P2Y12 Receptor; CYP2B6 (IC50 = 18.2 nM); CYP2C19 (IC50 = 524 nM)

Gene microarray analysis identified 79 genes that were differentially expressed (P<0.05 and fold-change >3) when cells were treated with or without clopidogrel. Gene ontology analysis revealed that response to stress and cell apoptosis dysfunction were ranked in the top 10 cellular events being affected, and that the major components of endoplasmic reticulum stress-mediated apoptosis pathway - CHOP and TRIB3- were up-regulated in a concentration- and time-dependent manner when cells were treated with clopidogrel. Pathway analysis demonstrated that multiple MAPK kinases were phosphorylated in clopidogrel-treated GES-1 cells, but that only SB-203580 (a p38-specific MAPK inhibitor) attenuated cell apoptosis and CHOP over-expression, both of which were induced by clopidogrel. Conclusions: Increased endoplasmic reticulum stress response is involved in clopidogrel-induced gastric mucosal injury, acting through p38 MAPK activation.[3]

In comparison to diabetic mice given with a vehicle, clopidogrel administered during the previous three months dramatically decreased the expression of fibronectin, collagen, and blood glucose. Renal fibrosis brought on by hyperglycemia is markedly improved by clopidogrel [1]. In comparison to aspirin monotherapy, clopidogrel and aspirin combination therapy (dual antiplatelet therapy) has been demonstrated to have substantial advantages. It has also been demonstrated to lower recurrent ischemic events following ACS and subacute stent thrombosis [2].

Clopidogrel is a potent antithrombotic drug that inhibits ADP-induced platelet aggregation. The results of large clinical trials have demonstrated an overall benefit of clopidogrel over aspirin in the prevention of vascular ischemic events (myocardial infarction, stroke, vascular death) in patients with a history of symptomatic atherosclerotic disease. The antiaggregating effect of clopidogrel is attributed to an irreversible inhibition of ADP binding to a purinergic receptor present at the platelet surface. Clopidogrel is not active in vitro and can be considered a precursor of an active metabolite formed in the liver. The chemical structure of this active metabolite and its biological activity have been described recently. Several purinergic receptors have been described on platelets; P2X (1), a calcium channel, and P2Y1 a Gq-coupled seven-transmembrane domain receptor, have been found not to be antagonized by clopidogrel. Another Gi (2)-coupled receptor (named P2Y12) has been recently cloned and stably expressed in CHO cells. These cells displayed a strong affinity for (33)P-2MeS-ADP, a stable analogue of ADP, the binding characteristics of which corresponded in all points to those observed on platelets. The binding of (33)P-2MeS-ADP to these cells was strongly inhibited by the active metabolite of clopidogrel with a potency that was consistent with that observed for this compound on platelets. In these transfected CHO cells, as in platelets, ADP and 2MeS-ADP induced adenylyl cyclase downregulation, an effect that was inhibited by the active metabolite of clopidogrel. These results demonstrate that this receptor corresponds to the previously called "P2t" platelet receptor and show that the active metabolite of clopidogrel binds in a covalent manner to this receptor, thus explaining how it blocks the aggregating effect of ADP on platelets[4].

The GES-1 cells were used as a model system, the effects of clopidogrel on the whole gene expression profile were evaluated by human gene expression microarray and gene ontology analysis, changes of the mRNA and protein expression were determined by real-time PCR and Western blot analysis, and cell viability and apoptosis were measured by MTT assay and flow cytometry analysis, respectively.[3]

New Zealand white rabbits (1.9-2.7 kg) were treated orally with vehicle or clopidogrel (3 or 10 mg/kg) for three days. On the fourth day, the rabbits were anesthetized for blood collection and then euthanized. The brain was collected, and the middle cerebral arteries were isolated. We used light transmission aggregometry and pressure myography to elucidate the mechanisms of the off-target effects associated with clopidogrel treatment. We confirmed that inhibition of P2Y12 activation by clopidogrel inhibited ADP-induced platelet aggregation but had no impact on P2Y12-independent arachidonic acid- or collagen-induced platelet aggregation. Analysis of middle cerebral arteries from clopidogrel treated rabbits showed that clopidogrel did not affect P2Y4, P2Y6, and P2Y14 receptor-mediated contraction but attenuated the contractile response after P2Y2 receptor activation. Further analysis determined P2Y2-mediated constriction was endothelium-dependent. Vasoconstriction is a primary component of hemostasis, and impaired vasoconstriction can prolong bleeding. These results suggest clopidogrel inhibits the endothelial P2Y2 receptor in the middle cerebral artery, which provides a mechanistic explanation for the adverse cerebral bleeding associated with the drug.[5]

Absorption, Distribution and Excretion
Following oral administration of 75 mg clopidogrel, the intestinal absorption rate is 50%. Clopidogrel can be taken on an empty stomach or with food. Food intake reduces the AUC of the active metabolite by 57%. The active metabolite of clopidogrel reaches its maximum concentration after 30–60 minutes. The Cmax of clopidogrel is 2.04 ± 2.0 ng/mL, and the time to peak concentration is 1.40 ± 1.07 hours. For patients with low metabolic capacity, the AUC of 300 mg clopidogrel is 45.1 ± 16.2 ng·h/mL; for those with moderate metabolic capacity, the AUC is 65.6 ± 19.1 ng·h/mL; and for those with high metabolic capacity, the AUC is 104.3 ± 57.3 ng·h/mL. The Cmax for slow metabolizers was 31.3 ± 13 ng/mL, for intermediate metabolizers it was 43.9 ± 14 ng/mL, and for rapid metabolizers it was 60.8 ± 34.3 ng/mL. After oral administration of radiolabeled clopidogrel, 50% was excreted in the urine and 46% in the feces within 5 days. The remaining portion of clopidogrel irreversibly binds to platelets until its end-of-life in platelets, approximately 8–11 days. The apparent volume of distribution of clopidogrel was 39,240 ± 33,520 L. The clearance rate of a 75 mg oral dose was 18,960 ± 15,890 L/h, and the clearance rate of a 300 mg oral dose was 16,980 ± 10,410 L/h. Protein binding: The protein binding rates of clopidogrel and its major circulating metabolites were very high (98% and 94%, respectively). In vitro studies showed that binding remained unsaturated at concentrations up to 100 μg/mL. Clopidogrel is rapidly absorbed after single or multiple daily oral doses of 75 mg. The absorption rate is at least 50%, depending on urinary excretion of clopidogrel metabolites. Time to peak concentration: After repeated daily doses of 75 mg, steady-state platelet aggregation inhibition is typically reached between day 3 and day 7. Peak plasma concentration: After repeated doses of 75 mg, the peak plasma concentration is approximately 3 mg/L (carboxylic acid derivative). Pharmacokinetics of the major circulating metabolite are linear (increasing dose-proportional) across the dose range of 50 to 150 mg. For more complete data on absorption, distribution, and excretion of clopidogrel (6 items), please visit the HSDB record page. Metabolites/Metabolites: 85-90% of the oral dose is metabolized in the liver via first-pass metabolism by carboxylesterase 1 to an inactive carboxylic acid metabolite. Approximately 2% of clopidogrel is oxidized to 2-oxoclopidogrel. The conversion rate is 35.8% for CYP1A2, 19.4% for CYP2B6, and 44.9% for CYP2C19, although other studies suggest that CYP3A4, CYP3A5, and CYP2C9 are also involved. 2-oxoclopidogrel is further metabolized to the active metabolite. The conversion rate is 32.9% for CYP2B6, 6.79% for CYP2C9, 20.6% for CYP2C19, and 39.8% for CYP3A4. CYP2C19 is involved in the formation of both the active metabolite and the 2-oxoclopidogrel intermediate metabolite. The pharmacokinetics and antiplatelet activity (as determined by in vitro platelet aggregation assays) of the clopidogrel active metabolite vary depending on the CYP2C19 genotype. Genetic variations in other CYP450 enzymes may also affect the formation of the clopidogrel active metabolite. Clopidogrel is primarily metabolized through two main pathways: one mediated by esterases, which hydrolyzes it to produce an inactive carboxylic acid derivative (accounting for 85% of circulating metabolites); the other mediated by various cytochrome P450 enzymes. Cytochromes first oxidize clopidogrel to the 2-oxoclopidogrel intermediate metabolite. This intermediate metabolite is then further metabolized to produce the active metabolite, the thiol derivative of clopidogrel. This metabolic pathway is mediated by CYP2C19, CYP3A, CYP2B6, and CYP1A2. The active thiol metabolite rapidly and irreversibly binds to platelet receptors, thereby inhibiting platelet aggregation throughout the platelet's lifespan.
Biological Half-Life
After oral administration of 75 mg clopidogrel, its half-life is approximately 6 hours, while the half-life of the active metabolite is approximately 30 minutes.
After a single oral dose of 75 mg clopidogrel, its half-life is approximately 6 hours. The half-life of the active metabolite is approximately 30 minutes.

Hepatotoxicity
During clopidogrel treatment, 1% to 3% of patients experience elevated serum enzymes. In several large clinical trials, the incidence of elevated serum ALT in the clopidogrel group was not higher than in the placebo group (or control group), and no clinically significant liver injury cases were reported. However, since its market launch, there have been over a dozen reported cases of clinically significant liver injury, all attributable to clopidogrel. Symptoms typically appear within 2 to 24 weeks of treatment (mean 6 weeks), presenting as fatigue and jaundice. Some patients experience fever, but rash and eosinophilia are uncommon. The common pattern of elevated liver enzymes is hepatocellular, but mixed or cholestatic liver enzyme elevations have also been reported (Case 1). Autoantibodies are rare. Most cases are self-limiting, resolving within 1 to 2 months, but rare cases of acute liver failure or decompensated liver function leading to death or requiring liver transplantation have also occurred. Probability Score: B (Highly probable but rare, a cause of clinically significant liver injury).

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Effects during pregnancy and lactation
◉ Overview of medication use during lactation
There is currently no publicly available information regarding the use of clopidogrel during lactation. Manufacturers have reported that in a few post-marketing cases, no adverse reactions were observed in breastfed infants when mothers used clopidogrel during lactation. Because there is currently no publicly available information regarding the use of clopidogrel during lactation, it is recommended to choose alternative medications, especially when breastfeeding newborns or premature infants. If the breastfeeding mother uses it, closely monitor the infant for bruising and bleeding.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.
◈ What is clopidogrel?
Clopidogrel is an antiplatelet drug that helps prevent blood clots. It has been used to prevent heart attacks and strokes. Clopidogrel is marketed under the brand name Plavix®. Sometimes, when people find out they are pregnant, they may consider changing their medication regimen or even stopping it entirely. However, it is essential to talk to your healthcare provider before making any changes. Your healthcare provider can discuss the benefits of treating your condition and the risks of not treating it during pregnancy.
◈ I am taking clopidogrel. Will taking clopidogrel affect my pregnancy?
There are currently no human studies to suggest that clopidogrel affects pregnancy. Animal studies have shown that clopidogrel does not affect fertility (the ability to conceive).
◈ Does taking clopidogrel increase the risk of miscarriage?
Miscarriage is common and can occur in any pregnancy for a variety of reasons. There are currently no human studies to suggest that clopidogrel increases the risk of miscarriage. Animal studies have shown that taking clopidogrel does not increase the risk of miscarriage.
◈ Does taking clopidogrel increase the risk of birth defects?
There is a 3-5% risk of birth defects in every pregnancy, known as the baseline risk. Information on the use of clopidogrel during pregnancy is limited. Animal studies have shown that taking clopidogrel does not increase the risk of birth defects. Of the 17 case reports of clopidogrel use during pregnancy, 16 infants did not report birth defects. One infant reported a heart defect. A single case report is insufficient to link drug exposure to birth defects. Furthermore, in all these reports, the pregnant women also took other medications during pregnancy. This makes it difficult to determine whether the reported heart defect was related to clopidogrel, the drug combination, or other factors.
◈ Does clopidogrel use during pregnancy increase the risk of other pregnancy-related problems?
Currently, no studies have assessed whether clopidogrel increases the risk of pregnancy-related problems such as preterm birth (delivery before 37 weeks of gestation) or low birth weight (birth weight less than 5 pounds 8 ounces [2500 grams]). Clopidogrel use during labor may increase the risk of maternal hemorrhage and postpartum hemorrhage (excessive blood loss). Patients taking clopidogrel also have an increased risk of spinal hematoma (blood pooling in the spinal cord) when receiving epidural anesthesia (injection of the drug into the spaces around the spinal nerves to relieve pain or numb a part of the body). Product labels and recommendations from professional medical associations, including the American Society of Regional Anesthesiology and Pain Medicine and the American Academy of Pain Medicine, suggest that all patients taking clopidogrel should discontinue use 5-7 days before delivery or epidural anesthesia.
◈ Will taking clopidogrel during pregnancy affect a child's future behavior or learning abilities?
Currently, there are no studies indicating whether clopidogrel causes behavioral or learning problems in children.
◈ Taking clopidogrel while breastfeeding:
Currently, there are no published studies on the use of clopidogrel while breastfeeding. A small number of infants exposed to clopidogrel through breast milk have not reported any side effects. If you suspect your infant has any symptoms (such as bruising or bleeding), contact your child's healthcare provider. There is a theoretical concern (not yet confirmed) that if an infant is exposed to clopidogrel through breast milk, the infant's platelet function may be affected. However, no reports of infants being exposed to clopidogrel through breast milk mention this.
◈ If men take clopidogrel, will it affect fertility or increase the risk of birth defects? Currently, no human studies have been conducted to determine whether clopidogrel affects male fertility (the ability to impregnate a partner) or increases the risk of birth defects (above background risk). Animal studies have not found any effect on fertility. Generally, exposure to clopidogrel by the father or sperm donor is unlikely to increase the risk of pregnancy. For more information, please see the “Paternal Exposure” information sheet on the MotherToBaby website at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/. Protein Binding Both the active and inactive metabolites of clopidogrel are 98% bound to proteins in plasma. Studies in dairy cows have shown that clopidogrel binds to serum albumin at a rate of 71-85.5%.

[1]. Clopidogrel Reduces Fibronectin Accumulation and Improves Diabetes-Induced Renal Fibrosis. Int J Biol Sci. 2019 Jan.
[2]. An insight into the interaction between clopidogrel and proton pump inhibitors By Shah, Bhavik S.; Parmar, Sanjay A.; Mahajan, Shailaja; Mehta, Anita A. From Current Drug Metabolism (2012), 13(2),225-235.
[3]. Increased endoplasmic reticulum stress response is involved in Clopidogrel-induced apoptosis of gastric epithelial cells. PLoS One. 2013 Sep 13;8(9):e74381.
[4]. P2Y12, a new platelet ADP receptor, target of Clopidogrel.Semin Vasc Med. 2003 May;3(2):113-22.
[5]. Clopidogrel treatment inhibits P2Y2-Mediated constriction in the rabbit middle cerebral artery [published online ahead of print, 2021 Oct 1]. Eur J Pharmacol. 2021;174545.

Clopidogrel is a thienopyridine compound, chemically named 4,5,6,7-tetrahydrothieno[3,2-c]pyridine, in which the hydrogen atom bonded to the nitrogen atom is replaced by an o-chlorobenzyl group, and the methylene hydrogen atom of the o-chlorobenzyl group is replaced by a methoxycarbonyl group (S-enantiomer). Clopidogrel is a P2Y12 receptor antagonist used to inhibit thrombus formation and prevent heart attacks. It has the effects of inhibiting platelet aggregation, anticoagulation, and antagonizing P2Y12 receptors. Clopidogrel belongs to the thienopyridine, monochlorobenzene, and methyl ester classes of compounds. Its function is similar to ticlopidine. Clopidogrel is a prodrug of platelet inhibitors used to reduce the risk of myocardial infarction and stroke. Clopidogrel is indicated for reducing the risk of myocardial infarction in patients with non-ST-segment elevation acute coronary syndrome (ACS), patients with ST-segment elevation myocardial infarction, and patients who have recently experienced myocardial infarction, stroke, or have been diagnosed with peripheral artery disease. Studies have shown that clopidogrel is superior to aspirin in reducing the incidence of cardiovascular events in patients with cardiovascular disease and can provide additional benefits to patients with acute coronary syndrome who are already taking aspirin. Clopidogrel was approved by the U.S. Food and Drug Administration (FDA) on November 17, 1997. Clopidogrel is a P2Y12 platelet inhibitor. Its mechanism of action is as a P2Y12 receptor antagonist and cytochrome P450 2C8 inhibitor. The physiological effect of clopidogrel is achieved by reducing platelet aggregation. Clopidogrel is a platelet aggregation inhibitor used to reduce the risk of myocardial infarction and stroke in patients with known atherosclerosis. Clopidogrel is associated with rare, specific, and clinically significant cases of acute liver injury. Clopidogrel is a thienopyridine drug with antiplatelet activity. Clopidogrel targets platelets, irreversibly binding to and altering their adenosine diphosphate (ADP) receptors, thereby blocking ADP binding to its receptors, inhibiting ADP-mediated activation of the glycoprotein complex GPIIb/IIIa, and inhibiting fibrinogen binding to platelets, as well as platelet adhesion and aggregation. This leads to prolonged bleeding time. Clopidogrel is a ticlopidine analogue and a platelet purinergic P2Y receptor antagonist that inhibits ADP-mediated platelet aggregation. It is used to prevent thromboembolism in patients with arterial occlusive disease, myocardial infarction, stroke, or atrial fibrillation. See also: clopidogrel bisulfate (in salt form); clopidogrel besylate (its active ingredient). Clopidogrel hydrochloride (salt form)...See more...

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Drug Indications
Clopidogrel is indicated for the reduction of the risk of myocardial infarction in patients with non-ST-segment elevation acute coronary syndrome (ACS), patients with ST-segment elevation myocardial infarction, and patients who have recently experienced myocardial infarction, stroke, or have a confirmed diagnosis of peripheral artery disease.
FDA Label
Clopidogrel is indicated for the prevention of atherosclerotic thrombotic events in adults who have experienced myocardial infarction (days to less than 35 days), ischemic stroke (7 days to less than 6 months), or have a confirmed diagnosis of peripheral artery disease.
For secondary prevention of atherosclerotic thrombotic events, clopidogrel is indicated for: adult patients with myocardial infarction (days to less than 35 days), ischemic stroke (7 days to less than 6 months), or diagnosed peripheral artery disease; adult patients with acute coronary syndromes: non-ST-segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), including patients who have received stent implantation after percutaneous coronary intervention, can be treated in combination with aspirin (ASA); ST-segment elevation acute myocardial infarction, can be treated in combination with aspirin in patients who have received percutaneous coronary intervention (including stent replacement) or patients who meet the criteria for thrombolytic/fibrinolytic therapy. For intermediate- to high-risk transient ischemic attacks (TIAs) or minor ischemic strokes (IS), clopidogrel in combination with aspirin is indicated for: adult patients with intermediate- to high-risk TIAs (ABCD2 score of 4) or minor ISs (NIHSS score of 3) within 24 hours of the occurrence of a TIA or IS event. Prevention of atherosclerotic thrombosis and thromboembolic events in patients with atrial fibrillation: For adult patients with atrial fibrillation who have at least one risk factor for vascular events, are unsuitable for vitamin K antagonist therapy, and have a low bleeding risk, clopidogrel can be used in combination with aspirin to prevent atherosclerotic thrombosis and thromboembolic events, including stroke. Secondary prevention of atherosclerotic thrombotic events: Clopidogrel is indicated for: adult patients with myocardial infarction (days to less than 35 days), ischemic stroke (7 days to less than 6 months), or a confirmed peripheral artery disease. Adult patients with acute coronary syndromes: Non-ST-segment elevation acute coronary syndromes (unstable angina or non-Q-wave myocardial infarction), including patients who have received stent implantation after percutaneous coronary intervention, can be treated in combination with aspirin (ASA). ST-segment elevation acute myocardial infarction can be treated in combination with aspirin in patients who have received percutaneous coronary intervention (including stent implantation) or are eligible for thrombolytic/fibrinolytic therapy. For patients with intermediate- to high-risk transient ischemic attacks (TIAs) or minor ischemic strokes (IS): Clopidogrel in combination with aspirin is indicated for adult patients with intermediate- to high-risk TIAs (ABCD2 score of 4) or minor ISs (NIHSS score of 3) within 24 hours of the occurrence of a TIA or IS event. For the prevention of atherosclerotic thrombosis and thromboembolic events in patients with atrial fibrillation: For adult patients with atrial fibrillation who have at least one vascular event risk factor, are unsuitable for vitamin K antagonist (VKA) therapy, and have a low bleeding risk, clopidogrel in combination with aspirin may be used to prevent atherosclerotic thrombosis and thromboembolic events, including stroke. Secondary prevention of atherosclerotic thrombotic events: Clopidogrel is indicated for: adult patients with myocardial infarction (days to less than 35 days), ischemic stroke (7 days to less than 6 months), or a confirmed peripheral artery disease; adult patients with acute coronary syndromes: non-ST-segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), including patients who have received stent implantation after percutaneous coronary intervention, can be treated in combination with aspirin (ASA); ST-segment elevation acute myocardial infarction, can be treated in combination with aspirin for patients who are suitable for thrombolytic therapy. Prevention of atherosclerotic thrombosis and thromboembolic events in patients with atrial fibrillation: For adult patients with atrial fibrillation who have at least one vascular event risk factor, are not suitable for vitamin K antagonist therapy, and have a low bleeding risk, clopidogrel can be used in combination with aspirin to prevent atherosclerotic thrombosis and thromboembolic events, including stroke. See Section 5.1 for more information.
Secondary prevention of atherosclerotic thrombotic events: Clopidogrel is indicated for adult patients with myocardial infarction (days to less than 35 days), ischemic stroke (7 days to less than 6 months), or a confirmed diagnosis of peripheral artery disease. Adult patients with acute coronary syndromes: Non-ST-segment elevation acute coronary syndromes (unstable angina or non-Q-wave myocardial infarction), including patients who have received stent implantation after percutaneous coronary intervention, should be used in combination with aspirin (ASA). ST-segment elevation acute myocardial infarction should be used in combination with aspirin for patients eligible for thrombolytic therapy. Prevention of atherosclerotic thrombosis and thromboembolic events in patients with atrial fibrillation: For adult patients with atrial fibrillation who have at least one vascular event risk factor, are unsuitable for vitamin K antagonist (VKA) therapy, and have a low bleeding risk, clopidogrel can be used in combination with aspirin to prevent atherosclerotic thrombosis and thromboembolic events, including stroke. Clopidogrel is indicated for the prevention of atherosclerotic thrombotic events in the following adult patients: patients with myocardial infarction (days to less than 35 days), ischemic stroke (7 days to less than 6 months), or diagnosed peripheral artery disease. For secondary prevention of atherosclerotic thrombotic events, clopidogrel is indicated for: - Adult patients with myocardial infarction (days to less than 35 days), ischemic stroke (7 days to less than 6 months), or diagnosed peripheral artery disease. - Adult patients with acute coronary syndromes: - Non-ST-segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), including patients who have received stent implantation after percutaneous coronary intervention, requiring combination therapy with aspirin (ASA). - ST-segment elevation acute myocardial infarction, requiring combination therapy with aspirin, for patients eligible for thrombolytic therapy. For patients with intermediate- to high-risk transient ischemic attacks (TIAs) or minor ischemic strokes (IS), clopidogrel in combination with aspirin is indicated for: - Adult patients experiencing an intermediate- to high-risk TIA (ABCD2 score of 4) or a minor IS (NIHSS score of 3) within 24 hours of occurrence. - Prevention of atherosclerotic thrombosis and thromboembolic events in patients with atrial fibrillation: For adult patients with atrial fibrillation who have at least one vascular event risk factor, are unsuitable for vitamin K antagonist (VKA) therapy, and have a low bleeding risk, clopidogrel in combination with aspirin is indicated for the prevention of atherosclerotic thrombosis and thromboembolic events, including stroke. See Section 5.1 for more information.
Secondary prevention of atherosclerotic thrombotic events: Clopidogrel is indicated for: Adult patients with a history of myocardial infarction (days to less than 35 days), ischemic stroke (7 days to less than 6 months), or a confirmed diagnosis of peripheral artery disease. Adult patients with acute coronary syndromes: - Non-ST-segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), including patients who have received stent implantation after percutaneous coronary intervention, should be used in combination with aspirin (ASA). - ST-segment elevation acute myocardial infarction should be used in combination with aspirin for patients who meet the criteria for thrombolytic therapy. Prevention of atherosclerotic thrombosis and thromboembolic events in patients with atrial fibrillation: For adult patients with atrial fibrillation who have at least one vascular event risk factor, are not suitable for vitamin K antagonist (VKA) therapy, and have a low bleeding risk, clopidogrel can be used in combination with aspirin to prevent atherosclerotic thrombosis and thromboembolic events, including stroke.
Prevention: Secondary prevention of atherosclerotic thrombotic events: Clopidogrel is indicated for: adult patients with myocardial infarction (days to less than 35 days), ischemic stroke (7 days to less than 6 months), or a confirmed diagnosis of peripheral artery disease. Adult patients with acute coronary syndrome: - Non-ST-segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), including patients who have received stent implantation after percutaneous coronary intervention, in combination with acetylsalicylic acid (ASA). - ST-segment elevation acute myocardial infarction, in combination with ASA for patients who meet the criteria for thrombolytic therapy. Prevention of atherosclerotic thrombosis and thromboembolic events in patients with atrial fibrillation: - For adult patients with atrial fibrillation who have at least one vascular event risk factor, are not suitable for vitamin K antagonist (VKA) therapy, and have a low bleeding risk, clopidogrel can be used in combination with aspirin to prevent atherosclerotic thrombosis and thromboembolic events, including stroke.
Secondary prevention of atherosclerotic thrombotic events: Clopidogrel is indicated for: adult patients with myocardial infarction (days to less than 35 days), ischemic stroke (7 days to less than 6 months), or a confirmed diagnosis of peripheral artery disease. Adult patients with acute coronary syndrome: For non-ST-segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), including patients who have received stent implantation after percutaneous coronary intervention, acetylsalicylic acid (ASA) can be used in combination. For ST-segment elevation acute myocardial infarction, ASA can be used in combination with other medications that meet the criteria for thrombolytic therapy. Prevention of atherosclerotic thrombosis and thromboembolic events in patients with atrial fibrillation: For adult patients with atrial fibrillation who have at least one vascular event risk factor, are unsuitable for vitamin K antagonist (VKA) therapy, and have a low bleeding risk, clopidogrel can be used in combination with aspirin to prevent atherosclerotic thrombosis and thromboembolic events, including stroke. Prevention of atherosclerotic thrombotic events: Clopidogrel is indicated for adult patients with myocardial infarction (days to less than 35 days), ischemic stroke (7 days to less than 6 months), or a confirmed diagnosis of peripheral artery disease. Secondary prevention of atherosclerotic thrombotic events: Clopidogrel is indicated for adult patients with myocardial infarction (days to less than 35 days), ischemic stroke (7 days to less than 6 months), or a confirmed peripheral artery disease. Adult patients with acute coronary syndromes: Non-ST-segment elevation acute coronary syndromes (unstable angina or non-Q-wave myocardial infarction), including patients who have received stent implantation after percutaneous coronary intervention, may be treated in combination with aspirin (ASA). ST-segment elevation acute myocardial infarction may be treated in combination with aspirin for patients on thrombolytic therapy. Prevention of atherosclerotic thrombosis and thromboembolic events in patients with atrial fibrillation: For adult patients with atrial fibrillation who have at least one vascular event risk factor, are unsuitable for vitamin K antagonist (VKA) therapy, and have a low bleeding risk, clopidogrel may be used in combination with aspirin to prevent atherosclerotic thrombosis and thromboembolic events, including stroke. See Section 5.1 for more information. Clopidogrel is indicated for the prevention of atherosclerotic thrombotic events in adults with: myocardial infarction (days to less than 35 days), ischemic stroke (7 days to less than 6 months), or a confirmed peripheral artery disease; non-ST-segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), including patients who have received stent implantation after percutaneous coronary intervention; in combination with acetylsalicylic acid (ASA); ST-segment elevation acute myocardial infarction; in combination with ASA for patients eligible for thrombolytic therapy; and patients with acute coronary syndrome. Clopidogrel is indicated for: adult patients with myocardial infarction (days to less than 35 days), ischemic stroke (7 days to less than 6 months), or a confirmed peripheral artery disease. Adult patients with acute coronary syndromes: Non-ST-segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), including patients who have received stent implantation after percutaneous coronary intervention, should be used in combination with aspirin (ASA). ST-segment elevation acute myocardial infarction should be used in combination with aspirin for patients who meet the criteria for thrombolytic therapy. For the prevention of atherosclerotic thrombosis and thromboembolic events in patients with atrial fibrillation: For adult patients with atrial fibrillation who have at least one vascular event risk factor, are unsuitable for vitamin K antagonist (VKA) therapy, and have a low bleeding risk, clopidogrel can be used in combination with aspirin to prevent atherosclerotic thrombosis and thromboembolic events, including stroke. Clopidogrel is indicated for the prevention of atherosclerotic thrombotic events in the following adult patients: myocardial infarction (days to less than 35 days), ischemic stroke (7 days to less than 6 months), or patients with a confirmed peripheral artery disease. Clopidogrel is indicated for the prevention of atherosclerotic thrombotic events in the following adult patients: those with myocardial infarction (days to less than 35 days), ischemic stroke (7 days to less than 6 months), or a confirmed peripheral artery disease; and adult patients with acute coronary syndromes: non-ST-segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), including patients who have received stent implantation after percutaneous coronary intervention, in combination with acetylsalicylic acid (ASA); ST-segment elevation acute myocardial infarction, in combination with ASA and in patients receiving thrombolytic therapy. For the prevention of atherosclerotic thrombosis and thromboembolic events in patients with atrial fibrillation: For adult patients with atrial fibrillation who have at least one vascular event risk factor, are unsuitable for vitamin K antagonist (VKA) therapy, and have a low bleeding risk, clopidogrel may be used in combination with aspirin to prevent atherosclerotic thrombosis and thromboembolic events, including stroke. Clopidogrel is indicated for the prevention of atherosclerotic thrombotic events in the following adult patients: myocardial infarction (days to less than 35 days), ischemic stroke (7 days to less than 6 months), or patients with a confirmed peripheral artery disease. See Section 5.1 for more information. Clopidogrel is indicated for the prevention of atherosclerotic thrombotic events in the following adult patients: myocardial infarction (days to less than 35 days), ischemic stroke (7 days to less than 6 months), or patients with a confirmed peripheral artery disease. Patients with acute coronary syndromes: Non-ST-segment elevation acute coronary syndromes (unstable angina or non-Q-wave myocardial infarction), including patients who have received stent implantation after percutaneous coronary intervention, should be used in combination with aspirin (ASA). ST-segment elevation acute myocardial infarction should be used in combination with aspirin in patients who are eligible for thrombolytic therapy. See Section 5.1 for more information. Clopidogrel is indicated for adults to prevent atherosclerotic thrombotic events in patients with myocardial infarction (days to less than 35 days), ischemic stroke (7 days to less than 6 months), or a history of peripheral artery disease. For more information, please see Section 5.1. Clopidogrel is indicated for the prevention of atherosclerotic thrombotic events in adults with: myocardial infarction (days to less than 35 days), ischemic stroke (7 days to less than 6 months), or a confirmed peripheral artery disease; and acute coronary syndromes: - non-ST-segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), including patients who have received stent implantation after percutaneous coronary intervention, in combination with acetylsalicylic acid (ASA); - ST-segment elevation acute myocardial infarction, in combination with aspirin for patients eligible for thrombolytic therapy. For more information, please see Section 5.1. Clopidogrel is indicated for the prevention of atherosclerotic thrombotic events in adults with: myocardial infarction (days to less than 35 days), ischemic stroke (7 days to less than 6 months), or a confirmed peripheral artery disease. Patients with acute coronary syndrome: - Non-ST-segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), including patients who have received stents after percutaneous coronary intervention, should be used in combination with aspirin. - ST-segment elevation acute myocardial infarction, in combination with aspirin for patients who are eligible for thrombolytic therapy. See Section 5.1 for more information. Clopidogrel is indicated for adults to prevent atherosclerotic thrombotic events in patients with: - Myocardial infarction (days to less than 35 days), ischemic stroke (7 days to less than 6 months), or a confirmed peripheral artery disease. - Patients with acute coronary syndrome: Non-ST-segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), including patients who have received stents after percutaneous coronary intervention, should be used in combination with acetylsalicylic acid (ASA). ST-segment elevation acute myocardial infarction, in combination with aspirin for patients who are eligible for thrombolytic therapy.
Prevention of Thromboembolic Events
Thromboembolic Events
Thromboembolic Events
Thromboembolic Events

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Mechanism of Action
Clopidogrel is activated in a two-step reaction to its thiol-containing active metabolite. This active form is a platelet inhibitor that irreversibly binds to the P2Y12 ADP receptor on platelets. This binding prevents ADP from binding to the P2Y12 receptor, the activation of the glycoprotein GPIIb/IIIa complex, and platelet aggregation.
Clopidogrel must be metabolized by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor, and subsequently the ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. This effect is irreversible. Therefore, platelets exposed to the active metabolite of clopidogrel are affected for their remaining lifespan (approximately 7 to 10 days). Platelet aggregation induced by agonists other than ADP was also inhibited because this active metabolite blocks the amplifying effect of released ADP on platelet activation. The P2Y12 receptor plays a crucial role in the regulation of platelet activation by various agonists, and the active metabolite of clopidogrel (a widely used antithrombotic drug) irreversibly antagonizes this effect. In this study, we used a rat model of erosive arthritis to investigate whether decreased platelet reactivity leads to a reduction in inflammatory response. We used a peptidoglycan-polysaccharide (PG-PS)-induced Lewis rat model of arthritis to assess the effects of clopidogrel on inflammation. The model was divided into four groups: 1) untreated group, 2) clopidogrel-treated group, 3) PG-PS-induced group, and 4) PG-PS-induced and clopidogrel-treated group. Compared with the PG-PS group, the PG-PS + clopidogrel group showed significant differences in the following aspects: increased joint diameter, more severe clinical inflammatory manifestations, elevated plasma levels of pro-inflammatory cytokines (IL-1β, interferon (IFN)γ, and IL-6), and elevated neutrophil and platelet counts. Plasma IL-10 levels were significantly lower in the PG-PS + clopidogrel group compared to the PG-PS group. Plasma platelet factor 4 (PF4) levels were elevated in both the PG-PS and PG-PS + clopidogrel groups, but PF4 levels did not change significantly after clopidogrel treatment, suggesting that the pro-inflammatory effect of clopidogrel may not be mediated by platelets, but rather by other cells. Histological analysis showed that in the PG-PS-induced arthritis animal model, clopidogrel treatment increased leukocyte infiltration in the joint inflammation area, and exacerbated synovial hyperplasia, angiogenesis, subsynovial fibrosis, and cartilage erosion. In summary, clopidogrel treatment exhibits a pro-inflammatory effect in PG-PS-induced arthritis animal models, and this pro-inflammatory effect may not be mediated by platelets.

C16H16CLNO2S

321.82

321.059

C, 59.72; H, 5.01; Cl, 11.02; N, 4.35; O, 9.94; S, 9.96

113665-84-2

Clopidogrel thiolactone;1147350-75-1;Clopidogrel hydrogen sulfate;120202-66-6; 1217643-68-9; 90055-48-4 (racemic); 120202-66-6 (sulfate);120202-67-7 (HBr); 120202-65-5 (HCl); 744256-69-7 (besylate);

60606

Colorless to light yellow ointment

1.3±0.1 g/cm3

423.7±45.0 °C at 760 mmHg

210.0±28.7 °C

0.0±1.0 mmHg at 25°C

1.617

4.23

0

4

4

21

381

1

ClC1=C(C=CC=C1)[C@H](N2CCC3=C(C2)C=CS3)C(OC)=O

GKTWGGQPFAXNFI-HNNXBMFYSA-N

InChI=1S/C16H16ClNO2S/c1-20-16(19)15(12-4-2-3-5-13(12)17)18-8-6-14-11(10-18)7-9-21-14/h2-5,7,9,15H,6,8,10H2,1H3/t15-/m0/s1

methyl (2S)-2-(2-chlorophenyl)-2-(6,7-dihydro-4H-thieno[3,2-c]pyridin-5-yl)acetate

clopidogrel; 113665-84-2; Zyllt; (S)-Clopidogrel; Thrombo; Plavix; (+)-Clopidogrel; (+)-(S)-Clopidogrel;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 50 mg/mL (155.37 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.77 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (7.77 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 3: 2.5 mg/mL (7.77 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)