PharmGKB: The Pharmacogenomics Knowledge Base

Drug/Small Molecule:
clopidogrel

2D structure

Overview

Trade Names: Clopidogrel [Ban:Inn]; Clopidogrel sulfate; Plavix
PharmGKB Accession Id: PA449053

Description

Clopidogrel, an antiplatelet agent structurally and pharmacologically similar to ticlopidine, is used to reduce atherosclerotic events such as myocardial infarction, stroke, and vascular death in patients who have had a recent stroke, recent MI, or have established peripheral vascular disease. (source: Drug Bank)

Indication

For the reduction of atherosclerotic events (myocardial infarction, stroke, and vascular death) in patients with atherosclerosis documented by recent stroke, recent myocardial infarction, or established peripheral arterial disease (source: Drug Bank)

ATC Therapeutic Category

  • B01AC:Platelet aggregation inhibitors excl. heparin

Pharmacology, Interactions, and Contraindications

Mechanism Of Action

The active metabolite of clopidogrel prevents binding of adenosine diphosphate (ADP) to its platelet receptor, impairing the ADP-mediated activation of the glycoprotein GPIIb/IIIa complex. It is proposed that the inhibition involves a defect in the mobilization from the storage sites of the platelet granules to the outer membrane. No direct interference occurs with the GPIIb/IIIa receptor. As the glycoprotein GPIIb/IIIa complex is the major receptor for fibrinogen, its impaired activation prevents fibrinogen binding to platelets and inhibits platelet aggregation. By blocking the amplification of platelet activation by released ADP, platelet aggregation induced by agonists other than ADP is also inhibited by the active metabolite of clopidogrel. (source: Drug Bank)

Pharmacology

Clopidogrel, an antiplatelet agent structurally and pharmacologically similar to ticlopidine, is used to reduce atherosclerotic events such as myocardial infarction, stroke, and vascular death in patients who have had a recent stroke, recent MI, or have established peripheral vascular disease. (source: Drug Bank)

Food Interactions

Take without regard to meals. (source: Drug Bank)

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

Hepatic, extensive and rapid, by hydrolysis to the main circulating metabolite, a carboxylic acid derivative, which accounts for approximately 85% of the circulating drug-related compounds. A glucuronic acid derivative of the carboxylic acid derivative has also been found in plasma and urine. Neither the parent compound nor the carboxylic acid derivative has a platelet inhibiting effect. (source: Drug Bank)

Protein Binding

98% (source: Drug Bank)

Absorption

Absorption is at least 50% based on urinary excretion of clopidogrel-related metabolites. Bioavailability has not been found to be affected by food. (source: Drug Bank)

Toxicity

Symptoms of acute toxicity include vomiting (in baboons), prostration, difficult breathing, and gastrointestinal hemorrhage. (source: Drug Bank)

Isomeric SMILES Code:

COC(=O)[C@H](c1ccccc1Cl)N2CCc3c(ccs3)C2 (source: Drug Bank)

In-Depth Annotations (In-Depth Annotation)

  1. rs2046934 at chr3:152540332 in MED12L, P2RY12
    This SNP was used to tag the H2 haplotype to show association with peripherial arterial disease and coronary artery disease.
    Variant Name:
    P2RY12:744T>C
    Related Drugs:
    clopidogrel, ticlopidine
    Evidence:
    http://www.pharmgkb.org/.../variant.jsp
  2. rs4244285 at chr10:96531606 in CYP2C19
    This loss-of-function variant CYP2C19*2 was associated with diminished platelet response to clopidogrel treatment and poorer cardiovascular outcomes.
    Variant Name:
    CYP2C19*2; CYP2C19:681G>A
    Related Drugs:
    clopidogrel
    Related Diseases:
    Cardiovascular Diseases
    Evidence:
    PMID:19706858

Curated Annotations (Curated Annotation)

  1. rs2046934 at chr3:152540332 in MED12L, P2RY12
    This is one of four SNPs that comprise H1/H2 haplotypes. The four SNPs (C139T, T744C, ins801A, G52T(=G50T) are in perfect LD, and T744C is frequently used as the tagging SNP. H1 is 139C/744T/no ins at 801A/52G. H2(minor haplotype) is 139T/744C/ins801A//52T. H2 haplotype has been found to be associated with enhanced platelet reactivity, peripheral artery disease, coronary artery disease(particularly in non-smokers)and with poor response to clopidogrel. In other studies, no association was found between haplotype and response to clopidogrel or aspirin or with cardiovascular events.
    Variant Name:
    P2RY12:T744C,P2RY12:i-T744C
    Related Drugs:
    aspirin, clopidogrel
    Related Diseases:
    Coronary Artery Disease, Peripheral Vascular Diseases
    Evidence:
    PMID:12912815
    PMID:14662702
    PMID:15795539
    PMID:16181985
    PMID:16405973
    PMID:16581111
    PMID:16769602
    PMID:16961627
    PMID:17337040
    PMID:17803810
  2. rs1045642 at chr7:86976581 in ABCB1
    The C3435T variant (rs1045642) at exon 26 in the ABCB1 was showed to influence clopidogrel absorption in patients with a cardiovascular disease. Plasma concentrations of clopidogrel and its active metabolite were reduced in patients carrying the TT genotype.
    Variant Name:
    ABCB1: C3435T
    Related Drugs:
    clopidogrel
    Related Diseases:
    Cardiovascular Diseases
    Evidence:
    PMID:17112805
    PMID:19106083
  3. rs1045642 at chr7:86976581 in ABCB1
    Risk or phenotype-associated genotype: TT. Phenotype: ABCB1 3435C>T genotype was significantly associated with the risk of cardiovascular death, myocardial infarction, or stroke (p=0.0064). ABCB1 3435 TT homozygotes had a 72% increased risk of cardiovascular death, myocardial infarction, or stroke compared with CT/CC individuals HR 1.72, 95% CI 1.22-2.44, p=0.002). CT heterozygotes were at similar risk to CC individuals (HR 0.94, 0.58-1.51). Study size/population: 1471 patients with acute coronary syndromes taking clopidogrel. Type of association: CO; GN; ADR
    Variant Name:
    ABCB1: 3435C>T
    Related Drugs:
    clopidogrel
    Related Diseases:
    Cardiovascular Diseases, Death, Sudden, Cardiac, Myocardial Infarction, Stroke
    Evidence:
    PMID:20801494
  4. rs1045642 at chr7:86976581 in ABCB1
    Risk or phenotype-associated genotype: CC. Phenotype: In patients with or without ST-elevation acute coronary syndrome a higher rate of of ischaemic events were observed for patients with the ABCB1 3435 CC genotype (high-expression group) than for those with polymorphisms of intermediate (CT) or low expression (TT) who were on clopidogrel. Study size: 5148 patients receiving 75 mg clopidogrel once daily Study population/ethnicity: predominantly white (98%) Type of association: GN
    Related Drugs:
    clopidogrel
    Evidence:
    PMID:20801498
  5. rs12777823 at chr10:96395492
    A GWAS found this variant (rs12777823) was the most significantly associated SNP with clopidogrel response. This SNP was in strong linkage disequilibrium with 12 further SNPs within the CYP2C18-CYP2C19-CYP2C9-CYP2C8 cluster (rs12777823; rs10109204; rs2025445; rs1326837; rs717238; rs2860838; rs2860903; rs9332105; rs9332113; rs12572351; rs10509679; rs1934951; rs1934680) and also with the loss-of-function variant CYP2C19*2 (rs4244285). Further findings in this study showed that the CYP2C19*2 genotype accounted for most of all the initially found association with diminished platelet response to clopidogrel.
    Related Drugs:
    clopidogrel
    Related Diseases:
    Cardiovascular Diseases
    Evidence:
    PMID:19706858
  6. rs12248560 at chr10:96511647 in CYP2C19
    Risk or phenotype-associated allele: T Phenotype: For both C/T (n=546) and T/T (n=76) allele carriers, significantly lower ADP-induced platelet aggregation values were found compared with wild-type homozygotes (C/C; n=902; P=0.039 and P=0.008, respectively). T allele carriage was significantly associated with an increased risk of bleeding. The study concludes that CYP2C19*17 carrier status is significantly associated with enhanced response to clopidogrel and an increased risk of bleeding. Study size: 1524 patients. Study population/ethnicity: patients with coronary artery disease and planned drug-eluting stent placement; pretreatment with 600 mg clopidogrel. Type of association: CO; GN
    Variant Name:
    CYP2C19: -806C>T; CYP2C19*17
    Related Drugs:
    clopidogrel
    Related Diseases:
    Coronary Disease
    Evidence:
    PMID:20083681
  7. rs12248560 at chr10:96511647 in CYP2C19
    Risk or phenotype-associated allele: T. Phenotype: Patients in the clopidogrel group who had any gain-of-function allele had a higher rate of events of major bleeding than did those without any gain-of-function or loss-of-function alleles. Study size: 5148 patients receiving 75 mg clopidogrel once daily Study population/ethnicity: predominantly white (98%) Significance metric(s): p=0.022 Type of association: GN
    Variant Name:
    CYP2C19*17 CYP2C19: -806C>T
    Related Drugs:
    clopidogrel
    Evidence:
    PMID:20801498
  8. rs28399504 at chr10:96512453 in CYP2C19
    Subjects who had previously experienced myocardial infarction and were receiving clopidogrel were almost twice as likely to experience a subsequent cardiovascular event if they carried any two CYP2C19 loss-of-function alleles (CYP2C19*2, CYP2C19*3, CYP2C19*4 or CYP2C19*5) relative to those with none. Patients from this study who underwent percutaneous coronary intervention and carried two CYP2C19 loss-of-function alleles had a 3.58 times greater risk of cardiovascular events as those with none. These results suggest that treatment with clopidogrel is less effective in individuals who are homozygous for CYP2C19 loss-of-function alleles than in those who do not carry CYP2C19 loss-of-function alleles.
    Variant Name:
    CYP2C19*4, CYP2C19:A1G
    Related Drugs:
    clopidogrel
    Related Diseases:
    Cardiovascular Diseases, Death, Myocardial Infarction, Stroke
    Evidence:
    PMID:19106083
  9. rs4986893 at chr10:96530400 in CYP2C19
    Subjects who had previously experienced myocardial infarction and were receiving clopidogrel were almost twice as likely to experience a subsequent cardiovascular event if they carried any two CYP2C19 loss-of-function alleles (CYP2C19*2, CYP2C19*3, CYP2C19*4 or CYP2C19*5) relative to those with none. Patients from this study who underwent percutaneous coronary intervention and carried two CYP2C19 loss-of-function alleles had a 3.58 times greater risk of cardiovascular events as those with none. These results suggest that treatment with clopidogrel is less effective in individuals who are homozygous for CYP2C19 loss-of-function alleles than in those who do not carry CYP2C19 loss-of-function alleles.
    Variant Name:
    CYP2C19*3, CYP2C19:G636A
    Related Drugs:
    clopidogrel
    Related Diseases:
    Cardiovascular Diseases, Death, Myocardial Infarction, Stroke
    Evidence:
    PMID:19106083
  10. rs4244285 at chr10:96531606 in CYP2C19
    Subjects who had previously experienced myocardial infarction and were receiving clopidogrel were almost twice as likely to experience a subsequent cardiovascular event if they carried any two CYP2C19 loss-of-function alleles (CYP2C19*2, CYP2C19*3, CYP2C19*4 or CYP2C19*5) relative to those with none. Patients from this study who underwent percutaneous coronary intervention and carried two CYP2C19 loss-of-function alleles had a 3.58 times greater risk of cardiovascular events as those with none. These results suggest that treatment with clopidogrel is less effective in individuals who are homozygous for CYP2C19 loss-of-function alleles than in those who do not carry CYP2C19 loss-of-function alleles.
    Variant Name:
    CYP2C19*2, CYP2C19:G681A
    Related Drugs:
    clopidogrel
    Related Diseases:
    Cardiovascular Diseases, Death, Myocardial Infarction, Stroke
    Evidence:
    PMID:19106083
  11. rs4244285 at chr10:96531606 in CYP2C19
    Subjects with acute coronary syndromes receiving treatment with clopidogrel and who carried two copies of CYP2C19 loss-of-function/reduced function alleles (two copies of CYP2C19*2; or one copy of CYP2C19*2 and one copy of CYP2C19*3, CYP2C19*4 or CYP2C19*8) had a relative increase of 53% in risk of death from cardiovascular causes, myocardial infarction, or stroke, as compared with noncarriers. Subjects were participants in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMTI) 38. 97.6% of the study participants were Caucasian. In a separate cohort of healthy subjects treated with clopidogrel, carriers of at least one reduced-function CYP2C19 allele had significantly lower levels of clopidogrel's active metabolite and diminished platelet inhibition.
    Variant Name:
    CYP2C19*2, CYP2C19:G681A
    Related Drugs:
    clopidogrel
    Related Diseases:
    Cardiovascular Diseases, Death, Myocardial Infarction, Stroke
    Evidence:
    PMID:19106084
  12. rs4244285 at chr10:96531606 in CYP2C19
    Risk or phenotype-associated allele: A. Phenotype: A meta-analysis associated CYP2C19*2 with increased risk of major cardiovascular events and stent thrombosis in patients with coronary artery disease receiving clopidogrel. Study size: 8043 (events), 4975 (stent thrombosis). Study population/ethnicity: Patients (mostly European) enrolled in studies of clopidogrel for acute coronary syndromes or stable coronary artery disease. Significance metric(s): RR = 1.96, CI = 1.14-3.37, p = 0.02 (events); RR = 3.82, CI = 2.23-6.54, p = 0.0001 (stent thrombosis). Type of association: CO.
    Variant Name:
    CYP2C19*2
    Related Drugs:
    clopidogrel
    Related Diseases:
    Angina, Unstable, Cardiovascular Diseases, Ischemia, Myocardial Infarction, Recurrence, Stroke, Thrombosis
    Evidence:
    PMID:20351750
Variant names are different names that have been used in the literature and other resources to refer to the same variant.

The following genes are in curated knowledge about this drug.

  Gene Relationship Evidence
Phenotype data available Genotype Data Available Literature annotations available Has annotations
ABCB1
  • CO
  •   
  • PK
  • FA
  • GN
Publications, Variants
No phenotype data Genotype Data Available Literature annotations available Not annotated
CYP1A2
  •   
  • PD
  • PK
  •   
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP2B6
  •   
  • PD
  • PK
  • FA
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP2C19
  • CO
  • PD
  • PK
  •   
  • GN
Publications, Variants
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP2C9
  • CO
  • PD
  • PK
  •   
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
CYP3A
  •   
  • PD
  • PK
  •   
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP3A4
  • CO
  • PD
  • PK
  •   
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP3A5
  •   
  • PD
  • PK
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
F2R
  •   
  •   
  •   
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
ITGA2
  •   
  •   
  •   
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
ITGB3
  •   
  •   
  •   
  •   
  • GN
Publications
No phenotype data No genotype data No literature annotations Not annotated
MED12L
  •   
  •   
  •   
  •   
  •   
Variants
No phenotype data No genotype data Literature annotations available Has annotations
P2RY1
  •   
  •   
  •   
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Has annotations
P2RY12
  • CO
  • PD
  • PK
  •   
  • GN
Publications, Variants

A list of non-curated publications that mention this drug along with other genes is available.

Drug Targets

Gene Description
P2RY12 Uncurated Annotation (source: Drug Bank)
SELP Uncurated Annotation (source: Drug Bank)

The following drugs are in curated knowledge about this drug.

  Drug Relationship Evidence
No phenotype data No genotype data Literature annotations available Not annotated
calcium channel blockers
  •   
  •   
  •   
  •   
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
omeprazole
  •   
  •   
  •   
  • FA
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Proton pump inhibitors
  • CO
  •   
  • PK
  •   
  • GN
Publications

A list of non-curated publications that mention this drug along with other drugs is available.

Curated Information

The following diseases are in curated knowledge about this drug.

  Disease Relationship Evidence
No phenotype data No genotype data Literature annotations available Not annotated
Acute coronary syndrome
  • CO
  •   
  •   
  •   
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
Angina, Unstable
  • CO
  •   
  •   
  •   
  • GN
Publications, Variants
No phenotype data No genotype data Literature annotations available Not annotated
Arteriosclerosis
  • CO
  •   
  •   
  •   
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
Cardiovascular Diseases
  • CO
  •   
  • PK
  •   
  • GN
Publications, Variants
No phenotype data No genotype data Literature annotations available Not annotated
Coronary Artery Disease
  • CO
  •   
  • PK
  • FA
  • GN
Publications, Variants
No phenotype data No genotype data Literature annotations available Not annotated
Coronary Disease
  • CO
  • PD
  • PK
  •   
  • GN
Publications, Variants
No phenotype data No genotype data Literature annotations available Not annotated
Death
  • CO
  •   
  • PK
  •   
  • GN
Publications, Variants
No phenotype data No genotype data Literature annotations available Not annotated
Death, Sudden, Cardiac
  • CO
  •   
  •   
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Ischemia
  • CO
  •   
  •   
  •   
  • GN
Publications, Variants
Phenotype data available Genotype Data Available Literature annotations available Not annotated
Myocardial Infarction
  • CO
  •   
  • PK
  •   
  • GN
Publications, Variants
No phenotype data No genotype data Literature annotations available Not annotated
Peripheral Vascular Diseases
  • CO
  •   
  •   
  •   
  •   
Publications, Variants
No phenotype data No genotype data Literature annotations available Not annotated
Recurrence
  • CO
  •   
  •   
  •   
  • GN
Publications, Variants
Phenotype data available No genotype data Literature annotations available Not annotated
Stroke
  • CO
  •   
  • PK
  •   
  • GN
Publications, Variants
No phenotype data No genotype data Literature annotations available Not annotated
Thrombosis
  • CO
  •   
  •   
  •   
  • GN
Publications, Variants

Non-Curated Information

A list of non-curated publications that mention this drug along with other diseases is available.

LinkOuts

Web Resource:
Wikipedia
DrugBank:
DB00758
KEGG Drug ID:
D00769
PubChem Compound ID:
60606
PubChem Substance ID:
196885

Common Searches

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Non-Curated Publications

A list of non-curated publications that mention this drug is available.

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