Azathioprine

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Structural formula
Structure of azathioprine
General
Non-proprietary name Azathioprine
other names
  • 6 - [(1-Methyl-4-nitro-1 H -imidazol-5-yl) sulfanyl] -7 H -purine ( IUPAC )
  • 6- (1-methyl-4-nitro-5-imidazolyl) mercaptopurine
Molecular formula C 9 H 7 N 7 O 2 S
External identifiers / databases
CAS number 446-86-6
EC number 207-175-4
ECHA InfoCard 100.006.525
PubChem 2265
ChemSpider 2178
DrugBank DB00993
Wikidata Q18939
Drug information
ATC code

L04 AX01

Drug class

Immunosuppressant

properties
Molar mass 277.26 g · mol -1
Physical state

firmly

Melting point

243-244 ° C

pK s value

7.87

solubility

very poor in water (272 mg · l −1 at 25 ° C), soluble in alkalis and ammonia water

safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
08 - Dangerous to health 07 - Warning

danger

H and P phrases H: 302-315-319-335-350
P: 201-261-305 + 351 + 338-308 + 313
Toxicological data

2500 mg kg −1 ( LD 50 ,  mouse ,  oral )

As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Azathioprine is a drug from the nitroimidazole group . It has an immunosuppressive effect, i.e. it suppresses the immune system . Azathioprine is used to prevent rejection reactions after organ transplants and in the treatment of various diseases that are associated with a disorder of the immune response.

Mechanism of action

In the human body, azathioprine is metabolized spontaneously (via glutathione ) and rapidly (via the enzyme glutathione-S-transferase ) to the metabolites 6-mercaptopurine and 1-methyl-4-nitro-5-thioimidazole. 6-mercaptopurine passes through the cell membrane and is further metabolized to active and inactive metabolites in various metabolic processes. The enzyme mainly responsible for the metabolism of 6-mercaptopurine is the polymorphic thiopurine methyl transferase; other enzymes such as xanthine oxidase , inosine monophosphate dehydrogenase , hypoxanthine guanine phosphoribosyltransferase, guanosine monophosphate synthetase, and inosine triphosphate pyrophosphatase are also involved in the formation of active and inactive metabolites. The biological activity of the azathioprine metabolite 1-methyl-4-nitro-5-thioimidazole, in contrast to 6-mercaptopurine, has not yet been fully understood.

pharmacology

Azathioprine blocks (via its metabolites) the synthesis of DNA and RNA (6-mercaptopurine, as an atypical nucleoside, interferes with DNA / RNA synthesis) and thus inhibits the reproduction of T and B cells , which are part of the immune system . The immune system normally protects the body by recognizing and fighting foreign cells or changed body cells (cancer cells, virus-infected cells). The most important defense cells are macrophages , natural killer cells and T and B lymphocytes.

If these reactions are misdirected, however, the immune system also fights its own tissue as a foreign body and tries to destroy it. It is then an autoimmune disease . Azathioprine is supposed to suppress this misdirected work of the immune system ( immunosuppression ).

Clinical information

application areas

as well as in inflammatory bowel diseases such as

Side effects

Possible side effects include a .: changes in blood count ( acquired isolated aplastic anemia , macrocytosis ), hair loss, increased risk of infection, nausea, vomiting, diarrhea and weight loss. Fever, joint pain and inflammation of the pancreas are possible hypersensitivity reactions .

Special warnings and precautions for use

Since azathioprine affects the blood-forming system, the treatment must be carried out under constant medical control and monitoring of the blood count.

In the doses that must be taken after a kidney transplant, azathioprine increases the risk of developing skin cancer by a factor of 50 to 250 over a period of 20 years. The probable cause is the interaction of UVA radiation and 6- thioguanine , a breakdown product of azathioprine.

The risk of a white blood cell deficiency caused by azathioprine is around 35 times higher if a polymorphism in the NUDT15 gene is present. The mutation occurs more frequently among East Asians.

Interactions with other drugs

Simultaneous use of the xanthine oxidase inhibitor allopurinol interferes with the breakdown of azathioprine and thereby intensifies its effect, so that the risk of agranulocytosis is also increased. If both drugs are used at the same time, the azathioprine dose should therefore be reduced to about 25%.

Pregnancy, breastfeeding and the desire to have children

The fertility of men and women is not affected by the medication of azathioprine. The examination of the quality and quantity of sperm from 18 men during and after discontinuation of azathioprine therapy did not reveal any differences. All parameters were within the WHO standard.

In the meantime, azathioprine therapy has been very well researched when trying to have children or during an existing pregnancy. According to the latest findings, there is no increased risk of malformations in the fetus during pregnancy with existing medication. Even extensive experience with the father's intake at the time of conception and ongoing azathioprine therapy showed no increased risk of malformations or pregnancy complications. From the point of view of the European and US drug authorities, there is no longer any need to discontinue therapy if the mother or father is planning to have children.

Small amounts of the preparation can pass into breast milk, so that late effects for the child cannot be ruled out, which is why it should not be used during breastfeeding.

synthesis

Starting from diethyl oxalate , methylamine is used to produce dimethyloxalamide. This is cyclized to the imidazole with phosphorus (V) chloride . After nitration and an S N reaction, azathioprine is obtained.

Synthesis of azathioprine

Trade names

Monopreparations

Azafalk (D), Azaimmun (D, CH), Azarek (CH), Colinsan (D), Immunoprin (A), Imurek (D, A, CH), Zytrim (D), various generics (D, A)

Individual evidence

  1. ↑ a b c Entry on azathioprine in the ChemIDplus database of the United States National Library of Medicine (NLM) .
  2. ↑ a b entry on azathioprine. In: Römpp Online . Georg Thieme Verlag, accessed on June 30, 2019.
  3. ↑ a b Entry on azathioprine in the GESTIS substance database of the IFA , accessed on February 1, 2016(JavaScript required) .
  4. ↑ a b Technical information: Imurek , December 2013.
  5. ↑ YA DeClerck, RB Ettenger, JA Ortega, AJ Pennisi: Macrocytosis and pure RBC anemia Caused by azathioprine. In: American journal of diseases of children. Volume 134, Number 4, April 1980, pp. 377-379, doi : 10.1001 / archpedi.1980.04490010035012 , PMID 6989234 .
  6. ↑ Instructions for use Imurek film-coated tablets , as of November 2004.
  7. ↑ Azathioprine and UVA Light Generate Mutagenic Oxidative DNA Damage . In: Science 2005, No. 309, pp. 1871-1874.
  8. ↑ Increased melanoma risk in kidney transplant recipients . In: Medical Tribune 49/2005.
  9. ↑ Yang SK, Hong M, Baek J, Choi H, Zhao W: A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia. Nat Genet. 2014 Sep; 46 (9): 1017-1020. doi : 10.1038 / ng.3060
  10. ↑ Karow: General and Special Pharmacology and Toxicology . 2010, p. 944.
  11. ↑ Rebecca Fischer-Betz: Azathioprine in Pregnancy ( Memento from April 21, 2014 in the Internet Archive ). Heinrich Heine University Düsseldorf, as of July 1, 2008.
  12. ↑ D. von Herrath, W. Thimme: Malformation risk in children under azathioprine treatment of the father? . Pharmaceutical Letter 2005, 39, 7.
  13. ↑ B. Missler-Karger: ro Special: Long-acting anti-inflammatory drugs in pregnancy and breastfeeding, Part 2: Azathioprine, methotrexate, ciclosporin. Retrieved June 3, 2013.
  14. ↑ Falk Foundation eV (PDF; 740 kB). As of 2008.