Details of Drug Interaction

Details of Drug-Drug Interaction

 Drug General Information (ID: DDI0T1IYR9)
  Drug Name Ticlopidine Drug Info Phenytoin Drug Info
  Drug Type Small molecule Small molecule
  Therapeutic Class Fibrinolytic Agents Anticonvulsants
  Structure

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

Recommended Action
      Management Given their narrow therapeutic index, caution is advised if phenytoin or other hydantoins must be used concomitantly with ticlopidine. Hydantoin levels and pharmacologic effects should be closely monitored and the dosage adjusted accordingly, particularly following initiation, discontinuation or change of dosage of ticlopidine in patients who are stabilized on their anticonvulsant regimen. Patients should be advised to contact their physician if they develop signs of phenytoin toxicity such as ataxia, dizziness, nausea, vomiting, and visual disturbances.

References
1 Donahue S, Flockhart DA, Abernethy DR "Ticlopidine inhibits phenytoin clearance." Clin Pharmacol Ther 66 (1999): 563-8. [PMID: 10613611]
2 Donahue SR, Flockhart DA, Abernathy DR, Jae-Wook Ko "Ticlopidine inhibition of phenytoin metabolism mediated by potent inhibition of CYP2C19." Clin Pharmacol Ther 62 (1997): 572-7. [PMID: 9390115]
3 Giancarlo GM, Venkatakrishnan K, Granda BW, vonMoltke LL, Greenblatt DJ "Relative contributions of CYP2C9 and 2C19 to phenytoin 4-hydroxylation in vitro: inhibition by sulfaphenazole, omeprazole, and ticlopidine." Eur J Clin Pharmacol 57 (2001): 31-6. [PMID: 11372587]
4 Ha-Duong NT, Dijols S, Macherey AC, Goldstein JA, Dansette PM, Mansuy D "Ticlopidine as a selective mechanism-based inhibitor of human cytochrome P450 2C19." Biochemistry 40 (2001): 12112-22. [PMID: 11580286]
5 Klaassen SL "Ticlopidine-induced phenytoin toxicity." Ann Pharmacother 32 (1998): 1295-8. [PMID: 9876809]
6 Ko JW, Desta Z, Soukhova NV, Tracy T, Flockhart DA "In vitro inhibition of the cytochrome P450 (CYP450) system by the antiplatelet drug ticlopidine: potent effect on CYP2C19 and CYP2D6." Br J Clin Pharmacol 49 (2000): 343-51. [PMID: 10759690]
7 Privitera M, Welty TE "Acute phenytoin toxicity followed by seizure breakthrough from a ticlopidine-phenytoin interaction." Arch Neurol 53 (1996): 1191-2. [PMID: 8912496]
8 Product Information. Ticlid (ticlopidine). Syntex Laboratories Inc, Palo Alto, CA.
9 Rindone JP, Bryan G "Phenytoin toxicity associated with ticlopidine administration." Arch Intern Med 156 (1996): 1113. [PMID: 8639000]
10 Riva R, Cerullo A, Albani F, Baruzzi A "Ticlopidine impairs phenytoin clearance: a case report." Neurology 46 (1996): 1172-3. [PMID: 8780118]