Details of Drug Interaction

Details of Drug-Drug Interaction

 Drug General Information (ID: DDIV63NUFD)
  Drug Name Phenytoin Drug Info Metronidazole Drug Info
  Drug Type Small molecule Small molecule
  Therapeutic Class Anticonvulsants Antiinfective Agents
  Structure

 Mechanism of Phenytoin-Metronidazole Interaction (Severity Level: Moderate)
     CYP450 enzyme inhibition Click to Show/Hide Mechanism Graph
Could Not Find 2D Structure
      Drug Name Phenytoin Metronidazole
      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 Phenytoin caused by Metronidazole mediated inhibition of CYP450 enzyme

Recommended Action
      Management Pharmacologic response and serum phenytoin levels should be monitored more closely whenever metronidazole is added to or withdrawn from therapy, and the phenytoin (or fosphenytoin) dosage adjusted as necessary. Patients should be advised to notify their physician if they experience potential symptoms of phenytoin toxicity such as nausea, vomiting, nystagmus, slurred speech, lethargy, tremor, ataxia, hyperreflexia, and dysarthria. Given its structural similarities to metronidazole, the same precaution may be applicable during therapy with tinidazole, although clinical data are lacking.

References
1 Blyden GT, Scavone JM, Greenblatt DJ "Metronidazole impairs clearance of phenytoin but not of alprazolam or lorazepam." J Clin Pharmacol 28 (1988): 240-5. [PMID: 3360972]
2 Jensen JC, Gugler R "Interaction between metronidazole and drugs eliminated by oxidative metabolism." Clin Pharmacol Ther 37 (1985): 407-10. [PMID: 3979002]
3 Product Information. Flagyl (metronidazole). Searle, Skokie, IL.
4 Product Information. Tindamax (tinidazole). Presutti Laboratories Inc, Arlington Heights, IL.