PharmGKB: The Pharmacogenomics Knowledge Base

Drug/Small Molecule:
azathioprine

2D structure

Overview

Generic Names: Azathioprin; Azathioprine Sodium; Azatioprin; Azothioprine
Trade Names: Azamun; Azanin; Azasan; Ccucol; Imuran; Imurek; Imurel; Muran
PharmGKB Accession Id: PA448515

Description

An immunosuppressive agent used in combination with cyclophosphamide and hydroxychloroquine in the treatment of rheumatoid arthritis. According to the Fourth Annual Report on Carcinogens (NTP 85-002, 1985), this substance has been listed as a known carcinogen. (Merck Index, 11th ed) (source: Drug Bank)

Indication

For use as an adjunct in the prevention of rejection in renal homotransplantation. Also for the management of severe, active rheumatoid arthritis unresponsive to rest, aspirin or other nonsteroidal anti-inflammatory drugs, or to agents in the class of which gold is an example. (source: Drug Bank)

ATC Therapeutic Category

  • L04AX:Other immunosuppressants

Pharmacology, Interactions, and Contraindications

Mechanism Of Action

Azathioprine antagonizes purine metabolism and may inhibit synthesis of DNA, RNA, and proteins. It may also interfere with cellular metabolism and inhibit mitosis. The mechanism of action of azathioprine in rheumatoid arthritis is not known but is most likely related to its immunosuppresive action. (source: Drug Bank)

Pharmacology

Azathioprine is a chemotherapy drug, now rarely used for chemotherapy but more for immunosuppression in organ transplantation and autoimmune disease such as rheumatoid arthritis or inflammatory bowel disease or Crohn's disease. It is a pro-drug, converted in the body to the active metabolite 6-mercaptopurine. Azathioprine acts to inhibit purine synthesis necessary for the proliferation of cells, especially leukocytes and lymphocytes. It is a safe and effective drug used alone in certain autoimmune diseases, or in combination with other immunosuppressants in organ transplantation. Its most severe side effect is bone marrow suppression, and it should not be given in conjunction with purine analogues such as allopurinol. The enzyme thiopurine S-methyltransferase (TPMT) deactivates 6-mercaptopurine. Genetic polymorphisms of TPMT can lead to excessive drug toxicity, thus assay of serum TPMT may be useful to prevent this complication. (source: Drug Bank)

Food Interactions

Take with food to reduce irritation. (source: Drug Bank)

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

Primarily converted to the active metabolites 6-mercaptopurine and 6-thioinosinic acid. (source: Drug Bank)

Protein Binding

Azathioprine and the metabolite mercaptopurine are moderately bound to serum proteins (30%). (source: Drug Bank)

Absorption

Well absorbed following oral administration. (source: Drug Bank)

Toxicity

The oral LD<sub>50</sub> for single doses of azathioprine in mice and rats are 2500 mg/kg and 400 mg/kg, respectively. Very large doses of this antimetabolite may lead to marrow hypoplasia, bleeding, infection, and death. (source: Drug Bank)

Isomeric SMILES Code:

CN1C=NC(=C1SC2=NC=NC3=C2NC=N3)[N+](=O)[O-] (source: Drug Bank)

In-Depth Annotations (In-Depth Annotation)

  1. rs1800584 at chr6:18238991 in NHLRC1, TPMT
    This splicing variant results in very low TPMT activity and risk for hematologic toxicity as a result of treatment with thiopurines.
    Variant Name:
    TPMT*4
    Related Drugs:
    azathioprine, mercaptopurine
    Evidence:
    http://www.pharmgkb.org/.../variant.jsp
  2. rs1800462 at chr6:18251934 in TPMT
    Carriers of this variant have low, no, or intermediate (in the case of heterozygotes) TPMT activity, putting them at risk for hematologic toxicity if treated with thiopurines.
    Variant Name:
    TPMT*2
    Related Drugs:
    azathioprine, mercaptopurine
    Evidence:
    http://www.pharmgkb.org/.../variant.jsp

Curated Annotations (Curated Annotation)

  1. rs55754655 at chr2:201234575 in AOX1
    A study in a cohort of 192 patients receiving azathioprine for inflammatory bowel disease found that this SNP in the AOX1 gene predicted lack of azathioprine response (p=0.035, OR 2.54, 95%CI 1.06-6.13).
    Variant Name:
    AOX1: c.3404A>G; Asn1135Ser
    Related Drugs:
    azathioprine
    Related Diseases:
    Inflammatory Bowel Diseases
    Evidence:
    PMID:19500084
  2. rs1142345 at chr6:18238897 in NHLRC1, TPMT
    Carriers of this variant have low, no, or intermediate (in the case of heterozygotes) TPMT activity, putting them at risk for hematologic toxicity if treated with thiopurines.
    Variant Name:
    TPMT*3C
    Related Drugs:
    azathioprine, mercaptopurine
    Evidence:
    PMID:15228163
  3. rs1800462 at chr6:18251934 in TPMT
    Carriers of this variant have low, no, or intermediate (in the case of heterozygotes) TPMT activity, putting them at risk for hematologic toxicity if treated with thiopurines.
    Variant Name:
    TPMT*2
    Related Drugs:
    azathioprine, mercaptopurine
    Evidence:
    PMID:15228163
  4. rs1127354 at chr20:3141842 in ITPA
    This polymorphism in the ITPA gene had the highest correlation with the change in SLE disease activity index score (r = 0.354, P = 0.006).
    Variant Name:
    ITPA: 94C>A; P32T
    Related Drugs:
    azathioprine
    Related Diseases:
    Lupus Erythematosus, Systemic
    Evidence:
    PMID:19129747
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
  •   
  • GN
Publications
No phenotype data Genotype Data Available Literature annotations available Not annotated
AOX1
  •   
  •   
  •   
  •   
  • GN
Publications, Variants
Phenotype data available No genotype data Literature annotations available Not annotated
BCL2L1
  •   
  •   
  •   
  • FA
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Has annotations
CYP2D6
  •   
  •   
  • PK
  •   
  • GN
Publications
No phenotype data Genotype Data Available Literature annotations available Not annotated
GSTA1
  •   
  •   
  • PK
  • FA
  •   
Publications
No phenotype data Genotype Data Available Literature annotations available Not annotated
GSTA2
  •   
  •   
  • PK
  • FA
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
GSTM1
  •   
  •   
  • PK
  • FA
  •   
Publications
Phenotype data available No genotype data Literature annotations available Not annotated
IMPDH1
  •   
  • PD
  •   
  • FA
  • GN
Publications
Phenotype data available No genotype data Literature annotations available Not annotated
IMPDH2
  •   
  • PD
  •   
  • FA
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
ITPA
  • CO
  • PD
  •   
  •   
  • GN
Publications, Variants
No phenotype data No genotype data Literature annotations available Not annotated
MAP2K1
  •   
  •   
  •   
  • FA
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
MOCOS
  •   
  •   
  •   
  •   
  • GN
Publications
Phenotype data available No genotype data Literature annotations available Not annotated
NFKB1
  •   
  •   
  •   
  • FA
  •   
Publications
No phenotype data Genotype Data Available No literature annotations Not annotated
NHLRC1
  •   
  •   
  •   
  •   
  •   
Variants
No phenotype data No genotype data Literature annotations available Not annotated
RAC1
  •   
  •   
  •   
  • FA
  •   
Publications
No phenotype data Genotype Data Available Literature annotations available Not annotated
RAC2
  •   
  •   
  •   
  • FA
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
SLC28A2
  •   
  • PD
  • PK
  •   
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
SLC28A3
  •   
  • PD
  • PK
  •   
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
SLC29A1
  •   
  • PD
  • PK
  •   
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
SLC29A2
  •   
  • PD
  • PK
  •   
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Has annotations
TPMT
  • CO
  • PD
  • PK
  • FA
  • GN
Publications, Variants
Phenotype data available No genotype data Literature annotations available Not annotated
VAV1
  •   
  •   
  •   
  • FA
  •   
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
XDH
  •   
  • PD
  • PK
  •   
  • GN
Publications

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

Drug Targets

Gene Description
IMPDH1 Uncurated Annotation (source: Drug Bank)
IMPDH2 Uncurated Annotation (source: Drug Bank)
AMPD3 Uncurated Annotation (source: Drug Bank)
AMPD1 Uncurated Annotation (source: Drug Bank)
AMPD2 Uncurated Annotation (source: Drug Bank)
ADSL Uncurated Annotation (source: Drug Bank)
GMPS Uncurated Annotation (source: Drug Bank)
GMPR Uncurated Annotation (source: Drug Bank)
GMPR2 Uncurated Annotation (source: Drug Bank)
HPRT1 Uncurated Annotation (source: Drug Bank)
PPAT Uncurated Annotation (source: Drug Bank)

PharmGKB Curated Pathways

The following drugs are in curated knowledge about this drug.

  Drug Relationship Evidence
Phenotype data available Genotype Data Available Literature annotations available Not annotated
warfarin
  •   
  •   
  •   
  •   
  •   
Publications

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

Drug Interactions

Drug Description
acenocoumarol Uncurated Annotation The thiopurine decreases the anticoagulant effect (source: Drug Bank)
allopurinol Uncurated Annotation Allopurinol increases the effect of thiopurine (source: Drug Bank)
dicumarol Uncurated Annotation The thiopurine decreases the anticoagulant effect (source: Drug Bank)
mesalazine Uncurated Annotation The 5-ASA derivative increases the toxicity of thiopurine (source: Drug Bank)
mivacurium Uncurated Annotation The agent decreases the effect of the muscle relaxant (source: Drug Bank)
olsalazine Uncurated Annotation The 5-ASA derivative increases the toxicity of thiopurine (source: Drug Bank)
pancuronium Uncurated Annotation The agent decreases the effect of the muscle relaxant (source: Drug Bank)
sulfasalazine Uncurated Annotation The 5-ASA derivative increase the toxicity of thiopurine (source: Drug Bank)
tubocurarine Uncurated Annotation The agent decreases the effect of the muscle relaxant (source: Drug Bank)
warfarin Uncurated Annotation The thiopurine decreases the anticoagulant effect (source: Drug Bank)

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
Colitis, Ulcerative
  • CO
  •   
  •   
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Crohn Disease
  • CO
  •   
  •   
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Hyperplasia
  • CO
  • PD
  •   
  •   
  • GN
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Inflammatory Bowel Diseases
  • CO
  • PD
  •   
  • FA
  • GN
Publications, Variants
No phenotype data No genotype data Literature annotations available Not annotated
Lupus Erythematosus, Systemic
  •   
  • PD
  • PK
  •   
  • GN
Publications, Variants
Phenotype data available Genotype Data Available Literature annotations available Not annotated
Neoplasms
  • CO
  • PD
  • PK
  • FA
  • GN
Publications
Phenotype data available Genotype Data Available Literature annotations available Not annotated
Precursor Cell Lymphoblastic Leukemia-Lymphoma
  •   
  • PD
  • PK
  •   
  •   
Publications
No phenotype data No genotype data Literature annotations available Not annotated
Rheumatic Diseases
  • CO
  •   
  •   
  •   
  •   
Publications

Non-Curated Information

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

Curated Phenotype Datasets

These datasets are sorted alphabetically by title.

  1. Analysis of variation in mouse TPMT expression and activity.
    • Genotype data available
    • Phenotype data available
    • No literature annotations
    • Not annotated
    • FA
    Submitted by Howard McLeod, PharmD involving TPMT, , azathioprine and mercaptopurine

Additional Datasets

These datasets are minimally curated and are sorted alphabetically by title.

  1. The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease

Downloads

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LinkOuts

Web Resource:
Wikipedia
DrugBank:
DB00993
KEGG Drug ID:
D00238
PubChem Compound ID:
2265
PubChem Substance ID:
9055

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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