scholarly journals The Pharmacogenetics of Cytochrome P450 2C19 Enzymes - Effects on Clopidogrel and Proton Pump Inhibitors

2014 ◽  
Vol 6 (1) ◽  
pp. 33
Author(s):  
Yusmiati Yusmiati ◽  
Dewi Muliaty
Keyword(s):  
Cytochrome P450 ◽  
Proton Pump Inhibitors ◽  
Proton Pump ◽  
Platelet Reactivity ◽  
Active Form ◽  
Anti Platelet Therapy ◽  
Cytochrome P450 2C19 ◽  
Cyp2c19 Gene ◽  
Anti Platelet Drug ◽  
Clopidogrel Therapy

BACKGROUND: Cytochrome P450 (CYP) enzymes play important roles in human, including drug metabolism. CYP2 is the largest family of human CYP, with its sequence comprising almost one third of all CYP sequences, and responsible for the metabolism of approximately 2% of clinically administrated drugs. One of the most important enzymes in this family is the CYP2C19 enzyme. The CYP2C19 gene is polymorphic, and the variation is common especially in the Asian population.CONTENT: CYP2C19 is responsible for the metabolism of various drugs, including proton pump inhibitors (PPIs) such as omeprazole and lansoprazole, psychotropic drugs including diazepam and imipramine, anticonvulsants such as phenobarbital and mephenytoin. and the recently most studied the anti-platelet drug, clopidogrel, and many others. Drugs metabolized predominantly by this enzyme like clopidogrel and PPIs might be much affected by the genotype status of CYP2C19. Clopidogrel is a pro-drug requiring a group of enzymes to convert to its active form, particularly the CYP2C19. PPIs are metabolized to its inactive metabolites mainly by CYP2C19 in the liver. Some PPIs are inhibitor of CYP2C19 enzymes, and interaction of PPIs and clopidogrel has been widely studied.SUMMARY: The association of CYP2C19 genotypes with the plasma level of active clopidogrel and platelet reactivity in individual taking this drug is well-established. Although conflicting results still exist for the association of CYP2C19 genotypes to the clinical outcomes of clopidogrel therapy, this effect seems to be consistent in patients receiving clopidogrel for coronary stents. Due to the interaction of certain PPIs and clopidogrel, the use of PPIs other than omeprazole is recommended, especially for patients taking dual anti platelet therapy of clopidogrel and aspirin.KEYWORDS: pharmacogenetics, CYP2C19, proton pump inhibitors, clopidogrel

Abstract 3998: Proton Pump Inhibitors Effect on Clopidogrel Effectiveness: The Clopidogrel Medco Outcomes Study

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Ronald E Aubert ◽  
Robert S Epstein ◽  
J R Teagarden ◽  
Fang Xia ◽  
Jianying Yao ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Proton Pump Inhibitors ◽  
Proton Pump ◽  
Stent Placement ◽  
Adverse Outcomes ◽  
Coronary Artery Stent ◽  
Cytochrome P450 2C19 ◽  
Potential Impact ◽  
One Year ◽  
The One

Background: The anti-platelet properties of clopidogrel are thought to be activated by cytochrome P450 2C19. This isoenzyme is potently inhibited by the most commonly prescribed proton pump inhibitors (PPIs) and therefore may interfere with clopidogrel activation and its anti-platelet effects. Methods: We investigated the potential impact of PPIs on the effectiveness of clopidogrel to prevent coronary artery stent re-stenosis through a retrospective cohort study using the National Medco Integrated Database file, which covers approximately 19 million lives. We selected patients who underwent stent placement at sometime during a one-year period in 2005–2006, who started taking clopidogrel at the time of stent placement, and who were at least 80% compliant during the ensuing year (n=14,383). We followed these patients for the one-year incidence of major adverse CV events: hospitalization for stroke, MI, angina or CABG. We compared those who took clopidogrel alone (n=9862) vs. those who took clopidogrel with PPIs (n=4521), adjusting for baseline differences in age, gender and comorbidity. Results: Stent patients with no preceding CV events taking PPIs with clopidogrel showed a 32.5% incidence of a major CV event within one year vs. 21.2% of patients not taking PPIs (adjusted OR 1.79, CI 1.62–1.97). A more pronounced effect was seen among patients with a preceding CV event; 39.8% vs 26.2% (adjusted OR of 1.86, CI 1.63–2.12). Conclusions: Our findings suggest that the drug interaction between PPIs and clopidogrel may result in serious adverse outcomes within one year of therapy initiation, and further support investigations into the effects of cytochrome P450 2C19 genetic polymorphisms.

184 RELATIONSHIPS OF CYTOCHROME P450 2C19 GENOTYPES WITH PHARMACOKINETICS AND ANTI-H. PYLORI EFFICACY OF PROTON PUMP INHIBITORS

1996 ◽  
Vol 19 (5) ◽  
pp. 593
Author(s):  
Y. Tanigawara ◽  
T. Kita ◽  
N. Aoyama ◽  
K. Shirakawa ◽  
F. Komada ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Proton Pump Inhibitors ◽  
Proton Pump ◽  
Cytochrome P450 2C19 ◽  
H Pylori

Evaluation of Six Proton Pump Inhibitors As Inhibitors of Various Human Cytochromes P450: Focus on Cytochrome P450 2C19

2012 ◽  
Vol 40 (9) ◽  
pp. 1698-1711 ◽  
Author(s):  
Tatyana Zvyaga ◽  
Shu-Ying Chang ◽  
Cliff Chen ◽  
Zheng Yang ◽  
Ragini Vuppugalla ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Proton Pump Inhibitors ◽  
Proton Pump ◽  
Cytochromes P450 ◽  
Cytochrome P450 2C19

Proton pump inhibitors, genetic polymorphisms and response to clopidogrel therapy

2011 ◽  
Vol 105 (06) ◽  
pp. 933-944 ◽  
Author(s):  
Himawan Fernando ◽  
Anthony Dart ◽  
Karlheinz Peter ◽  
James Shaw
Keyword(s):  
Genetic Polymorphisms ◽  
Proton Pump Inhibitors ◽  
Proton Pump ◽  
Active Form ◽  
Poor Response ◽  
Current Evidence ◽  
Considerable Proportion ◽  
Gi Bleeding ◽  
Clopidogrel Therapy ◽  
Coronary Syndromes

SummaryClopidogrel has become part of the mainstay of therapy for acute coronary syndromes and in patients post stenting. Clopidogrel is a pro drug and is metabolised by liver enzymes, particularly CYP2C19, into its active form. A considerable proportion of patients have a poor response to clopidogrel and this may be due to several factors. Genetic polymorphisms involved in clopidogrel’s absorption, metabolism and activity at the platelet may interfere with its antiplatelet actions. Further, proton pump inhibitors (PPI) may interfere with clopidogrel’s actions by functionally reducing the ability of CYP2C19 to convert clopidogrel to its active metabolite. By attenuating clopidogrel’s actions, both polymorphisms and drug interactions may increase the risk of thrombotic events during clopidogrel therapy. This review will explore the current evidence relating to the association between PPIs, genetic polymorphisms and poor response to clopidogrel. Routine genetic testing cannot be recommended for patients receiving dual antiplatelet therapy (DAPT). However, it may have a role for patients with an episode of stent thrombosis, prior to planned high-risk stenting or major bleeding. Regarding concomitant clopidogrel and PPI therapy, it is recommended that only patients with previous gastrointestinal (GI) bleeding or multiple risk factors for GI bleeding should be prescribed gastroprotection. This is due to the uncertainty surrounding the clinical significance of this interaction given the discordant biochemical and clinical data, conflicting results from observational studies and the limitations of the COGENT study. Pantoprazole seems least likely to interact with clopidogrel and most suitable for use in patients receiving DAPT.

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