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Differences Among Proton Pump Inhibitors (PPI) Inhibition of CYP450 Enzymes and Ability to Inhibit the Activation of Clopidogrel (Plavix)

Summary:

  • While the combination of aspirin and clopidogrel are beneficial in patients with drug eluting stents, they are known to increase the risk for ulcers, which is why proton pump inhibitors were initially recommended by several professional organizations.
  • Based on the known pharmacokinetic profiles of the PPIs, it would be suggestive that lansoprazole and omeprazole to be the most potent inhibitors of 2C19 and thus more likely to inhibit the activation of clopidogrel. 
  • Pantoprazole and rabeprazole would appear to be the least likely to inhibit 2C19, thereby potentially causing the least interference with clopidogrel activation.
  • The clinical impact on this should be taken into consideration.

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Reviewers: 
Jon D. Herrington, PharmD, BCPS, BCOP
Last Reviewed: October 2015

Explanation

  • It is now known that the proton pump inhibitor (PPI) class of medications can have a potential negative impact on the ability of clopidogrel to adequately inhibit platelet aggregation for the purposes of preventing stent thrombosis.1-5  The current PPIs on the market include dexlansoprazole (Kapidex), esomeprazole (Nexium), omeprazole (Prilosec; Zegerid), lansoprazole (Prevacid), pantoprazole (Protonix), and rabeprazole (AcipHex).  Their effects on the metabolism of clopidogrel is summarized below.6-17 

    The use of both aspirin and clopidogrel are increasing due to their proven benefits in both primary and secondary prevention of cardiovascular disease (CVD) and now more importantly in patients with received drug eluting stents.18-20  Unfortunately, this combination of antiplatelet drug therapy is also known to increase the patient's risk for clinically relevant gastrointestinal (GI) bleeding.21  The potential for this adverse event has become increasingly important since the publication of a position statement sponsored by the American Heart Association (AHA) stating that patients receiving drug eluting stents should receive at least 12 months of aspirin and clopidogrel therapy.20  Due to the necessary use of both aspirin and clopidogrel therapy in patients given a drug eluting stent and recognizing the increased risk for GI bleeding, the American College of Cardiology Foundation (ACCF), in collaboration with the AHA and American College of Gastroenterology, published an Expert Consensus Document in 2008 that recommends the addition of a PPI as the preferred class of agents for the treatment and prophylaxis against aspirin-associated GI injury.21  Unfortunately, it is now known that PPIs can inhibit the activation of clopidogrel thereby decreasing its ability to inhibit platelet aggregation or stent thrombosis.  

    What is the mechanism by which PPIs can decrease the ability of clopidogrel to inhibit platelet aggregation?
    Clopidogrel is an agent that binds to and irreversibly blocks the P2Y12receptor on the surface of platelets from adenosine diphosphate (ADP) thereby inhibiting platelet aggregation.14-16 However, clopidogrel is a prodrug that, in its parent form, is devoid of antiplatelet activity.  As such, it must undergo a two-step metabolic activation process in the liver in order to generate the clopidogrel active metabolite (CAM).14-17  These sequential activating steps are achieved via oxidation of clopidogrel by hepatic CYP isoenzymes to the inactive 2-oxoclopidogrel, which is then further oxidized to the CAM.  The CYP enzymes involved in clopidogrel's activation include CYP1A2, 2B6, 2C9, 2C19, and CYP3A4.14,17  Of these enzymes, it is now evident that CYP2C19 appears to be primarily responsible for the conversion of clopidogrel to its active form and is thus important for its antiplatelet efficacy.1-4,14,17,22 

    Since PPIs are involved in causing this drug interaction, do all of the PPI's inhibit the activation of clopidogrel to the same degree?
    An evaluation of the pharmacokinetic profiles of all of the PPIs shows that they are all substrates of CYP2C9, 2C19, and 3A4 for their own metabolism and elimination.6-13  In addition, they are also known to be inhibitors of 2C9, 2C19, and even 3A4.  However, based on the maximal drug concentrations achieved with common doses used in patients with the wild type for 2C19 (an extensive metabolizer; EM) or with a genetic polymorphism for 2C9 (poor metabolizers; PM), they are primarily inhibitors of 2C19.6-11  This is in part determined by evaluating the maximal drug concentrations with oral administration and comparing their similarities to the inhibitory constants (Ki).  In addition, it is also important to recognize that if higher doses could get closer to the Ki's for other CYP enzymes thereby resulting in their inhibition as well.  This is relevant since clopidogrel can also be activated by more than one CYP enzyme.  

    What is an inhibitory constant and how does that translate into understanding drug interactions?
    In short, the Ki is the concentration of the inhibitor that is required in order to decrease the maximal rate of the reaction by half.  Therefore the smaller the Ki, the smaller amount of medication needed in order to inhibit the activity of that enzyme.  If a Ki is much larger than the maximal drug concentrations a patient is typically exposed to, then that drug is not likely to inhibit the activity of that enzyme.  This can be seen by evaluating the Kifor PPIs on 3A4 activity, where the Ki is significantly higher for most PPIs than their respective concentrations in both EM and PM at doses commonly seen in practice.  However, it is important to recognize that when interpreting the table below that the exposure to drug concentrations are influenced by the doses a patient receives and the slight variation in Ki is based on the biologic system used in the studies conducted.  Until further evidence defines the risk with PPIs and clopidogrel use, evaluating the known data may offer some help to clinicians or institutions trying to discern a PPI that may be less likely to cause interactions with clopidogrel.  

    Since we are not aware of any definitive pharmacodynamic studies using the same conditions and methods for all of the PPIs, the available data suggest that pantoprazole has the greatest ability to inhibit 2C9 and racemic lansoprazole (containing both R- and S-isomers) has the greatest ability to inhibit 2C19.11  While the Ki for dexlansoprazole is not specifically known for any of the CYP enzymes, it is essentially the R-isomer of lansoprazole, which has a Ki larger than S-lansoprazole or the S-isomer.6,11  As such, dexlansoprazole may possibly cause less inhibition of 2C19 than using regular lansoprazole.  It is also worth noting that dexlansoprazole's product package insert indicates there should be no drug interactions with any of the CYP enzymes.6  However, based on the known Ki for R-lansoprazole, this information provided by the product insert should be taken with caution until further evidence exists. 

    Second to lansoprazole's inhibition of 2C19, racemic omeprazole appears to be the next most potent inhibitor of CYP2C19.11  Since esomeprazole is the S-isomer of omeprazole, it is also an inhibitor of 2C19.7  While it would initially appear that esomeprazole's Ki for 2C19 may be less likely to interact with clopidogrel, it is important to recognize that esomeprazole has a slower clearance from the body compared to omeprazole (which is its claimed clinical benefit) and thus can potentially inhibit 2C19 for a longer period of time.7 

    The PPIs that would appear to potentially cause the least amount of inhibition of 2C19 are pantoprazole and rabeprazole.11  As will be seen in parts 2 and 3 of this series, there is some preliminary data to suggest that pantoprazole may not cause significant adverse clinical events or adversely impact platelet inhibition to the same degree as other PPIs.  As it relates to rabeprazole, the thioester metabolite is known to be a more potent inhibitor of 2C9, 2C19, 2D6, and 3A4 than its parent form. 

    Conclusion
    Based on the known pharmacokinetic profiles of the PPIs and the available literature, it would be suggestive that lansoprazole and omeprazole to be the most potent inhibitors of 2C19 and thus, have a greater inhibition of the activation of clopidogrel.  In addition, pantoprazole and rabeprazole appear to be the least likely to inhibit 2C19 and thus could cause less interference with clopidogrel activation.  The next 2 issues in this series will summarize the data regarding effects on platelet function while on these this combination as well as clinical data on cardiovascular outcomes with the purpose of translating this pharmacokinetic data into the clinical setting.

    References:

    1. Juurlink DN, Gomes T, Ko DT et al.  A population-based study of the drug interaction between proton pump inhibitors and clopidogrel.  CMAJ  2009;180:713-8.
    2. The Clopidogrel Medco Outcomes Study.  A national study of the effect of individual proton pump inhibitors on cardiovascular outcomes in patients treated with clopidogrel following coronary stenting: The Clopidogrel Outcomes Study.  Presented at the 2009 Scientific Sessions of the Society for Cardiovascular Angiography and Interventions.
    3. Ho PM, Maddox TM, Wang L et al.  Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome.  JAMA  2009;301:937-44.
    4. Dunn SP, Macaulay TE, Brennan DM et al.  Abstract 3999; Baseline proton pump inhibitor use is associated with increased cardiovascular events with and without the use of clopidogrel in the CREDO trial.  Circulation 2008;118:S_815.
    5. 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  2008;52:1038-9.
    6. Dexlansoprazole (Kapidex®) product package insert.  Takeda Pharmaceuticals America, Inc.  Deerfield, IL  January 2009.
    7. Esomeprazole (Nexium®) product package insert.  AstraZeneca Pharmaceuticals LP.  Wilmington, DE.  June 2009.
    8. Lansoprazole (Prevacid®) product package insert.  Takeda Pharmaceuticals America, Inc.  Deerfield, IL  January 2009.
    9. Pantoprazole (Protonix®) product package insert.  Wyeth Pharmaceuticals Inc. Philadelphia, PA.  May 2008.
    10. Rabeprazole (Aciphex®) product package insert.  Eisai Co., Ltd.  Tokyo, Japan.  January 2009. 
    11. 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  2004;32:821-7.
    12. Liu, KH, Kim MJ, Shon JH et al.  Stereoselective inhibition of cytochrome P450 forms by lansoprazole and omeprazole in vitro.  Xenobiotica  2005;25:27-38.
    13. Ko JW, Sukkhova N, Thacker D et al.  Evaluation of omeprazole and lansoprazole as inhibitors of cytochrome P450 isoforms.  Drug Metab Dispos  1997;25:853-62.
    14. Clopidogrel (Plavix) product package insert.  Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership.  Bridgewater, NJ.  May 2009.
    15. Savi P, Labouret C, Delesque N et al.  P2y(12), a new platelet ADP receptor, target of clopidogrel.  Biochem Biophys Res Commun  2001;283:379-83.
    16. Savi P, Zachayus JL, Delesque-Touchard N et al.  The active metabolite of Clopidogrel disrupts P2Y12 receptor oligomers and partitions them out of lipid rafts.  Proc Natl Acad Sci USA  2006;103:11069-74.
    17. Mega JL, Close SL, Wiviott SD et al. Cytochrome P450 metabolism and response to clopidogrel.  N Eng J Med 2009;360:411-3.
    18. Canadian Cardiovascular Society, American Academy of Family Physicians, American College of Cardiology et al.  2007 focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.  J Am Coll Cardiol  2008;51:210-47.
    19. Anderson JL, Adams CD, Antman EM et al.  ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine.  J Am Coll Cardiol 2007;50:e1-e157.
    20. Grines CL, Bonow RO, Casey DE Jr et al.  Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery disease: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and the American Dental Association, with representation from the American College of Physicians.  Circulation  2007;115:813-8.
    21. Bhatt DL, Scheiman J, Abraham NS et al.  ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risk of antiplatelet therapy and NSAID use: a report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents.  Circulation  2008;118:1894-909.
    22. Freedman JE, Hylek EM.  Clopidogrel, genetics, and drug responsiveness.  N Eng J Med  2009;360:411-3.

MESH Terms & Keywords

  • Proton Pump Inhibitor, PPI, Clopidogrel, Plavix, Dexlansoprazole, Kapidex, Esomeprazole, Nexium, Omeprazole, Prilosec, Zegerid, Lansoprazole, Prevacid, Pantoprazole, Protonix, Rabeprazole, Aciphex, CYP450, 2C19