Drug-Drug Interaction between Clopidogrel and PPIs, Specifically Concerning CYP2C19
This Jmol Exploration was created using the Jmol Exploration Webpage Creator from the MSOE Center for BioMolecular Modeling.
A patient presents to Shopko pharmacy to pick up his new prescription for clopidogrel (Plavix),an antiplatelet to prevent thrombus formation due to a recently placed stent. The patient was also picking up his other medications, one of which included omeprazole. During the consultation by the pharmacist, the patient was very concerned about drug-drug interactions. He had heard that some medications can cause increased bleeding while others cause clotting. The patient wanted to know if his current medications were okay to take with clopidogrel. The pharmacist informed the patient that only a small portion of the population that takes omeprazole and clopidogrel together could experience an increase in clot formation because of a deficiency in an enzyme called CYP2C19. The pharmacist assured the patient that this is uncommon and that they still should be monitored frequently by their physician and if needed, dose adjustments can be made to prevent these adverse effects.
Many patients suffer from both gastroesophogel reflux disease (GERD) and platelet aggregation. Proton pump inhibitors (PPIs) such as omeprazole are commonly used for acid reflux. Clopidogrel is commonly used as an antiplatelet therapy for patients with stents. Both drugs are metabolized by CYP2C19; therefore, when taken together there is a drug-drug interaction and potential for a reduced therapeutic effect.
Clopidogrel is a thienopyridine P2Y12 inhibitor of platelet function and is a cornerstone of cardiovascular pharmacotherapy, with aspirin, in the prevention of myocardial infarction (MI), stent thrombosis after acute coronary syndromes (ACS), and percutaneous coronary intervention (PCI).1 Other clinical indications for clopidogrel are as follows: peripheral arterial disease prophylaxis, acute ST elevation myocardial infarction prophylaxis, revascularization, and stroke.1,2 The prophylactic clopidogrel dose is one 75mg tablet once a day and loading doses can range from 300-600mg.2 Clopidogrel inhibits the P2Y12 receptor by irreversibly binding on the platelet surface and prevents adenosine diphosphate (ADP) from binding to the receptor; therefore, inhibiting ADP from inducing platelet activation.1
Clopidogrel requires a two-step oxidative process utilizing the CYP2C19 enzyme. Even though there is no crystal structure of clopidogrel bound to human CYP2C19, there is a crystal structure of the homologous rabbit enzyme, CYP2B4, bound to clopidogrel. Clopidogrel, goes through an oxidation step to become 2-oxo-clopidogrel, by oxidizing the thiofuran ring4 which allows the ring to be close to the heme. Then through another oxidation step, 2-oxo-clopidogrel becomes the thio metabolite. These two structures are classified as tautomers of one another. The thio metabolite contains a chiral center and a free sulfur that will eventually form the sulfide bridge, inhibiting platelet activation.5
Like clopidogrel, PPIs have an irreversible mechanism that occurs through a sulfide bridge. PPIs are a special class of medications that work to irreversibly inhibit proton pumps in the stomach. The main clinical use for PPIs is for the management of GERD. Furthermore, PPIs are given to treat patients who develop gastro-intestinal bleeding from prolonged antiplatelet therapy.2 Doses for PPIs range from 20-80mg daily and can be divided into two doses to provide continuous relief for GERD and related symptoms. The structure of a PPI consists of a benzimidazole, a free sulfur, and a pyridine ring. The pyridine ring becomes charged in the caniliculus due to its pKa.5 This helps keep the drug localized near the proton pump.5 The charge on the benzimidazole will help the structure cyclize, specifically between the sulfur and the pyridine ring, before it becomes an active drug.5 PPIs get metabolized by CYP2C19 via mediated oxidation.
Omeprazole is a PPI that CYP2C19 metabolizes. Omeprazole is a substrate with strong affinity for CYP2C19 compared to other PPIs which have a weaker affinity.6 CYP2C19 works to O-demethylate the benzimidazole and hydroxylate the pyridine ring. This structure is ready for further modification in the acidic environment of the parietal cell of the stomach as well as the caniliculus.6 Omeprazole is then converted to an inactive 5-hydroxyomeprazole by CYP2C19. This inactive form is activated by an acidic environment and then is able to produce its therapeutic effect.
Clopidogrel can bind into and occupy CYP2C19 leading to high levels of omeprazole in the body. This interaction, theoretically, going from clopidogrel to its active metabolite, is more problematic because omeprazole can occupy CYP2C19 and prevent clopidogrel from exerting its mechanism of action. Furthermore, if clopidogrel is able to be converted to 2-oxo-clopidogrel, the compound still needs to go through a second oxidation step to be converted into its active metabolite and risks not reaching this second step if omeprazole binds to CYP2C19 during this process. This interaction would reduce the effectiveness of clopidogrel's antiplatelet activity and would be expected to lead specifically to an increased risk of vascular events in proton pump inhibitor users compared with non-users.7 Given this mechanism, exploring this interaction could prove to have clinical significance in future patients being treated with clopidogrel and a PPI.
There is no crystal structure of clopidogrel bound to human CYP2C19; however, there is a crystal structure of the homologous rabbit enzyme, CYP2B4, bound to clopidogrel. The rabbit enzyme CYP2B4 shares 78% sequence identity with human CYP2B6.8 CYP2B6 produces the same thiolactone intermediate during clopidogrel metabolism as CYP2C19 and it has been assumed that both enzymes are inactivated by a related mechanism.7 Because of these similarities, the rabbit enzyme CYP2B4 can be used to infer the mechanistic relationship in the human enzyme CYP2B6, which can then be used to estimate the action of the human CYP2C19.
Clopidogrel was found to occupy a trilobe of electron density above the heme plane with the chlorophenyl group most closely approaching the heme ring that lays beneath.8 Due to clopidogrel's stereocenter, it is easier to fit in the electron density and exhibit a single orientation, which points the chlorophenyl ring towards the heme.8
When clopidogrel is in complex with CYP2B4, the two points of the clopidogrel molecule that comes closest to the heme iron structure, are two carbon atoms, each at 3.6Å. There is no coordination between the thiol structure and the heme ring. With the lack of tight binding from the clopidogrel thiol ring, the drug will have more rotational freedom in the binding cleft.
With no hydrogen bonding occurring with the molecule, it must rely on multiple Van Der Waals forces of the hydrophobic phenylalanine side chains to hold the molecule in place.8
Phenylalanine 206 converges over the top of the clopidogrel molecule and will act as a temporary frame for the surrounding amino acids. Secondary to the phenylalanine, there is an interaction with nearby hydrophobic amino acids: valine and isoleucine. With the placement of the carboxymethyl moiety, it is not within range of 5Å of any polar side chains that would undergo possible hydrogen bonding arrangements.
As mentioned in the previous sections, clopidogrel, a thienopyridine prodrug, has to go through a two-step oxidation process to become an active thiol metabolite that is needed to bind to the ADP/P2Y12 receptor to initiate antiplatelet therapy.9 Inhibiting platelet aggregation can greatly reduce the risk for myocardial infarction, vascular disease, and stroke.8 These oxidation steps are done primarily by CYP2C19 enzymes that are found in the liver. PPIs also need to be metabolized to be active and are done so primarily by CYP2C19. If a patient is taking both drugs, there is potential that the two will competitively bind to the enzyme. This can lead to a reduced therapeutic effect, since both drugs need to be metabolized in order to perform their mechanism of action.
More specifically, clopidogrel is oxidized primarily by CYP2C19 to 2-oxo-clopidogrel and then is oxidized again primarily by CYP2C19 to an active thio metabolite. If the first oxidation step is slowed this would cause the prodrug to go towards the pathway of an inactive metabolite. As mentioned in the Jmol section, when clopidogrel is bound to CYP2B4, a rabbit enzyme and crystal homologous of human CYP2C19, it is held in place by phenylalanine amino acids that are in the enzyme as the drug itself does not hydrogen bond to any part of the enzyme's active site.8 This way 2-oxo-clopidogrel will have a single preferred orientation where the thiol will be close to the heme in order to proceed to its second oxidation step.
Omeprazole, an R-enantiomer, most often requires CYP2C19 for activation.9 Therefore, it is crucial for it to bind to CYP2C19 to reach its active state. PPIs are shown to reduce the risk of severe gastrointestinal bleeding caused caused from prolonged antiplatelet therapy in patients.8 However, the combination of clopidogrel and a PPI outweigh the risk of possible cardiovascular events when needing to treat this adverse effect.4
Clinically, patients who are on a prolonged antiplatelet therapy are at a high risk of developing severe gastrointestinal hemorrhage and it has been shown that the use of PPIs greatly reduces this risk.2,8 Patients that are on an antiplatelet therapy need to be to reduce the risk of a cardiovascular event, such as, myocardial infarction, vascular disease, and stroke.2 Chemically, it has been discussed that taking clopidogrel and omeprazole together will prevent one or the other from reaching its active state and the patient is expected to receive a reduced therapeutic effect. However, the COGENT trial showed that clinically when a patient is taking clopidogrel and omeprazole there was a great risk reduction in gastrointestinal bleeding and did not see an increased risk for cardiovascular events.2 Therefore, if the patient population has a normal function of CYP2C19, then this interaction could be theorized as not very severe due to the clinical research indicating that there is not an unsafe interaction. However, in special patient populations where there is a reduced function of CYP2C19, the patient will have lower levels of the clopidogrel active metabolite, thus causing less platelet inhibition and higher rates of major adverse cardiovascular events.2 Patients with an overactive function of CYP2C19 show a greater bioavailability in PPIs, where an interaction could be more evident clinically.2 Overall, if a patient needs to be on both medications and are unsure of their CYP2C19 function, then a recommendation should be given to have the patient take clopidogrel and omeprazole at different times in the day (i.e. clopidogrel in the morning and the PPI in the evening) which will help prevent a drug-drug interaction.6
1. Dunn, SP, Steinhubl, SR., Bauer, D, et al. Impact of proton pump inhibitor therapy on the efficacy of clopidogrel in the CAPRIE and CREDO trials. J. AM. Heart Assoc. 2013; 2:e004564. doi10.1161/JAHA. 112.004564
2. Bhatt, DL, Cryer, BL, Contant, CF, et al. clopidogrel with or without omeprazole in coronary artery disease. N. Engl. J. Med. 2010; 363, 1909-1917.
3. Mega, JL, Close, SL, Wiviott, SD, et al. Cytochrome p450 genetic polymorphism and the response to prasugrel: relation to pharmacokinetic, Pharmacodynamic, and Clinical outcomes. Circ. 2009; 119: 2553-2560, doi: 10.1161/CIRCULATIONAHA. 109.851949
4. Drepper, MD, Spahr, L, Frossard, JL. Clopidogrel and proton pump inhibitors - where do we stand in 2012?. World J. Gastroenterol. 2012; 18(18), 2161-2171. doi: 10.3748/wjg.v18.i18.2161.
5. Lemke, TL. Foye's Principles of Medicinal Chemistry. Baltimore, MD: Lippincott Williams & Wilkins; 2008.
6. Furuta, T, Iwaki, T, Umemura, K. Influences of different proton pump inhibitors on the anti-platelet function of clopidogrel in relation to CYP2C19 genotypes. Br. J. Clin. Pharmacol. 2010; 70(3), 383-392. doi: 10.1111/j.1365-2125.2010.03717.x.
7. Smeeth, L., Douglas, I.J., Evans, S.J., Hingorani, A.D., Grosso, A.M., Timmis, A., Hemmingway, H. (2012). Clopidogrel and interaction with proton pump inhibitors: comparison between cohort and within person study designs. British Medical Journal. 345:e4388
8. Gay, SC, Roberts, AG, Maekawa, K, et al. Structures of cytochrome P450 2B4 complexed with the antiplatelet drug ticlopidine and clopidogrel. Biochemistry, 2010. 49(40), 8709-8720. doi: 10.1021/bi100914z.
9. Mega, JL, Close, SL, Wiviott, SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N. Engl. J. Med. 2009. 360(4), 354-362. doi: 10.1056/NEJMoa0809171.