Details of Drug Interaction

Details of Drug-Drug Interaction

 Drug General Information (ID: DDI3LJKQCW)
  Drug Name Ticlopidine Drug Info Clopidogrel Drug Info
  Drug Type Small molecule Small molecule
  Therapeutic Class Fibrinolytic Agents Antiplatelet Agents
  Structure

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

Recommended Action
      Management Based on existing data, patients treated with clopidogrel should preferably avoid the concomitant use of potent CYP450 2C19 inhibitors such as fluconazole, fluoxetine, fluvoxamine, and ticlopidine. Concomitant use of selective serotonin reuptake inhibitors or ticlopidine with clopidogrel may also potentiate the risk of bleeding complications due to additive or synergistic effects on the clotting cascade.

References
1 Collet JP, Hulot JS, Pena A, et al. "Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study." Lancet 373 (2009): 309-17. [PMID: 19108880]
2 Frere C, Cuisset T, Morange PE, et al. "Effect of Cytochrome P450 Polymorphisms on Platelet Reactivity After Treatment With Clopidogrel in Acute Coronary Syndrome." Am J Cardiol 101 (2008): 1088-1093. [PMID: 18394438]
3 Gilard M, Arnaud B, Cornily JC, et al "Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study." J Am Coll Cardiol 51 (2008): 256-60. [PMID: 18206732]
4 Gilard M, Arnaud B, Le Gal G, Abgrall JF, Boschat J "Influence of omeprazol on the antiplatelet action of clopidogrel associated to aspirin." J Thromb Haemost 4 (2006): 2508-9. [PMID: 16898956]
5 Hirsh-Rokach B, Spectre G, Shai E, et al. "Differential impact of selective serotonin reuptake inhibitors on platelet response to clopidogrel: a randomized, double-blind, crossover trial." Pharmacotherapy 35 (2015): 140-147. [PMID: 25689244]
6 Hulot JS, Bura A, Villard E, et al. "Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects." Blood (2006):. [PMID: 16772608]
7 Juurlink DN, Gomes T, Ko DT, et al "A population-based study of the drug interaction between proton pump inhibitors and clopidogrel." CMAJ 180 (2009): 713-8. [PMID: 19176635]
8 Lau WC, Gurbel PA "The drug-drug interaction between proton pump inhibitors and clopidogrel." CMAJ 180 (2009): 699-700. [PMID: 19332744]
9 Li XQ, Andersson TB, Ahlstrom M, Weidolf L "Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities." Drug Metab Dispos 32 (2004): 821-7. [PMID: 15258107]
10 Mega JL, Close SL, Wiviott SD, et al. "Cytochrome p-450 polymorphisms and response to clopidogrel." N Engl J Med 360 (2009): 354-62. [PMID: 19106084]
11 Moayyedi P, Sadowski DC "Proton pump inhibitors and clopidogrel -- hazardous drug interaction or hazardous interpretation of data?" Can J Gastroenterol 23 (2009): 251-2. [PMID: 19373416]
12 Pezalla E, Day D, Pulliadath I "Initial assessment of clinical impact of a drug interaction between clopidogrel and proton pump inhibitors." J Am Coll Cardiol 52 (2008): 1038-9. [PMID: 18786491]
13 Siller-Matula JM, Spiel AO, Lang IM, Kreiner G, Christ G, Jilma B "Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel." Am Heart J 157 (2009): 148.e1-5. [PMID: 19081411]
14 Simon T, Verstuyft C, Mary-Krause M, et al "Genetic determinants of response to clopidogrel and cardiovascular events." N Engl J Med 360 (2009): 363-75. [PMID: 19106083]
15 Small DS, Farid NA, Payne CD, et al. "Effects of the proton pump inhibitor lansoprazole on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel." J Clin Pharmacol 48 (2008): 475-84. [PMID: 18303127]
16 Varenhorst C, Janes S, Erlinge D, et al "Genetic variation of CYP2C19 affects both pharmacokinetic and pharmacodynamic responses to clopidogrel but not prasugrel in aspirin-treated patients with coronary artery disease." Eur Heart J 30 (2009): 1744-52. [PMID: 19429918]