AZATHIOPRINE

Details

Stereochemistry	ACHIRAL
Molecular Formula	C9H7N7O2S
Molecular Weight	277.263
Optical Activity	NONE
Defined Stereocenters	0 / 0
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

Structure Search

SMILES

CN1C=NC(=C1SC2=NC=NC3=C2N=CN3)[N+]([O-])=O

InChI

InChIKey=LMEKQMALGUDUQG-UHFFFAOYSA-N

InChI=1S/C9H7N7O2S/c1-15-4-14-7(16(17)18)9(15)19-8-5-6(11-2-10-5)12-3-13-8/h2-4H,1H3,(H,10,11,12,13)

HIDE SMILES / InChI

Molecular Formula	C9H7N7O2S
Molecular Weight	277.263
Charge	0
Count

Stereochemistry	ACHIRAL
Additional Stereochemistry	No
Defined Stereocenters	0 / 0
E/Z Centers	0
Optical Activity	NONE

Description
Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/016324s037,017391s016lbl.pdf
Curator's Comment: description was created based on several sources, including https://www.ncbi.nlm.nih.gov/pubmed/18020555

Azathioprine remains one of the most important and widely prescribed drugs for immunosuppression/immunomodulation in autoimmune disease over 30 years after its introduction. Azathioprine is licensed for the treatment of only a limited range of autoimmune disorders, which is probably a reflection on the age of the drug. Widening the license for a drug is both costly and time consuming, and it would make no commercial sense for manufacturers to do so, at this late stage of life, for azathioprine. However, azathioprine is now so well established as an immunomodulating drug in autoimmune disorders that it represents the gold standard by which other drugs are compared. Azathioprine is indicated as an adjunct for the prevention of rejection in renal homotransplantation. It is also indicated for the management of active rheumatoid arthritis to reduce signs and symptoms. The combined use of azathioprine tablets with disease modifying anti-rheumatic drugs (DMARDs) has not been studied for either added benefit or unexpected adverse effects. The use of azathioprine tablets with these agents cannot be recommended. Azathioprine 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. Azathioprine is metabolized to 6-mercaptopurine (6-MP). Both compounds are rapidly eliminated from blood and are oxidized or methylated in erythrocytes and liver; no azathioprine or mercaptopurine is detectable in urine after 8 hours. Activation of 6-mercaptopurine occurs via hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and a series of multi-enzymatic processes involving kinases to form 6-thioguanine nucleotides (6-TGNs) as major metabolites.

CNS Activity

Approval Year

Targets

Primary Target	Pharmacology	Condition	Potency
Hypoxanthine-guanine phosphoribosyltransferase 4 Target ID: CHEMBL2360 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/016324s037,017391s016lbl.pdf	Inhibitor 8228

Conditions

Condition	Modality	Targets	Highest Phase	Product
Rheumatoid arthritis 313 Sources: http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/016324s037,017391s016lbl.pdf	Palliative		Approved 8360	IMURAN Approved Use Azathioprine tablets are indicated as an adjunct for the prevention of rejection in renal homotransplantation. It is also indicated for the management of active rheumatoid arthritis to reduce signs and symptoms. Renal Homotransplantation Azathioprine tablets are indicated as an adjunct for the prevention of rejection in renal homotransplantation. Experience with over 16,000 transplants shows a 5-year patient survival of 35% to 55%, but this is dependent on donor, match for HLA antigens, anti-donor or anti-B-cell alloantigen antibody, and other variables. The effect of azathioprine tablets on these variables has not been tested in controlled trials. Rheumatoid Arthritis Azathioprine tablets are indicated for the treatment of active rheumatoid arthritis (RA) to reduce signs and symptoms. Aspirin, non-steroidal anti-inflammatory drugs and/or low dose glucocorticoids may be continued during treatment with azathioprine tablets. The combined use of azathioprine tablets with disease modifying anti-rheumatic drugs (DMARDs) has not been studied for either added benefit or unexpected adverse effects. The use of azathioprine tablets with these agents cannot be recommended. Launch Date -5.63328E10

C_max

Value	Dose	Co-administered	Analyte	Population
69.5 ng/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/9048271	600 mg single, oral dose: 600 mg route of administration: Oral experiment type: SINGLE co-administered:		MERCAPTOPURINE ANHYDROUS plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

AUC

Value	Dose	Co-administered	Analyte	Population
135.8 ng × h/mL EXPERIMENT https://www.ncbi.nlm.nih.gov/pubmed/9048271	600 mg single, oral dose: 600 mg route of administration: Oral experiment type: SINGLE co-administered:		MERCAPTOPURINE ANHYDROUS plasma	Homo sapiens population: HEALTHY age: ADULT sex: FEMALE / MALE food status: FASTED

Doses

Dose	Population	Adverse events
2 mg/kg 1 times / day multiple, oral Recommended Dose: 2 mg/kg, 1 times / day Route: oral Route: multiple Dose: 2 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/15362028 Page: p.735	unhealthy, 18–70 n = 71 Health Status: unhealthy Condition: Crohn's disease Age Group: 18–70 Sex: M+F Population Size: 71 Sources: https://pubmed.ncbi.nlm.nih.gov/15362028 Page: p.735	Disc. AE: Discomfort epigastric, Serum transaminase increased... AEs leading to discontinuation/dose reduction: Discomfort epigastric (severe, 1.4%) Serum transaminase increased (5.6%) Leukopenia (9.9%) Pancreatitis (acute, 4.2%) Thrombocytopenia (1.4%) Sources: https://pubmed.ncbi.nlm.nih.gov/15362028 Page: p.735
2 mg/kg 1 times / day multiple, oral Recommended Dose: 2 mg/kg, 1 times / day Route: oral Route: multiple Dose: 2 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/19109574 Page: p.2797	unhealthy, 25.2–78.6 n = 63 Health Status: unhealthy Condition: Wegener's granulomatosis \|microscopic polyangiitis Age Group: 25.2–78.6 Sex: M+F Population Size: 63 Sources: https://pubmed.ncbi.nlm.nih.gov/19109574 Page: p.2797	Disc. AE: Hepatotoxicity, Digestion impaired... AEs leading to discontinuation/dose reduction: Hepatotoxicity (6.3%) Digestion impaired (4.8%) Sources: https://pubmed.ncbi.nlm.nih.gov/19109574 Page: p.2797
7500 mg single, oral Overdose Dose: 7500 mg Route: oral Route: single Dose: 7500 mg Co-administed with:: prednisone, p.o(1 g) Sources: https://pubmed.ncbi.nlm.nih.gov/4588639 Page: p.134	unhealthy, 44 n = 1 Health Status: unhealthy Condition: Renal Homotransplantation Age Group: 44 Sex: M Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/4588639 Page: p.134	Disc. AE: Vomiting, Diarrhea... AEs leading to discontinuation/dose reduction: Vomiting (mild) Diarrhea (mild) Sources: https://pubmed.ncbi.nlm.nih.gov/4588639 Page: p.134
5 mg/kg 1 times / day multiple, oral Recommended Dose: 5 mg/kg, 1 times / day Route: oral Route: multiple Dose: 5 mg/kg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/016324s039lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Renal Homotransplantation Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/016324s039lbl.pdf Page: p.1	Disc. AE: Malignant neoplasm NOS, Lymphoma... AEs leading to discontinuation/dose reduction: Malignant neoplasm NOS Lymphoma Hepatosplenic T-cell lymphoma Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/016324s039lbl.pdf Page: p.1

AEs

AE	Significance	Dose	Population
Thrombocytopenia	1.4% Disc. AE	2 mg/kg 1 times / day multiple, oral Recommended Dose: 2 mg/kg, 1 times / day Route: oral Route: multiple Dose: 2 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/15362028 Page: p.735	unhealthy, 18–70 n = 71 Health Status: unhealthy Condition: Crohn's disease Age Group: 18–70 Sex: M+F Population Size: 71 Sources: https://pubmed.ncbi.nlm.nih.gov/15362028 Page: p.735
Serum transaminase increased	5.6% Disc. AE	2 mg/kg 1 times / day multiple, oral Recommended Dose: 2 mg/kg, 1 times / day Route: oral Route: multiple Dose: 2 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/15362028 Page: p.735	unhealthy, 18–70 n = 71 Health Status: unhealthy Condition: Crohn's disease Age Group: 18–70 Sex: M+F Population Size: 71 Sources: https://pubmed.ncbi.nlm.nih.gov/15362028 Page: p.735
Leukopenia	9.9% Disc. AE	2 mg/kg 1 times / day multiple, oral Recommended Dose: 2 mg/kg, 1 times / day Route: oral Route: multiple Dose: 2 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/15362028 Page: p.735	unhealthy, 18–70 n = 71 Health Status: unhealthy Condition: Crohn's disease Age Group: 18–70 Sex: M+F Population Size: 71 Sources: https://pubmed.ncbi.nlm.nih.gov/15362028 Page: p.735
Pancreatitis	acute, 4.2% Disc. AE	2 mg/kg 1 times / day multiple, oral Recommended Dose: 2 mg/kg, 1 times / day Route: oral Route: multiple Dose: 2 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/15362028 Page: p.735	unhealthy, 18–70 n = 71 Health Status: unhealthy Condition: Crohn's disease Age Group: 18–70 Sex: M+F Population Size: 71 Sources: https://pubmed.ncbi.nlm.nih.gov/15362028 Page: p.735
Discomfort epigastric	severe, 1.4% Disc. AE	2 mg/kg 1 times / day multiple, oral Recommended Dose: 2 mg/kg, 1 times / day Route: oral Route: multiple Dose: 2 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/15362028 Page: p.735	unhealthy, 18–70 n = 71 Health Status: unhealthy Condition: Crohn's disease Age Group: 18–70 Sex: M+F Population Size: 71 Sources: https://pubmed.ncbi.nlm.nih.gov/15362028 Page: p.735
Digestion impaired	4.8% Disc. AE	2 mg/kg 1 times / day multiple, oral Recommended Dose: 2 mg/kg, 1 times / day Route: oral Route: multiple Dose: 2 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/19109574 Page: p.2797	unhealthy, 25.2–78.6 n = 63 Health Status: unhealthy Condition: Wegener's granulomatosis \|microscopic polyangiitis Age Group: 25.2–78.6 Sex: M+F Population Size: 63 Sources: https://pubmed.ncbi.nlm.nih.gov/19109574 Page: p.2797
Hepatotoxicity	6.3% Disc. AE	2 mg/kg 1 times / day multiple, oral Recommended Dose: 2 mg/kg, 1 times / day Route: oral Route: multiple Dose: 2 mg/kg, 1 times / day Sources: https://pubmed.ncbi.nlm.nih.gov/19109574 Page: p.2797	unhealthy, 25.2–78.6 n = 63 Health Status: unhealthy Condition: Wegener's granulomatosis \|microscopic polyangiitis Age Group: 25.2–78.6 Sex: M+F Population Size: 63 Sources: https://pubmed.ncbi.nlm.nih.gov/19109574 Page: p.2797
Diarrhea	mild Disc. AE	7500 mg single, oral Overdose Dose: 7500 mg Route: oral Route: single Dose: 7500 mg Co-administed with:: prednisone, p.o(1 g) Sources: https://pubmed.ncbi.nlm.nih.gov/4588639 Page: p.134	unhealthy, 44 n = 1 Health Status: unhealthy Condition: Renal Homotransplantation Age Group: 44 Sex: M Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/4588639 Page: p.134
Vomiting	mild Disc. AE	7500 mg single, oral Overdose Dose: 7500 mg Route: oral Route: single Dose: 7500 mg Co-administed with:: prednisone, p.o(1 g) Sources: https://pubmed.ncbi.nlm.nih.gov/4588639 Page: p.134	unhealthy, 44 n = 1 Health Status: unhealthy Condition: Renal Homotransplantation Age Group: 44 Sex: M Population Size: 1 Sources: https://pubmed.ncbi.nlm.nih.gov/4588639 Page: p.134
Hepatosplenic T-cell lymphoma	Disc. AE	5 mg/kg 1 times / day multiple, oral Recommended Dose: 5 mg/kg, 1 times / day Route: oral Route: multiple Dose: 5 mg/kg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/016324s039lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Renal Homotransplantation Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/016324s039lbl.pdf Page: p.1
Lymphoma	Disc. AE	5 mg/kg 1 times / day multiple, oral Recommended Dose: 5 mg/kg, 1 times / day Route: oral Route: multiple Dose: 5 mg/kg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/016324s039lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Renal Homotransplantation Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/016324s039lbl.pdf Page: p.1
Malignant neoplasm NOS	Disc. AE	5 mg/kg 1 times / day multiple, oral Recommended Dose: 5 mg/kg, 1 times / day Route: oral Route: multiple Dose: 5 mg/kg, 1 times / day Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/016324s039lbl.pdf Page: p.1	unhealthy Health Status: unhealthy Condition: Renal Homotransplantation Sources: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/016324s039lbl.pdf Page: p.1

Sourcing

Vendor/Aggregator	ID	URL
ChEBI	CHEBI:2948	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:2948
ChemicalBook	CB2170327	https://www.chemicalbook.com/ChemicalProductProperty_EN_CB2170327
MolPort	MolPort-000-745-914	https://www.molport.com/shop/molecule-link/MolPort-000-745-914
MolPort	MolPort-000-764-262	https://www.molport.com/shop/molecule-link/MolPort-000-764-262
Selleck Chemicals	Azathioprine(Azasan)	http://www.selleckchem.com/products/Azathioprine(Azasan).html
ZINC	ZINC000004258316	http://zinc15.docking.org/substances/ZINC000004258316
eMolecules	533997	https://www.emolecules.com/cgi-bin/more?vid=533997
eMolecules	731311	https://www.emolecules.com/cgi-bin/more?vid=731311

PubMed

Title	Date	PubMed
Enalapril and reversible acute renal failure.	1992	1315003
[IgA nephropathy (Berger's disease) in children].	1992 Dec	1492913
[Hepatic hemangiomas and rheumatoid arthritis in patients treated with azathioprine].	1992 Oct	1420764
Post-renal transplant azathioprine-induced pancreatitis.	1999 Oct	10528684
[Autoimmune hepatitis complicated by intolerable pain of lower extremities and shock due to azathioprine].	2000 Apr	10863328
Cyclosporine withdrawal in stable renal transplant recipients after azathioprine-mycophenolate mofetil conversion.	2000 Dec	11127309
Hepatocellular carcinoma and focal hepatic glycogenosis after prolonged azathioprine therapy.	2000 Jul	10923928
Portal hypertension in the presence of minimal liver damage in Crohn's disease on long-term azathioprine: possible endothelial cell injury.	2000 May	10833103
Cardiac and vascular abnormalities in renal transplant patients: differential effects of cyclosporin and azathioprine.	2000 May-Jun	10928294
CMV infection of liver transplant recipients: comparison of antigenemia and molecular biology assays.	2001	11389774
Immunosuppressive therapy in patients with thyroid eye disease: an overview of current concepts.	2001 Apr	11275939
Veno-occlusive disease, nodular regenerative hyperplasia and hepatocellular carcinoma after azathioprine treatment in a patient with ulcerative colitis.	2001 Mar	11293451
Azathioprine inhibits vaccinia virus replication in both BSC-40 and RAG cell lines acting on different stages of virus cycle.	2002 Aug 15	12202208
[Complicated antiphospholid antibody syndrome].	2002 Jul 5	12098096
Azathioprine in refractory sprue: results from a prospective, open-label study.	2002 Oct	12385445
Bilateral macular hemorrhage caused by azathioprine-induced aplastic anemia in a corneal graft recipient.	2002 Oct	12352092
[Treatment of rheumatoid arthritis].	2003	15098369
Low-dose azathioprine is effective and safe for maintenance of remission in patients with ulcerative colitis.	2003	14505127
[The influence of azathioprine on the osteogenesis of the limbs].	2003	12829883
CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes.	2003 Apr	12697733
Colchicine-induced myopathy in a teenager with familial Mediterranean fever.	2003 Dec	14632592
Hyperprolactinemia caused by azathioprine.	2003 Jan	12488716
Severe villus atrophy and chronic malabsorption induced by azathioprine.	2003 Jun	12806628
Systemic lupus erythematosus with presentation as vertigo and vertical nystagmus: report of one case.	2003 May-Jun	14521022
Use of infliximab, an anti-tumor necrosis alpha antibody, for inflammatory dermatoses.	2003 Sep-Oct	14973643
Fibrosing cholestatic hepatitis in renal transplant recipient with CMV infection: a case report.	2004	15783120
Effect of antimetabolite immunosuppressants on Flaviviridae, including hepatitis C virus.	2004 Feb 27	15084936
Adverse drug reactions to azathioprine therapy are associated with polymorphism in the gene encoding inosine triphosphate pyrophosphatase (ITPase).	2004 Mar	15167706
Genetic determinants of the pre- and post-azathioprine therapy thiopurine methyltransferase activity phenotype.	2004 Oct	15571267
Increased incidence of azathioprine-induced pancreatitis in Crohn's disease compared with other diseases.	2004 Oct 15	15479355
[Life-threatening adverse effects of pharmacologic antihyperuricemic therapy].	2004 Sep	15493119
Severe cholestatic hepatitis caused by azathioprine.	2005	15803861
Monozygotic twins concordant for intestinal Behçet's disease.	2005 Apr	15870978
Thiopurine methyltransferase (TPMT) heterozygosity and enzyme activity as predictive tests for the development of azathioprine-related adverse events.	2005 Apr 15	15792824

Patents

Sample Use Guides

In Vivo Use Guide

Rheumatoid Arthritis: is given on a daily basis. The initial dose should be approximately 1.0 mg/kg (50 to 100 mg) given as a single dose or on a twice-daily schedule. The dose may be increased, beginning at 6 to 8 weeks and thereafter by steps at 4-week intervals, if there are no serious toxicities and if initial response is unsatisfactory. Dose increments should be 0.5 mg/kg daily, up to a maximum dose of 2.5 mg/kg per day. Therapeutic response occurs after several weeks of treatment, usually 6 to 8 an adequate trial should be a minimum of 12 weeks.

Route of Administration: Oral

In Vitro Use Guide

Unknown

Substance Class	Chemical Created by `admin` on `Wed Jul 05 22:42:54 UTC 2023` Edited by `admin` on `Wed Jul 05 22:42:54 UTC 2023`
Record UNII	MRK240IY2L
Record Status	`Validated (UNII)`
Record Version

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Name

Type

Language

AZATHIOPRINE

Official Name

English

AZATHIOPRINE [MART.]

Common Name

English

BW-57-322

Code

English

AZATHIOPRINE [HSDB]

Common Name

English

AZATHIOPRINE [MI]

Common Name

English

AZATHIOPRINUM [WHO-IP LATIN]

Common Name

English

1H-PURINE, 6-((1-METHYL-4-NITRO-1H-IMIDAZOL-5-YL)THIO)

Common Name

English

AZATHIOPRINE [VANDF]

Common Name

English

NSC-39084

Code

English

AZATHIOPRINE [JAN]

Common Name

English

AZASAN

Brand Name

English

AZATHIOPRINE [EP IMPURITY]

Common Name

English

AZATHIOPRINE [USP-RS]

Common Name

English

AZATHIOPRINE [IARC]

Common Name

English

AZATHIOPRINE [ORANGE BOOK]

Common Name

English

IMURAN

Brand Name

English

6-[(1-Methyl-4-nitroimidazol-5-yl)thio]purine

Systematic Name

English

azathioprine [INN]

Common Name

English

6-((1-METHYL-4-NITROIMIDAZOL-5-YL)THIO)PURINE6-((1-METHYL-4-NITRO-1H-IMIDAZOL-5-YL)THIO)-1H-PURINE

Systematic Name

English

AZATHIOPRINE [USP MONOGRAPH]

Common Name

English

AZATHIOPRINE [USAN]

Common Name

English

AZATHIOPRINE [WHO-IP]

Common Name

English

Azathioprine [WHO-DD]

Common Name

English

AZATHIOPRINE [EP MONOGRAPH]

Common Name

English

Classification Tree Code System Code

LIVERTOX

NBK548332