Eptifibatide monoacetate is a cyclic heptapeptide that has anti-platelet action and functions as a competitive antagonist for the activated platelet glycoprotein IIb/IIIa receptor[1].

Absorption, Distribution and Excretion
/Breast Milk/ It is unclear whether epitubatide is distributed in human breast milk. Epitubatide binds to approximately 25% of plasma proteins, primarily albumin (9-16%). The volume of distribution (VOD) of epitubatide in patients with coronary artery disease is approximately 185-260 mL/kg, while in healthy individuals it is slightly higher (220-270 mL/kg). Epitubatide is a synthetic platelet glycoprotein IIb/IIIa receptor inhibitor that has been investigated as an antithrombotic agent for various acute ischemic coronary syndromes. This study aimed to characterize the distribution of (14)C-epitubatide in humans following a single intravenous (iv) bolus dose. (14)C-epitubatide (approximately 50 μCi) was administered as a single intravenous bolus dose of 135 μg/kg to eight healthy men. Blood, exhaled carbon dioxide, urine, and fecal samples were collected within 72 hours after administration, and their radioactivity was analyzed using liquid scintillation counting. Simultaneously, epitubatin and its deamide derivatives (DEs) in plasma and urine samples were determined using liquid chromatography-mass spectrometry. At the initial sampling time (5 minutes), the mean (± standard deviation) peak concentration of plasma epitubatin was 879 ± 251 ng/mL, followed by a biexponential decrease in concentration, with a mean distribution half-life of 5 ± 2.5 minutes and a mean terminal elimination half-life of 1.13 ± 0.17 hours. The plasma epitubatin concentration and radioactivity levels decreased synchronously, with the majority of the radioactivity (82.4%) attributed to epitubatin. Within 72 hours of administration of ¹⁴C-epitubatin, approximately 73% of the administered radioactivity was recovered. The primary route of elimination was urine (accounting for 98% of the total recovered radioactivity), while fecal (1.5%) and respiratory (0.8%) excretions were less significant. Eptibatide is cleared via renal and non-renal mechanisms, with renal clearance accounting for approximately 40% of total clearance. In the first 24 hours after administration, the drug is primarily excreted in the urine as unmodified eptibatide (34%), DE (19%), and a more polar metabolite (13%). Plasma clearance of eptibatide is directly proportional to body weight and estimated creatinine clearance, and inversely proportional to age. Following a single intravenous injection of (14)C radiolabeled eptibatide (135 μg/kg) in healthy men, renal clearance was on average approximately 40–50% of systemic clearance. Clearance was reduced by 50% in patients with moderate to severe renal impairment (estimated creatinine clearance less than 50 mL/min). Systemic clearance was lower in older patients with coronary artery disease than in younger adults. For more complete data on absorption, distribution, and excretion of eptibatide (9 items), please visit the HSDB records page.

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Metabolism/Metabolites
(14) C-labeled epitubatide is extensively metabolized in rats and monkeys to deamidated epitubatide and several polar metabolites. Drug-derived radioactive material excreted in rat bile was identified as deamidated epitubatide, which is reabsorbed in the intestine and further metabolized to more polar metabolites. Plasma and urinary metabolite profiles in rats and monkeys showed similar metabolic distributions of epitubatide in both species. Epitubatide is primarily metabolized via deamidation to a metabolite that possesses approximately 41% of the platelet aggregation inhibitory activity of the parent compound, and is also metabolized through the formation of other more polar metabolites. Approximately 27% of the epitubatide dose is broken down in plasma into naturally occurring amino acids; no major non-amino acid metabolites were detected in human plasma.

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Biological Half-Life
In cynomolgus monkeys, a single intravenous injection of 2 mg/kg (14)C-epitubatide resulted in a decrease in plasma (14)C-epitubatide-derived radioactivity concentrations over a half-life of approximately 12 hours. Within 5 minutes of administration, approximately 93% of the total plasma (14)C was unmetabolized epitubatide and rapidly eliminated over a half-life of 17 minutes.
In rats, a single intravenous injection of 2 mg/kg of the radiolabeled drug resulted in a rapid decrease in plasma (14)C-epitubatide-derived radioactivity concentrations over a terminal half-life of approximately 5 hours. Unmetabolized epitubatide decreased over an apparent half-life of approximately 8 minutes. Following single intravenous injections of 2 and 20 mg/kg epitubatide, plasma epitubatide concentrations were dose-dependent, while the half-life (11 to 12 minutes) was dose-independent, indicating linear pharmacokinetics within the 2 to 20 mg/kg dose range. The mean half-life of epitubatide in patients with coronary artery disease is 2.5–2.8 hours. The mean half-life in healthy individuals is reported to be 0.83–2.4 hours. …This study aimed to describe the distribution of epitubatide in the human body following a single intravenous bolus injection of (14)C-epitubatide. Eight healthy men received a single intravenous bolus injection of 135 μg/kg of (14)C-epitubatide (approximately 50 μCi). At the initial sampling time (5 minutes), the mean (± standard deviation) peak plasma concentration of epitubatide reached 879 ± 251 ng/mL, followed by a generally biexponential decline in concentration, with a mean distribution half-life of 5 ± 2.5 minutes and a mean terminal elimination half-life of 1.13 ± 0.17 hours.

Toxicity Summary
Identification and Use: Eptifibatide (trade name: Integrilin) is indicated for reducing the composite endpoint of death, new-onset myocardial infarction (MI), or urgent intervention requirement in patients undergoing percutaneous coronary intervention (PCI), including coronary artery stenting. Human Exposure and Toxicity: Information on acute toxicity of eptifibatide is limited. Generally, overdose of eptifibatide in humans may produce extended effects of the drug's pharmacological action, primarily manifested as bleeding. Case reports of eptifibatide-related thrombocytopenia highlight the importance of monitoring platelet counts after treatment with this drug. In a human lymphocyte chromosomal aberration assay, eptifibatide did not demonstrate genotoxicity. Animal Studies: Single-dose toxicity studies were conducted in rats, rabbits, and monkeys; at doses up to 500 μg/kg/min, administered via continuous intravenous infusion over 90 minutes, no death occurred, and all animals tolerated the drug well. In rabbits, female rabbits receiving 50 and 500 μg/kg/min (lasting 90 minutes) showed a dose-dependent decrease in platelet count, attributed to eptifibatide administration. In monkeys, the observed adverse effects were limited to petechial hemorrhage in the thigh and/or abdomen, lasting 1 to 3 days. Three out of five monkeys died or were euthanized during the study period due to anemia caused by contusions, excessive bleeding, and/or petechial hemorrhage. Total albumin and globulin levels were decreased in all monkeys. Autopsy revealed focal hemorrhage in multiple organs. In a rat fertility study, administration of eptifibatide had no effect on the pregnancy process. No fertility or parental toxicity was observed at daily doses up to 72.0 mg/kg (equivalent to 24 times the maximum recommended daily dose for humans), nor were any effects on parental reproductive function observed. In the Ames study, eptifibatide did not show genotoxicity at doses up to 667 μg/mL; in the mouse lymphoma cell forward mutation assay, eptifibatide also did not show genotoxicity at doses up to 1,000 μg/mL; and in the mouse micronucleus assay, eptifibatide did not show genotoxicity.

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Effects during pregnancy and lactation
◉ Overview of use during lactation
There is currently no publicly available information regarding the use of eptifibatide during lactation. Because eptifibatide is a peptide drug, it is unlikely to be absorbed by infants, as it is likely to be destroyed in the infant's gastrointestinal tract. Until more data are available, lactating women should use eptifibatide with caution, especially when breastfeeding newborns or premature infants. If a lactating woman uses this drug, the infant should be closely monitored for bruising and bleeding.
◉ Effects on breastfed infants
As of the revision date, no relevant published information was found.
◉ Effects on Lactation and Breast Milk
As of the revision date, no relevant published information was found.

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Drug Interactions
Concomitant use of platelet aggregation inhibitors and anticoagulants (especially at high doses) may increase the risk of bleeding; therefore, close monitoring for bleeding is necessary, especially at the arterial puncture site. If severe bleeding occurs (e.g., pressure hemostasis is ineffective), eptifibatide and concomitant heparin treatment should be discontinued immediately, and appropriate treatment measures should be taken as needed (e.g., protamine sulfate can be used in patients receiving heparin). In healthy individuals, enoxaparin sodium (1 mg/kg, subcutaneously every 12 hours for a total of 4 times) does not affect the pharmacokinetics or pharmacodynamics (platelet aggregation) of eptifibatide. The manufacturer notes that caution should be exercised when eptifibatide is used in combination with oral anticoagulants.
In a small number of patients with acute myocardial infarction, eptifibatide has been used in combination with thrombolytic agents (e.g., alteplase, streptokinase, tenecteplase) to reduce the risk of re-occlusion of the infarct-related artery. Some clinicians believe that combining short-acting platelet aggregation inhibitors such as eptifibatide with thrombolytic therapy may achieve optimal efficacy while minimizing bleeding risk. However, the use of drugs affecting platelet function after thrombolysis may increase the risk of thrombolytic therapy-related bleeding complications, including the need for transfusions, and its efficacy has not yet been definitively proven; therefore, the combination of eptifibatide and thrombolytic therapy should be considered an investigational treatment and should be conducted with caution. Limited preclinical and clinical data indicate that in patients receiving eptifibatide (0.5 mcg/kg/min, intravenous infusion) monotherapy or in combination with aspirin, heparin, or both, there are no significant pharmacokinetic or pharmacodynamic interactions (e.g., additive effects on platelet aggregation inhibition) between eptifibatide and aspirin. Although the combination of eptifibatide and aspirin can prolong bleeding time up to five times from baseline, a similar prolongation of bleeding time has been observed with aspirin in combination with placebo. However, because eptifibatide inhibits platelet aggregation, caution should be exercised when used concomitantly with other drugs that affect hemostasis, including thrombolytics, oral anticoagulants, nonsteroidal anti-inflammatory drugs (NSAIDs), or dipyridamole. However, in a large, multicenter clinical study (ESPRIT), eptifibatide was routinely used in combination with clopidogrel or ticlopidine in patients undergoing coronary artery stenting. To minimize potential additive pharmacological effects, the manufacturer of eptifibatide states that concomitant treatment with other platelet glycoprotein (GP IIb/IIIa) receptor inhibitors (e.g., abciximab, tirofiban) should be avoided.

[1]. Platelet glycoprotein IIb/IIIa inhibitors in percutaneous coronary intervention: focus on the pharmacokinetic-pharmacodynamic relationships of eptifibatide. Clin Pharmacokinet. 2003;42(8):703-20.

Therapeutic Uses
Platelet Aggregation Inhibitors
/Clinical Trials/ ClinicalTrials.gov is a registry and results database that tracks human clinical studies funded by public and private institutions worldwide. The website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov includes summary information about the study protocol, including: the disease or condition; the intervention (e.g., the medical product, behavior, or procedure under investigation); the title, description, and design of the study; participation requirements (eligibility criteria); the location of the study; contact information for the study location; and links to relevant information from other health websites, such as the NLM's MedlinePlus (for providing patient health information) and PubMed (for providing citations and abstracts of academic articles in the medical field). Eptibatide is included in the database.
Eptimethotrexate is indicated for reducing the incidence of the composite endpoint of death or new myocardial infarction (MI) in patients with acute coronary syndrome (ACS) (unstable angina (UA)/non-ST-segment elevation myocardial infarction (NSTEMI)), including patients receiving medical therapy and those undergoing percutaneous coronary intervention (PCI).
Eptimethotrexate is indicated for reducing the incidence of the composite endpoint of death, new myocardial infarction (MI), or emergency intervention in patients undergoing PCI (including those undergoing coronary artery stenting). /Included in US Product Label/
In a minority of patients, eptimethotrexate has been used in combination with thrombolytic agents (e.g., alteplase, tenecteplase) to prevent coronary re-occlusion after acute myocardial infarction. /Not Included in US Product Label/
Drug Warnings
The most common and serious side effect of eptimethotrexate treatment is bleeding. In clinical studies, bleeding complications were reported in 35% to 75% of patients receiving different doses of eptifibatide. These complications were usually minor and occurred at the vascular access site (e.g., femoral artery puncture) (e.g., patients undergoing percutaneous coronary intervention (PCI)). Bleeding is an extension of the pharmacological effects of eptifibatide and is primarily classified according to the criteria of the TIMI (Thrombolysis in Myocardial Infarction) study group in clinical trials. Minor bleeding is generally defined as spontaneous gross hematuria or spontaneous hematemesis; observed blood loss with a decrease in hemoglobin concentration of 3-5 g/dL or a decrease in hematocrit of at least 10%; or a decrease in hemoglobin or hematocrit of 4-5 g/dL or 12-15%, respectively, without a definite bleeding site. Major bleeding is defined as intracranial hemorrhage or significant bleeding with a decrease in hemoglobin or hematocrit of at least 5 g/dL or at least 15%. Because eptifibatide increases the risk of bleeding, it is contraindicated in patients with a history of bleeding tendency or active abnormal bleeding within the past 30 days (e.g., elevated hemostatic parameters, recent non-compressive vascular puncture, gastrointestinal or genitourinary bleeding). A low baseline hematocrit (below 30%) may indicate recent undetected bleeding, and such patients may not tolerate additional bleeding events; therefore, eptifibatide should not be used in these patients. Epitifibatide is contraindicated in patients with: severe uncontrolled hypertension (systolic blood pressure greater than 200 mmHg or diastolic blood pressure greater than 110 mmHg, and currently receiving antihypertensive therapy); recent (within 6 weeks) major surgery; a history of stroke or any hemorrhagic stroke within 30 days; currently receiving or planning to receive other GP IIb/IIIa receptor inhibitor therapy; and patients undergoing renal dialysis. There are currently no data on the use of eptifibatide in patients with serum creatinine concentrations ≥ 4 mg/dL; patients with serum creatinine concentrations between 2 and 4 mg/dL should have their dose reduced.
FDA Pregnancy Risk Classification: B / No evidence of risk to humans. Although adverse reactions have been observed in animal studies, adequate, well-controlled studies in pregnant women have not shown an increased risk of fetal malformations; or, in the absence of adequate human studies, animal studies have shown no fetal risk. The possibility of harm to the fetus is small, but it still exists. /
The safety and efficacy of Integrilin in pediatric patients have not been studied.
For more complete data on drug warnings for epitubatide (15 of them), please visit the HSDB records page.

C37H53N11O11S2

831.961864233017

891.336

1248559-53-6

Eptifibatide;188627-80-7

12001375

Typically exists as solid at room temperature

11

14

10

61

1550

5

CC(=O)O.C1C[C@H]2C(=O)N[C@@H](CSSCCC(=O)N[C@H](C(=O)NCC(=O)N[C@H](C(=O)N[C@H](C(=O)N2C1)CC3=CNC4=CC=CC=C43)CC(=O)O)CCCCN=C(N)N)C(=O)N

KWKBRYJYRIUYEI-QMYFOHRPSA-N

InChI=1S/C35H49N11O9S2.C2H4O2/c36-30(51)25-18-57-56-13-10-27(47)42-22(8-3-4-11-39-35(37)38)31(52)41-17-28(48)43-23(15-29(49)50)32(53)44-24(14-19-16-40-21-7-2-1-6-20(19)21)34(55)46-12-5-9-26(46)33(54)45-25;1-2(3)4/h1-2,6-7,16,22-26,40H,3-5,8-15,17-18H2,(H2,36,51)(H,41,52)(H,42,47)(H,43,48)(H,44,53)(H,45,54)(H,49,50)(H4,37,38,39);1H3,(H,3,4)/t22-,23-,24-,25-,26-;/m0./s1

acetic acid;2-[(3S,6S,12S,20R,23S)-20-carbamoyl-12-[4-(diaminomethylideneamino)butyl]-3-(1H-indol-3-ylmethyl)-2,5,8,11,14,22-hexaoxo-17,18-dithia-1,4,7,10,13,21-hexazabicyclo[21.3.0]hexacosan-6-yl]acetic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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