Details of Drug Interaction

Details of Drug-Drug Interaction

 Drug General Information (ID: DDIP9SN587)
  Drug Name Cimetidine Drug Info Fosphenytoin Drug Info
  Drug Type Small molecule Small molecule
  Therapeutic Class Antiulcer Agents Anticonvulsants
  Structure

 Mechanism of Cimetidine-Fosphenytoin Interaction (Severity Level: Major)
     CYP450 enzyme inhibition Click to Show/Hide Mechanism Graph
Could Not Find 2D Structure
      Drug Name Cimetidine Fosphenytoin
      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).
    Click to Show/Hide
      Mechanism Description
  • Decreased metabolism of Fosphenytoin caused by Cimetidine 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 Fosphenytoin caused by Cimetidine mediated inhibition of CYP450 enzyme

Recommended Action
      Management The use of cimetidine should generally be avoided in patients treated with phenytoin because safer alternatives exist, such as other H2-receptor antagonists or proton pump inhibitors. These agents (except omeprazole) have demonstrated a lack of interaction with phenytoin in pharmacokinetic studies, and only rare cases of suspected interaction have been reported, if any.

References
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14 Khan AY, Kalimuddin MN, Gorman JM "Neuropsychiatric manifestations of phenytoin toxicity in an elderly patient." J Psychiatr Pract 13 (2007): 49-54. [PMID: 17242593]
15 Labenz J, Petersen KU, Rosch W, Koelz HR "A summary of Food and Drug Administration-reported adverse events and drug interactions occurring during therapy with omeprazole, lansoprazole and pantoprazole." Aliment Pharmacol Ther 17 (2003): 1015-1019. [PMID: 12694083]
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20 Product Information. Aciphex (rabeprazole) Janssen Pharmaceuticals, Titusville, NJ.
21 Product Information. Axid (nizatidine). Lilly, Eli and Company, Indianapolis, IN.
22 Product Information. Nexium (esomeprazole) Astra-Zeneca Pharmaceuticals, Wilmington, DE.
23 Product Information. Pepcid (famotidine). Merck & Co, Inc, West Point, PA.
24 Product Information. Prevacid (lansoprazole). TAP Pharmaceuticals Inc, Deerfield, IL.
25 Product Information. Prilosec (omeprazole). Merck & Co, Inc, West Point, PA.
26 Product Information. Protonix (pantoprazole) Wyeth-Ayerst Laboratories, Philadelphia, PA.
27 Product Information. Zantac (ranitidine). Glaxo Wellcome, Research Triangle Park, NC.
28 Rafi JA, Frazier LM, Driscoll-Bannister SM, O'Hara KA, Garnett WR, Pugh CB "Effect of over-the-counter cimetidine on phenytoin concentrations in patients with seizures." Ann Pharmacother 33 (1999): 769-74. [PMID: 10466901]
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31 Smith SR, Kendall MJ "Ranitidine versus cimetidine: a comparison of their potential to cause clinically important drug interactions." Clin Pharmacokinet 15 (1988): 44-56. [PMID: 3042245]
32 Sorkin EM, Darvey DL "Review of cimetidine drug interactions." Drug Intell Clin Pharm 17 (1983): 110-20. [PMID: 6130930]
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