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
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?
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
PPIs are involved in causing this drug interaction, do all of the PPI's inhibit
the activation of clopidogrel to the same degree?
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
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
What is an inhibitory constant and how does that
translate into understanding drug interactions?
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.
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
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
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.
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.
- Juurlink DN, Gomes T, Ko DT et al. A population-based study of the
drug interaction between proton pump inhibitors and clopidogrel. CMAJ
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.
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.
SP, Macaulay TE, Brennan DM et al. Abstract 3999; Baseline proton pump
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- Pezalla E, Day D, Pulliadath I. Initial
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and proton pump inhibitors. J Am Coll Cardiol 2008;52:1038-9.
- Dexlansoprazole (Kapidex®) product package insert. Takeda Pharmaceuticals America, Inc. Deerfield, IL January 2009.
- Esomeprazole (Nexium®) product package insert. AstraZeneca Pharmaceuticals LP. Wilmington, DE. June 2009.
- Lansoprazole (Prevacid®) product package insert. Takeda Pharmaceuticals America, Inc. Deerfield, IL January 2009.
- Pantoprazole (Protonix®) product package insert. Wyeth Pharmaceuticals Inc. Philadelphia, PA. May 2008.
- Rabeprazole (Aciphex®) product package insert. Eisai Co., Ltd. Tokyo, Japan. January 2009.
XQ, Andersson TB, Ahlstrom M, Weidolf L. Comparison of inhibitory
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lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450
activities. Drug Metab Dispos 2004;32:821-7.
KH, Kim MJ, Shon JH et al. Stereoselective inhibition of cytochrome
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JW, Sukkhova N, Thacker D et al. Evaluation of omeprazole and
lansoprazole as inhibitors of cytochrome P450 isoforms. Drug Metab
(Plavix) product package insert. Bristol-Myers Squibb/Sanofi
Pharmaceuticals Partnership. Bridgewater, NJ. May 2009.
- Savi P,
Labouret C, Delesque N et al. P2y(12), a new platelet ADP receptor,
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- Mega JL, Close SL, Wiviott SD et al. Cytochrome P450 metabolism and response to clopidogrel. N Eng J Med 2009;360:411-3.
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