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targets (1) enzymes (5)
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Identification
Name Prasugrel
Accession Number DB06209
Type small molecule
Groups approved
Description

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.
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
CS-747
LY-640315
Salts
  • Prasugrel Hydrochloride
Brand names
Name Company
Effient Daiichi Sankyo Co.
Efient Daiichi Sankyo Co.
Prasita Daiichi Sankyo Co.
Brand mixtures Not Available
Categories
  • Antiplatelet Agents
CAS number 150322-43-3
Weight Average: 373.441
Monoisotopic: 373.114792406
Chemical Formula C20H20FNO3S
InChI Key InChIKey=DTGLZDAWLRGWQN-UHFFFAOYSA-N
InChI
InChI=1S/C20H20FNO3S/c1-12(23)25-18-10-14-11-22(9-8-17(14)26-18)19(20(24)13-6-7-13)15-4-2-3-5-16(15)21/h2-5,10,13,19H,6-9,11H2,1H3
Plain Text
IUPAC Name
5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4H,5H,6H,7H-thieno[3,2-c]pyridin-2-yl acetate
SMILES
CC(=O)OC1=CC2=C(CCN(C2)C(C(=O)C2CC2)C2=CC=CC=C2F)S1
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Organic
Classes Not Available
Substructures Not Available
Pharmacology
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.
Mechanism of action Prasugrel is an thienopyridine 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.
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.
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 Not Available
Toxicity LD50 (rat) 1,000 - 2,000 mg/kg; LD50 (rabbit) > 1,000 mg/kg
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Eli lilly and co
Packagers Not Available
Dosage forms
Form Route Strength
Tablet Oral 5 mg, 10 mg
Prices Not Available
Patents
Country Patent Number Approved Expires (estimated)
United States 6693115 2001-07-03 2021-07-03
United States 5288726 1992-09-08 2012-09-08
Canada 2077695 2002-08-20 2012-09-08
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
References
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
External Links
Resource Link
KEGG Drug D05597 Link_out
PubChem Compound 6918456 Link_out
PubChem Substance 99443238 Link_out
ChemSpider 5293653 Link_out
RxList http://www.rxlist.com/effient-drug.htm Link_out
Drugs.com http://www.drugs.com/cdi/prasugrel.html Link_out
PDRhealth http://www.pdrhealth.com/drugs/effient Link_out
Wikipedia http://en.wikipedia.org/wiki/Prasugrel Link_out
ATC Codes
  • B01AC22
AHFS Codes
  • 20:12.18
PDB Entries Not Available
FDA label show (1000 KB)
MSDS show (134 KB)
Interactions
Drug Interactions
Drug Interaction
Ginkgo biloba Additive anticoagulant/antiplatelet effects may increase bleed risk. Concomitant therapy should be avoided.
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.
Food Interactions
  • Despite being a CYP3A4 inducer, grapefruit juice does not affect the pharmacokinetics of prasugrel
Targets

1. P2Y purinoceptor 12

Pharmacological action: yes
Actions: antagonist

Receptor for ADP and ATP coupled to G-proteins that inhibit the adenylyl cyclase second messenger system. Not activated by UDP and UTP. Involved in platelets aggregation

Organism class: human
UniProt ID: Q9H244 Link_out
Gene: P2RY12 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  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 Jul;6(7):1153-9. Epub 2008 Jul 1. Pubmed
Enzymes

1. Cocaine esterase

Actions: substrate
UniProt ID: O00748 Link_out

References:
  1. 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

2. Cytochrome P450 3A4

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. 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

3. Cytochrome P450 2B6

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P20813 Link_out
Gene: CYP2B6 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. 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. Cytochrome P450 2C9

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. This enzyme contributes to the wide pharmacokinetics variability of the metabolism of drugs such as S- warfarin, diclofenac, phenytoin, tolbutamide and losartan

UniProt ID: P11712 Link_out
Gene: CYP2C9
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. 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

5. Cytochrome P450 2C19

Actions: substrate

Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and imipramine

UniProt ID: P33261 Link_out
Gene: CYP2C19 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. 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
Comments
Drug created on March 19, 2008 10:17 / Updated on April 20, 2013 15:48