIERVIGRNRSPCMQDRGHMPYTDAVVHEVQRYIDLIPTSLPHAVTCDVKFRNYLIPKGTTILTSLTSVLHDNKEFPNPEMFDPRHFLDEGGNFKKSNYFMPFSAGKRICVGEGLARMELFLFLTFILQNFNLKSLIDPKDLDTTPVVNGFASVPPFYQLCFIPV
Gene Name CYP2C19
Uniprot ID CP2CJ_HUMAN
KEGG Pathway hsa:1557
Protein Family Cytochrome P450 family
Protein Function
A cytochrome P450 monooxygenase involved in the metabolism of polyunsaturated fatty acids (PUFA) (PubMed:18577768, PubMed:19965576, PubMed:20972997). 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:18577768, PubMed:19965576, PubMed:20972997). Catalyzes the hydroxylation of carbon-hydrogen bonds. Hydroxylates PUFA specifically at the omega-1 position (PubMed:18577768). Catalyzes the epoxidation of double bonds of PUFA (PubMed:20972997, PubMed:19965576). Also metabolizes plant monoterpenes such as limonene. Oxygenates (R)- and (S)-limonene to produce carveol and perillyl alcohol (PubMed:11950794). Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine. Hydroxylates fenbendazole at the 4' position (PubMed:23959307).
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      Mechanism Description
  • Decreased metabolism of Ethotoin caused by Fluconazole mediated inhibition of CYP450 enzyme
      Mechanism 2 CYP450 2C9 inhibitor CYP450 2C9 substrate
      Key Mechanism Factor 2
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 Ethotoin caused by Fluconazole mediated inhibition of CYP450 enzyme

Recommended Action
      Management Close clinical monitoring of patient response, tolerance, and serum hydantoin concentrations is recommended whenever fluconazole is added, discontinued, or the dose changed. Patients should be advised to notify their doctor if they experience symptoms of toxicity (drowsiness, visual disturbances, change in mental status, nausea, or ataxia). A reduction in hydantoin dosage may be necessary.

References
1 Blum RA, Wilton JH, Hilligoss DM, et al "Effect of fluconazole on the disposition of phenytoin." Clin Pharmacol Ther 49 (1991): 420-5. [PMID: 2015731]
2 Cadle RM, Zenon GJ III, Rodriguez-Barradas MC, Hamil RJ "Fluconazole-induced symptomatic phenytoin toxicity." Ann Pharmacother 28 (1994): 191-5. [PMID: 8173131]
3 Cerner Multum, Inc. "Australian Product Information.".
4 Cerner Multum, Inc. "UK Summary of Product Characteristics.".
5 Grant SM, Clissold SP "Fluconazole: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in superficial and systemic mycoses." Drugs 39 (1990): 877-916. [PMID: 2196167]
6 Holechek MJ "Medication review: fluconazole." ANNA J 18 (1991): 585-6. [PMID: 1750792]
7 Howitt KM, Oziemski MA "Phenytoin toxicity induced by fluconazole." Med J Aust 151 (1989): 603-4. [PMID: 2556633]
8 Lazar JD, Wilner KD "Drug interactions with fluconazole." Rev Infect Dis 12 Suppl 3 (1990): s327-33. [PMID: 2330488]
9 Mitchell AS, Holland JT "Fluconazole and phenytoin: a predictable interaction." Br Med J 298 (1989): 1315. [PMID: 2544241]
10 Morrow JD "Fluconazole: a new triazole antifungal agent." Am J Med Sci 302 (1991): 129-32. [PMID: 1897559]
11 Product Information. Diflucan (fluconazole). Roerig Division, New York, NY.
12 Product Information. Dilantin (phenytoin). Parke-Davis, Morris Plains, NJ.
13 Touchette MA, Chandrasekar PH, Milad MA, Edwards DJ "Contrasting effects of fluconazole and ketoconazole on phenytoin and testosterone disposition in man." Br J Clin Pharmacol 34 (1992): 75-8. [PMID: 1633070]
14 Vincent-Ballereau FN, Patey ON, Lafaix C "Fluconazole: review and situation among antifungal drugs in the treatment of opportunistic mycoses of human immuno-deficiency virus infections." Pharm Weekbl Sci 13 (1990): 45-57. [PMID: 1870943]