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药品详细

Prasugrel(普拉格雷)

化学结构式图
中文名
普拉格雷
英文名
Prasugrel
分子式
C20H20FNO3S
化学名
5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4H,5H,6H,7H-thieno[3,2-c]pyridin-2-yl acetate
分子量
Average: 373.441
Monoisotopic: 373.114792406
CAS号
150322-43-3
ATC分类
B01A 抗血栓药
药物类型
small molecule
阶段
approved
商品名
同义名
基本介绍

Prasugrel, a thienopyridine derivative, is a platelet activation and aggregation inhibitor structurally and pharmacologically related to clopidogrel and ticlopidine. Similar to clopidogrel, prasugrel is a prodrug that requires enzymatic transformation in the liver to its active metabolite, R-138727. R-138727 irreversibly binds to P2Y12 type ADP receptors on platelets thus preventing activation of the GPIIb/IIIa receptor complex. As a result, inhibition of ADP-mediated platelet activation and aggregation occurs. Prasugrel was developed by Daiichi Sankyo Co. and is currently marketed in the United States and Canada in cooperation with Eli Lilly and Company for acute coronary syndromes planned for percutaneous coronary intervention (PCI). FDA approved in 2009.

生产厂家
  • Eli lilly and co
封装厂家
参考
Synthesis Reference Not Available
General Reference
  1. Dovlatova NL, Jakubowski JA, Sugidachi A, Heptinstall S: The reversible P2Y antagonist cangrelor influences the ability of the active metabolites of clopidogrel and prasugrel to produce irreversible inhibition of platelet function. J Thromb Haemost. 2008 May 15;. Pubmed
  2. Tagarakis GI: Ticagrelor and Prasugrel: Two Novel, Most-Promising Antiplatelet Agents. Recent Pat Cardiovasc Drug Discov. 2010 Sep 27. Pubmed
  3. Angiolillo DJ: The evolution of antiplatelet therapy in the treatment of acute coronary syndromes: from aspirin to the present day. Drugs. 2012 Nov 12;72(16):2087-116. doi: 10.2165/11640880-000000000-00000. Pubmed
  4. Jeong YH, Tantry US, Gurbel PA: Importance of potent P2Y receptor blockade in acute myocardial infarction: focus on prasugrel. Expert Opin Pharmacother. 2012 Aug;13(12):1771-96. doi: 10.1517/14656566.2012.704909. Epub 2012 Jul 12. Pubmed
剂型
规格
化合物类型
Type small molecule
Classes Not Available
Substructures Not Available
适应症
药理
Indication Indicated in combination with acetylsalicylic acid (ASA) to prevent atherothrombotic events in patients with acute coronary syndrome (ACS) who are to be managed with percutaneous coronary intervention (PCI). May be used in patients with unstable angina (UA), non-ST elevation myocardial infarction (NSTEMI), ST-elevation myocardial infarction (STEMI) who are to be managed with PCI. Prasugrel is not recommended in patients 75 years of age or greater, those that weigh<60kg, and patients with a history of stroke or transient ischemic attack due to increased risk of fatal and intracranial bleeding.
Pharmacodynamics Prasugrel is a member of the thienopyridine class of ADP receptor inhibitors, like ticlopidine (trade name Ticlid) and clopidogrel (trade name Plavix). These agents reduce the aggregation ("clumping") of platelets by irreversibly binding to P2Y12 receptors. Compared to clopidogrel, prasugrel inhibits adenosine diphosphate–induced platelet aggregation more rapidly, more consistently, and to a greater extent than do standard and higher doses of clopidogrel in healthy volunteers and in patients with coronary artery disease, including those undergoing PCI. The increased potency of prasugrel appears to be due to more efficient conversion to its active metabolite. However, it carries a higher risk of bleed compared to clopidogrel, which may be a result of its higher potency. Prasugrel produces inhibition of platelet aggregation to 20 μM or 5 μM ADP, as measured by light transmission aggregometry.
Mechanism of action Prasugrel is an thienopyridine and a prodrug which inhibits ADP receptors by irreversibly acting on the P2Y12 receptor on platelets. The active metabolite of prasugrel prevents binding of adenosine diphosphate (ADP) to its platelet receptor, impairing the ADP-mediated activation of the glycoprotein GPIIb/IIIa complex. Prasugrel is proposed to have a similar mechanism of action to clopidogrel.
Absorption 79% or greater of the dose is absorbed after oral administration. Absorption and metabolism occur rapidly and peak plasma concentrations (Cmax) are reached approximately 30 minutes following oral administration. Administration with a high fat, high calorie meal did not affect the AUC of the active metabolite in healthy individuals, but the Cmax was decreased by ~49% and the Tmax was increased to 0.5 to 1.5 hours. Prasugrel may be administered with or without food.
Volume of distribution

44-68L
Protein binding Approximately 98% of the active metabolite was bound to human serum albumin in a 4% buffered solution. The major inactive metabolites are also highly bound to human plasma proteins.
Metabolism
Prasugrel is not detected in plasma following oral administration. It is rapidly hydrolyzed in the intestine to thiolactone by human carboxylesterase (hCE) 2. This intermediate is further metabolized to its active metabolite, R-138727, in a single step by cytochrome P450 enzymes in the liver (primarily CYP3A4 and CYP2B6 and to a lesser extent by CYP2C9 and CYP2C19). The active metabolite is further metabolized by S-methylation or cysteine conjugation to two inactive metabolites. Unlike clopidogrel, transformation of prasugrel to its active metabolite does not appear to be affected by cytochrome P450 polymorphisms.

Important The metabolism module of DrugBank is currently in beta. Questions or suggestions? Please contact us.

Substrate Enzymes Product
Prasugrel
R-95913 Details
R-95913
R-138727 Details
Route of elimination Approximately 68% of the orally administered dose is excreted in urine and 27% in the feces, as inactive metabolites. The active metabolite is not expected to be removed by dialysis.
Half life The active metabolite has an elimination half-life of about 7.4 hours (range 2-15 hours).
Clearance

Apparent clearance = 112 – 166 L/hr
Toxicity LD50 (rat) 1,000 - 2,000 mg/kg; LD50 (rabbit) > 1,000 mg/kg
Affected organisms
  • Humans and other mammals
Pathways Not Available
理化性质
Properties
State solid
Experimental Properties
Property Value Source
logP 3.536 MSDS
Predicted Properties
Property Value Source
water solubility 2.37e-03 g/l ALOGPS
logP 3.67 ALOGPS
logP 4.31 ChemAxon
logS -5.2 ALOGPS
pKa (strongest acidic) 14.25 ChemAxon
pKa (strongest basic) 5.48 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 3 ChemAxon
hydrogen donor count 0 ChemAxon
polar surface area 46.61 ChemAxon
rotatable bond count 6 ChemAxon
refractivity 96.81 ChemAxon
polarizability 37.7 ChemAxon
药物相互作用
Drug Interaction
Ginkgo biloba Additive anticoagulant/antiplatelet effects may increase bleed risk. Concomitant therapy should be avoided.
Ibuprofen Coadministration with NSAIDS used chronically may increase the risk of bleeding.
Ketoconazole Ketoconazole is a potent inhibitor of CYP3A4 which decreases the Cmax of prasugrel due to a reduction of prasugrel bioactivation. However, there was no reduction of inhibition of platelet aggregation.
Lansoprazole Lansoprazole is a CYP2C19 substrate which decreases AUC and Cmax of prasugrel. Despite these decreases, there was no significant reduction of inhibition of platelet aggregation.
Ritonavir Ritonavir is a inhibitor of CYP3A4, thus blocking the bioactivation of prasugrel. As a result, a reduction in prasugrel efficiency may be observed in patients.
Warfarin Coadministration with warfarin may increase the risk of bleeding.
食物相互作用
  • Despite being a CYP3A4 inducer, grapefruit juice does not affect the pharmacokinetics of prasugrel

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