Azathioprine (AZA), sold under the brand name Imuran, among others, is an
immunosuppressive medication.
[ It is used in ]rheumatoid arthritis
Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are inv ...
, granulomatosis with polyangiitis
Granulomatosis with polyangiitis (GPA), previously known as Wegener's granulomatosis (WG), is a rare long-term systemic disorder that involves the formation of granulomas and inflammation of blood vessels (vasculitis). It is a form of vasculitis ...
, Crohn's disease
Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea (which may be bloody if inflammation is severe), fever, abdominal distensi ...
, ulcerative colitis
Ulcerative colitis (UC) is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary symptoms of active disease are abdominal pain and diarrhea mixed with blood (hematochezia). Weight loss, fever, and ...
, and systemic lupus erythematosus
Lupus, technically known as systemic lupus erythematosus (SLE), is an autoimmune disease in which the body's immune system mistakenly attacks healthy tissue in many parts of the body. Symptoms vary among people and may be mild to severe. Commo ...
, and in kidney transplant
Kidney transplant or renal transplant is the organ transplant of a kidney into a patient with end-stage kidney disease (ESRD). Kidney transplant is typically classified as deceased-donor (formerly known as cadaveric) or living-donor transplant ...
s to prevent rejection. It is listed by the International Agency for Research on Cancer as a group 1 carcinogen (carcinogenic to humans). It is taken by mouth or injected into a vein.
Common side effects include bone-marrow suppression and vomiting
Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose.
Vomiting can be the result of ailments like food poisoning, gastroenter ...
.[ Bone-marrow suppression is especially common in people with a genetic deficiency of the enzyme thiopurine S-methyltransferase.][ Other serious risk factors include an increased risk of certain ]cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
s.[ Use during ]pregnancy
Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins.
Pregnancy usually occurs by sexual intercourse, but ...
may result in harm to the baby.[ Azathioprine is in the ]purine analogue
Purine analogues are antimetabolites that mimic the structure of metabolic purines.
Examples
* Nucleobase analogues
**Thiopurines such as thioguanine are used to treat acute leukemias and remissions in acute granulocytic leukemias.
***Azathioprin ...
and antimetabolite family of medications.[ It works via ]6-thioguanine
Tioguanine, also known as thioguanine or 6-thioguanine (6-TG) is a medication used to treat acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and chronic myeloid leukemia (CML). Long-term use is not recommended. It is given by mouth. ...
to disrupt the making of RNA and DNA by cells.[
Azathioprine was first made in 1957.] It is on the World Health Organization's List of Essential Medicines. In 2018, it was the 358th most commonly prescribed medication in the United States, with more than 800thousand prescriptions.
Medical uses
Azathioprine is used alone or in combination with other immunosuppressive therapy to prevent rejection following organ transplantation, and to treat an array of autoimmune disease
An autoimmune disease is a condition arising from an abnormal immune response to a functioning body part. At least 80 types of autoimmune diseases have been identified, with some evidence suggesting that there may be more than 100 types. Nearly a ...
s, including rheumatoid arthritis
Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are inv ...
, pemphigus
Pemphigus ( or ) is a rare group of blistering autoimmune diseases that affect the skin and mucous membranes.
The name is derived from the Greek root ''pemphix'', meaning "pustule".
In pemphigus, autoantibodies form against desmoglein, whic ...
, systemic lupus erythematosus, Behçet's disease
Behçet's disease (BD) is a type of inflammatory disorder which affects multiple parts of the body. The most common symptoms include painful sores on the mucous membranes of the mouth and other parts of the body, inflammation of parts of the ey ...
, and other forms of vasculitis
Vasculitis is a group of disorders that destroy blood vessels by inflammation. Both arteries and veins are affected. Lymphangitis (inflammation of lymphatic vessels) is sometimes considered a type of vasculitis. Vasculitis is primarily caused ...
, autoimmune hepatitis
Autoimmune hepatitis, formerly known as lupoid hepatitis, plasma cell hepatitis, or autoimmune chronic active hepatitis, is a chronic, autoimmune disease of the liver that occurs when the body's immune system attacks liver cells, causing the live ...
, atopic dermatitis
Atopic dermatitis (AD), also known as atopic eczema, is a long-term type of inflammation of the skin ( dermatitis). It results in itchy, red, swollen, and cracked skin. Clear fluid may come from the affected areas, which often thickens over tim ...
, myasthenia gravis
Myasthenia gravis (MG) is a long-term neuromuscular junction disease that leads to varying degrees of skeletal muscle weakness. The most commonly affected muscles are those of the eyes, face, and swallowing. It can result in double vision, ...
, neuromyelitis optica
Neuromyelitis optica spectrum disorders (NMOSD), including neuromyelitis optica (NMO), are autoimmune diseases characterized by acute inflammation of the optic nerve ( optic neuritis, ON) and the spinal cord ( myelitis). Episodes of ON and myeli ...
(Devic's disease), restrictive lung disease
Restrictive lung diseases are a category of extrapulmonary, pleural, or parenchymal respiratory diseases that restrict lung expansion, resulting in a decreased lung volume, an increased work of breathing, and inadequate ventilation and/or oxygena ...
, and others. It is also an important therapy and steroid-sparing agent for inflammatory bowel disease
Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the colon and small intestine, Crohn's disease and ulcerative colitis being the principal types. Crohn's disease affects the small intestine and large intestine, as well ...
(such as Crohn's disease and ulcerative colitis) and for multiple sclerosis
Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This ...
.
In the United States, it is approved by the Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
for use in kidney transplantation
Kidney transplant or renal transplant is the organ transplant of a kidney into a patient with end-stage kidney disease (ESRD). Kidney transplant is typically classified as deceased-donor (formerly known as cadaveric) or living-donor transplantat ...
from human donors, and for rheumatoid arthritis.
Transplantation
Azathioprine is used to prevent rejections of kidney or liver allografts, usually in conjunction with other therapies including corticosteroids
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are invol ...
, other immunosuppressants, and local radiation therapy
Radiation therapy or radiotherapy, often abbreviated RT, RTx, or XRT, is a therapy using ionizing radiation, generally provided as part of cancer treatment to control or kill malignant cells and normally delivered by a linear accelerator. Rad ...
. The administration protocol starts either at the time of transplantation or within the following two days.
Rheumatoid arthritis
Being a disease-modifying antirheumatic drug
Disease-modifying antirheumatic drugs (DMARDs) comprise a category of otherwise unrelated disease-modifying drugs defined by their use in rheumatoid arthritis to slow down disease progression. The term is often used in contrast to nonsteroida ...
(DMARD), azathioprine has been used for the management of the signs and symptoms of adult rheumatoid arthritis
Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are inv ...
. Nonsteroidal anti-inflammatory drugs and corticosteroids may be combined or continued (if they were already in use) with azathioprine, but the combination with other DMARDs is not recommended.
Inflammatory bowel disease
Azathioprine has been used in the management of moderate to severe chronically active Crohn's disease, to maintain clinical remission (absence of disease activity) in corticosteroid-dependent patients, and to provide benefit in people with fistulizing Crohn's disease. The onset of action is slow, and it may require several months to achieve clinical response.
Azathioprine treatment is associated with an increased risk of lymphoma
Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). In current usage the name usually refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include en ...
, but if this is due to the drug or a predisposition related to Crohn's disease is unclear. Lower doses of azathioprine are used as a therapy in children with refractory or corticosteroid-dependent Crohn's disease, without causing many side effects. It may also be used to prevent flares in those with ulcerative colitis
Ulcerative colitis (UC) is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary symptoms of active disease are abdominal pain and diarrhea mixed with blood (hematochezia). Weight loss, fever, and ...
.
Others
Azathioprine is sometimes used in systemic lupus erythematosus, requiring a maintenance dose of 15 mg or higher of prednisone
Prednisone is a glucocorticoid medication mostly used to suppress the immune system and decrease inflammation in conditions such as asthma, COPD, and rheumatologic diseases. It is also used to treat high blood calcium due to cancer and ad ...
in those who experience recurrent flares.
It is used as an add-on therapy when steroid therapy is given by mouth for pemphigus and myasthenia gravis, as a "steroid-sparing" agent. Azathioprine is also used to maintain remission in people who have granulomatosis with polyangiitis.[
It can be very effective in eczema and atopic dermatitis, though it is not commonly used.] The British National Eczema Society lists it as a third-line treatment for severe to moderate cases of these skin diseases.
It was widely used for the treatment of multiple sclerosis until the first half of the 1990s. Concerns about increased risk of malignancy
Malignancy () is the tendency of a medical condition to become progressively worse.
Malignancy is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not s ...
has led to a decreased use, yet it is still used in maintenance treatment for people who frequently relapse
In internal medicine, relapse or recidivism is a recurrence of a past (typically medical) condition. For example, multiple sclerosis and malaria often exhibit peaks of activity and sometimes very long periods of dormancy, followed by relapse or ...
. A 2007 Cochrane review
Cochrane (previously known as the Cochrane Collaboration) is a British international charitable organisation formed to organise medical research findings to facilitate evidence-based choices about health interventions involving health professi ...
found that azathioprine reduced the number of relapses in the first year of treatment and disease progression in the first two to three years and did not find an increase in cancer, and noted the need for direct comparison of azathioprine and interferon beta
The type-I interferons (IFN) are cytokines which play essential roles in inflammation, immunoregulation, tumor cells recognition, and T-cell responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p21.3 cyto ...
, conflicting conclusions regarding cancer, and the potential for long-term risks.
A widely used therapy for idiopathic pulmonary fibrosis was azathioprine in combination with prednisone and ''N''-acetylcysteine
Acetylcysteine, also known as ''N''-acetylcysteine (NAC), is a medication that is used to treat paracetamol overdose and to loosen thick mucus in individuals with chronic bronchopulmonary disorders like pneumonia and bronchitis. It has been us ...
. A 2012 study showed that outcomes were worse with this combination than with placebo.
Adverse effects
Nausea and vomiting are common adverse effects, especially at the beginning of a treatment. Such cases are met with taking azathioprine after meals or transient intravenous
Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...
administration. Side effects that are probably hypersensitivity
Hypersensitivity (also called hypersensitivity reaction or intolerance) refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. They are usually referred to as an over-reaction of the immune ...
reactions include dizziness, diarrhea, fatigue
Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...
, and rashes. Hair loss is often seen in transplant patients receiving the drug, but rarely occurs under other indications. Because azathioprine suppresses the bone marrow, patients can develop anaemia
Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, th ...
and be more susceptible to infection
An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable di ...
; regular monitoring of the blood count is recommended during treatment. Acute pancreatitis
Acute pancreatitis (AP) is a sudden inflammation of the pancreas. Causes in order of frequency include: 1) a gallstone impacted in the common bile duct beyond the point where the pancreatic duct joins it; 2) heavy alcohol use; 3) systemic disea ...
can also occur, especially in patients with Crohn's disease. Treatment is discontinued in up to 30% of patients due these effects but therapeutic drug monitoring of the biologically active metabolites, ''i.e.'' thiopurine nucleotides can help to optimize the efficacy and safety. Clinically, most hospitals resort to on-exchange LC-MS (liquid chromotography - mass spectrometry) but the newly developed approach of porous graphitic carbon based chromatography hyphenated with mass spectrometry appears superior with respect to patient care in this respect.
Under FDA rules, like many other immunosuppressants, the use of this drug excludes eligibility for blood donation
A blood donation occurs when a person voluntarily has blood drawn and used for transfusions and/or made into biopharmaceutical medications by a process called fractionation (separation of whole blood components). Donation may be of whole bl ...
.
It is listed by the International Agency for Research on Cancer
The International Agency for Research on Cancer (IARC; french: Centre International de Recherche sur le Cancer, CIRC) is an intergovernmental agency forming part of the World Health Organization of the United Nations.
Its role is to conduct and ...
as a group 1 carcinogen (carcinogenic to humans).
Pharmacogenetics
The enzyme thiopurine S-methyltransferase (TPMT) is responsible for various activation and deactivation steps in azathioprine's mechanism of action. The first metabolic step that azathioprine undergoes in the body is the conversion to 6-mercaptopurine
Mercaptopurine (6-MP), sold under the brand name Purinethol among others, is a medication used for cancer and autoimmune diseases. Specifically it is used to treat acute lymphocytic leukemia (ALL), acute promyelocytic leukemia (APL), Crohn's dis ...
(6-MP; see Pharmacokinetics
Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...
), which is itself an immunosuppressant
Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent activity of the immune system.
Classification
Immunosuppressive drugs can be classified in ...
prodrug
A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the dru ...
. The TPMT enzyme is responsible, in part, for the methylation
In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These ...
of 6-MP into the inactive metabolite 6-methylmercaptopurine - this methylation
In the chemical sciences, methylation denotes the addition of a methyl group on a substrate, or the substitution of an atom (or group) by a methyl group. Methylation is a form of alkylation, with a methyl group replacing a hydrogen atom. These ...
prevents 6-MP from further conversion into active, cytotoxic
Cytotoxicity is the quality of being toxic to cells. Examples of toxic agents are an immune cell or some types of venom, e.g. from the puff adder (''Bitis arietans'') or brown recluse spider (''Loxosceles reclusa'').
Cell physiology
Treating c ...
thioguanine nucleotide (TGN) metabolites. Certain genetic variation
Genetic variation is the difference in DNA among individuals or the differences between populations. The multiple sources of genetic variation include mutation and genetic recombination. Mutations are the ultimate sources of genetic variation, b ...
s within the TPMT gene can lead to decreased or absent TPMT enzyme activity, and individuals who are homozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
or heterozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
...
for these types of genetic variation
Genetic variation is the difference in DNA among individuals or the differences between populations. The multiple sources of genetic variation include mutation and genetic recombination. Mutations are the ultimate sources of genetic variation, b ...
s may have increased levels of TGN metabolites and an increased risk of severe bone marrow suppression ( myelosuppression) when receiving azathioprine. In many ethnicities, ''TPMT'' polymorphisms that result in decreased or absent TPMT activity occur with a frequency of approximately 5%, meaning that about 0.25% of patients are homozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
for these variants. However, an assay of TPMT activity in red blood cell
Red blood cells (RBCs), also referred to as red cells, red blood corpuscles (in humans or other animals not having nucleus in red blood cells), haematids, erythroid cells or erythrocytes (from Greek ''erythros'' for "red" and ''kytos'' for "hol ...
s or a TPMT genetic test
Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, ...
can identify patients with reduced TPMT activity, allowing for the adjustment of azathioprine dose or avoidance of the drug entirely. The FDA-approved drug label for azathioprine recommends testing for TPMT activity to identify patients at risk for myelotoxicity. Indeed, testing for TPMT activity is one of the few examples of pharmacogenetics being translated into routine clinical care. Missense SNP in NUDT15
Nudix hydrolase 15 is a protein that in humans is encoded by the NUDT15 gene.
Function
This gene encodes an enzyme that belongs to the Nudix hydrolase superfamily. Members of this superfamily catalyze the hydrolysis of nucleoside diphosphat ...
(e.g., rs116855232, inducing R139C)) has been identified to be a causal factor for AZA-induced leukopenia through a genome wide association study (GWAS) in East Asians.
Cancers
Azathioprine is listed as a human carcinogen
A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis (the formation of cancer). This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive sub ...
in the 12th Report on Carcinogens by the National Toxicology Program
The National Toxicology Program (NTP) is an inter-agency program run by the United States Department of Health and Human Services to coordinate, evaluate, and report on toxicology within public agencies.
The National Toxicology Program is headqua ...
of U.S. Department of Health and Human Services
The United States Department of Health and Human Services (HHS) is a cabinet-level executive branch department of the U.S. federal government created to protect the health of all Americans and providing essential human services. Its motto is " ...
, asserting that it is "known to be a human carcinogen based on sufficient evidence of carcinogenicity from studies in humans." Since August 2009, the U.S. FDA has required warnings to be placed on packaging with respect to increased risks of certain cancers.
The risks involved seem to be related both to the duration and the dosage used. People who have previously been treated with an alkylating agent
Alkylation is the transfer of an alkyl group from one molecule to another. The alkyl group may be transferred as an alkyl carbocation, a free radical, a carbanion, or a carbene (or their equivalents). Alkylating agents are reagents for effectin ...
may have an excessive risk of cancers if treated with azathioprine. Epidemiological studies by International Agency for Research on Cancer
The International Agency for Research on Cancer (IARC; french: Centre International de Recherche sur le Cancer, CIRC) is an intergovernmental agency forming part of the World Health Organization of the United Nations.
Its role is to conduct and ...
have provided "sufficient" evidence of azathioprine carcinogenicity in humans (group 1 Group 1 may refer to:
* Alkali metal, a chemical element classification for Alkali metal
* Group 1 (racing), a historic (until 1981) classification for Touring car racing, applied to standard touring cars. Comparable to modern FIA Group N
* Group On ...
), although the methodology of past studies and the possible underlying mechanisms are questioned.
The various diseases requiring transplantation may in themselves increase the risks of non-Hodgkin lymphoma
Non-Hodgkin lymphoma (NHL), also known as non-Hodgkin's lymphoma, is a group of blood cancers that includes all types of lymphomas except Hodgkin lymphomas. Symptoms include enlarged lymph nodes, fever, night sweats, weight loss, and tiredne ...
, squamous cell carcinoma
Squamous-cell carcinomas (SCCs), also known as epidermoid carcinomas, comprise a number of different types of cancer that begin in squamous cells. These cells form on the surface of the skin, on the lining of hollow organs in the body, and on the ...
s of the skin, hepatobiliary carcinomas, and mesenchymal tumours to which azathioprine may add additional risks. Those receiving azathioprine for rheumatoid arthritis may have a lower risk than those undergoing transplantation.
Cases of hepatosplenic T-cell lymphoma
Hepatosplenic T-cell lymphoma is a rare form of lymphoma that is generally incurable, except in the case of an allogeneic stem cell transplant.
It is a systemic neoplasm comprising medium-sized cytotoxic T-cells that show significant sinusoidal ...
– a rare type of lymphoma
Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). In current usage the name usually refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include en ...
– have been reported in patients treated with azathioprine. The majority occurred in patients with inflammatory bowel disease
Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the colon and small intestine, Crohn's disease and ulcerative colitis being the principal types. Crohn's disease affects the small intestine and large intestine, as well ...
. Adolescents and young adult males were the majority of cases. They presented with a very aggressive disease course, and with one exception, died of the lymphoma. The FDA has required changes to the labeling to inform users and clinicians of the issue.
Skin cancers
In transplant patients, skin cancer
Skin cancers are cancers that arise from the skin. They are due to the development of abnormal cells that have the ability to invade or spread to other parts of the body. There are three main types of skin cancers: basal-cell skin cancer (BCC) ...
is 50 to 250 times more common than in the general population, and between 60 and 90% of patients are affected 20 years after transplantation. The use of immunosuppressive medication including azathioprine in organ transplantation has been linked to increased rates of developing skin cancer. Azathioprine causes the accumulation of 6-thioguanine
Tioguanine, also known as thioguanine or 6-thioguanine (6-TG) is a medication used to treat acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and chronic myeloid leukemia (CML). Long-term use is not recommended. It is given by mouth. ...
(6-TG) in patients' DNA, which might trigger cancer when the patient is later exposed to ultraviolet light
Ultraviolet (UV) is a form of electromagnetic radiation with wavelength from 10 nm (with a corresponding frequency around 30 PHz) to 400 nm (750 THz), shorter than that of visible light, but longer than X-rays. UV radiatio ...
. Patients taking azathioprine were found to be abnormally sensitive to UVA light.
Overdose
Large single doses are generally well tolerated; a patient who took 7.5 g azathioprine (150 tablets) at once showed no relevant symptoms apart from vomiting, slightly decreased white blood cell count, and marginal changes in liver function parameters. Main symptoms of long-term overdosing are infections of unclear origin, mouth ulcers, and spontaneous bleeding, all of which are consequences of its bone-marrow suppression.
Interactions
Other purine analogues, such as allopurinol, inhibit xanthine oxidase, the enzyme that breaks down azathioprine, thus increasing the toxicity of azathioprine. Low doses of allopurinol, though, have been shown to safely enhance the efficacy of azathioprine, especially in inflammatory bowel disease nonresponders. This may still lead to lower lymphocyte counts and higher rates of infection, therefore the combination requires careful monitoring.
Azathioprine decreases the effects of the anticoagulant
Anticoagulants, commonly known as blood thinners, are chemical substances that prevent or reduce coagulation of blood, prolonging the clotting time. Some of them occur naturally in blood-eating animals such as leeches and mosquitoes, where t ...
warfarin
Warfarin, sold under the brand name Coumadin among others, is a medication that is used as an anticoagulant (blood thinner). It is commonly used to prevent blood clots such as deep vein thrombosis and pulmonary embolism, and to prevent st ...
and of nondepolarizing muscle relaxants, but increases the effect of depolarizing muscle relaxants. It can also interfere with niacin
Niacin, also known as nicotinic acid, is an organic compound and a form of vitamin B3, an essential human nutrient. It can be manufactured by plants and animals from the amino acid tryptophan. Niacin is obtained in the diet from a variet ...
(vitamin B3), resulting in at least one case to pellagra and fatal medullary aplasia.
Pregnancy and breastfeeding
Azathioprine can cause birth defects. A 2003 population-based study in Denmark showed that the use of azathioprine and related mercaptopurine resulted in a seven-fold incidence of fetal abnormalities, as well as a 20-fold increase in miscarriage
Miscarriage, also known in medical terms as a spontaneous abortion and pregnancy loss, is the death of an embryo or fetus before it is able to survive independently. Miscarriage before 6 weeks of gestation is defined by ESHRE as biochemica ...
. Birth defects in a child whose father was taking azathioprine have also been reported. Although no adequate and well-controlled studies have taken place in humans, when given to animal
Animals are multicellular, eukaryotic organisms in the biological kingdom Animalia. With few exceptions, animals consume organic material, breathe oxygen, are able to move, can reproduce sexually, and go through an ontogenetic stage ...
s in doses equivalent to human dosages, teratogenesis was observed. Transplant patients already on this drug should not discontinue on becoming pregnant. This contrasts with the later-developed drugs tacrolimus and mycophenolate, which are contraindicated during pregnancy.
Traditionally, as for all cytotoxic drugs, the manufacturer advises not to breastfeed whilst taking azathioprine, but the "lactation risk category" reported by Thomas Hale in his book ''Medications and Mothers' Milk'' lists azathioprine as "L3", termed "moderately safe".
Pharmacology
Pharmacokinetics
Azathioprine is absorbed from the gut to about 88%. Bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation.
By definition, when a medication is administered intravenously, its bioavailability is 100%. Ho ...
varies greatly between individual patients, between 30 and 90%, because the drug is partly inactivated in the liver. Highest blood plasma concentrations, counting not only the drug itself, but also its metabolites, are reached after 1–2 hours, and the average plasma half-life is 26 to 80 minutes for azathioprine and 3–5 hours for drug plus metabolites. 20 to 30% are bound to plasma proteins
Blood-proteins, also termed plasma proteins, are proteins present in blood plasma. They serve many different functions, including transport of lipids, hormones, vitamins and minerals in activity and functioning of the immune system. Other blood p ...
while circulating in the bloodstream.
Azathioprine is a prodrug
A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the dru ...
, a substance that is not an active drug itself, but is activated in the body. This happens in several steps; at first, it is slowly and almost completely converted to 6-mercaptopurine
Mercaptopurine (6-MP), sold under the brand name Purinethol among others, is a medication used for cancer and autoimmune diseases. Specifically it is used to treat acute lymphocytic leukemia (ALL), acute promyelocytic leukemia (APL), Crohn's dis ...
(6-MP) by reductive cleavage of the thioether
In organic chemistry, an organic sulfide (British English sulphide) or thioether is an organosulfur functional group with the connectivity as shown on right. Like many other sulfur-containing compounds, volatile sulfides have foul odors. A su ...
(– S–). This is mediated by glutathione
Glutathione (GSH, ) is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources such as reactive oxygen species, free radicals, pe ...
and similar compounds in the intestinal wall, the liver, and on red blood cells, without the aid of enzymes. 6-MP is metabolized analogously to natural purines, giving thioguanosine triphosphate
Guanosine-5'-triphosphate (GTP) is a purine nucleoside triphosphate. It is one of the building blocks needed for the synthesis of RNA during the transcription process. Its structure is similar to that of the guanosine nucleoside, the only ...
(TGTP) and thio deoxyguanosine triphosphate (TdGTP) via thioinosine monophosphate (TIMP) and several further intermediates. On a second path, the sulfur atom of 6-MP and TIMP is methyl
In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in ...
ated. The end products of azathioprine metabolism are thiouric acid (38%) and various methylated and hydroxyl
In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydrox ...
ated purines, which are excreted via the urine.
Mechanism of action
Azathioprine inhibits purine synthesis. Purines are needed to produce DNA and RNA. By inhibiting purine synthesis, less DNA and RNA are produced for the synthesis of white blood cell
White blood cells, also called leukocytes or leucocytes, are the cells of the immune system that are involved in protecting the body against both infectious disease and foreign invaders. All white blood cells are produced and derived from mult ...
s, thus causing immunosuppression.
Azathioprine is converted within tissues to 6-MP, some of which is converted, in turn, to 6-thioguanine
Tioguanine, also known as thioguanine or 6-thioguanine (6-TG) is a medication used to treat acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and chronic myeloid leukemia (CML). Long-term use is not recommended. It is given by mouth. ...
by the addition of an amino group. Both 6-MP and 6-thioguanine are conjugated with ribose
Ribose is a simple sugar and carbohydrate with molecular formula C5H10O5 and the linear-form composition H−(C=O)−(CHOH)4−H. The naturally-occurring form, , is a component of the ribonucleotides from which RNA is built, and so this com ...
, and then phosphorylated to form the nucleotides thioinosinic acid and thioguanylic acid, respectively. These nucleotides masquerade, respectively, as inosinic acid
Inosinic acid or inosine monophosphate (IMP) is a nucleotide (that is, a nucleoside monophosphate). Widely used as a flavor enhancer, it is typically obtained from chicken byproducts or other meat industry waste. Inosinic acid is important in ...
and guanylic acid
Guanosine monophosphate (GMP), also known as 5′-guanidylic acid or guanylic acid (conjugate base guanylate), is a nucleotide that is used as a monomer in RNA. It is an ester of phosphoric acid with the nucleoside guanosine. GMP consists of the ...
; the former is the starting point for purine nucleotide biosynthesis, while the latter is one of the building blocks of DNA and RNA.
* The nucleotides are incorporated into newly synthesized (but nonfunctional) DNA, halting replication.
* The nucleotides act to inhibit glutamine- phosphoribosyl pyrophosphate amidotransferase (GPAT), one of the enzymes involved in purine biosynthesis, one of the earlier steps in the synthesis of DNA and RNA. They achieve GPAT inhibition through a form of negative feedback called product inhibition. Because actively replicating cells (such as cancer cells and the T cell
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
s and B cell
B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted o ...
s of the immune system
The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinte ...
) are most active in synthesizing purine, making new DNA, these cells are most strongly affected.
* A portion of the nucleotides is additionally phosphorylated to the triphosphate forms. These bind to GTP-binding protein Rac1, blocking synthesis of the protein Bcl-xL, thus sending activated T cells and mononuclear cell
In immunology, agranulocytes (also known as nongranulocytes or mononuclear leukocytes) are one of the two types of leukocytes (white blood cells), the other type being granulocytes. Agranular cells are noted by the absence of granules in thei ...
s into apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...
(programmed cell death). Increased apoptosis of mononuclear cells is seen in inflammatory bowel disease patients treated with azathioprine.
Chemistry
Azathioprine is a thiopurine
The thiopurine drugs are purine antimetabolites widely used in the treatment of acute lymphoblastic leukemia, autoimmune disorders (e.g., Crohn's disease, rheumatoid arthritis), and organ transplant recipients.
Metabolism is catalyzed by S-meth ...
linked to a second heterocycle
A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different elements as members of its ring(s). Heterocyclic chemistry is the branch of organic chemistry dealing with the synthesis, properties, and ...
(an imidazole
Imidazole (ImH) is an organic compound with the formula C3N2H4. It is a white or colourless solid that is soluble in water, producing a mildly alkaline solution. In chemistry, it is an aromatic heterocycle, classified as a diazole, and has non ...
derivative) via a thioether
In organic chemistry, an organic sulfide (British English sulphide) or thioether is an organosulfur functional group with the connectivity as shown on right. Like many other sulfur-containing compounds, volatile sulfides have foul odors. A su ...
. It is a pale yellow solid with a slightly bitter taste and a melting point of 238–245 °C. It is practically insoluble in water and only slightly soluble in lipophilic solvents such as chloroform, ethanol, and diethylether. It dissolves in alkaline aqueous solutions, where it hydrolyze
Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile.
Biological hydrolysis i ...
s to 6-mercaptopurine.
Azathioprine is synthesized from 5-chloro-1-methyl-4-nitro-1''H''-imidazole and 6-mercaptopurine in dimethyl sulfoxide
Dimethyl sulfoxide (DMSO) is an organosulfur compound with the formula ( CH3)2. This colorless liquid is the sulfoxide most widely used commercially. It is an important polar aprotic solvent that dissolves both polar and nonpolar compounds a ...
. The synthesis of the former starts with an amide
In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it i ...
from methylamine
Methylamine is an organic compound with a formula of . This colorless gas is a derivative of ammonia, but with one hydrogen atom being replaced by a methyl group. It is the simplest primary amine.
Methylamine is sold as a solution in methanol, ...
and diethyl oxalate
Oxalate (IUPAC: ethanedioate) is an anion with the formula C2O42−. This dianion is colorless. It occurs naturally, including in some foods. It forms a variety of salts, for example sodium oxalate (Na2C2O4), and several esters such as dimethyl ...
, which is then cyclized and chlorinated with phosphorus pentachloride
Phosphorus pentachloride is the chemical compound with the formula PCl5. It is one of the most important phosphorus chlorides, others being PCl3 and POCl3. PCl5 finds use as a chlorinating reagent. It is a colourless, water-sensitive and mois ...
; the nitro group is introduced with nitric and sulfuric acid
Sulfuric acid (American spelling and the preferred IUPAC name) or sulphuric acid ( Commonwealth spelling), known in antiquity as oil of vitriol, is a mineral acid composed of the elements sulfur, oxygen and hydrogen, with the molecular fo ...
.
History
Azathioprine was synthesized by George Herbert Hitchings and Gertrude Elion in 1957 (named BW 57-322) to produce 6-MP in a metabolically active, but masked form, and at first used as a chemotherapy
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemother ...
drug.
Robert Schwartz investigated the effect of 6-MP on the immune response in 1958 and discovered that it profoundly suppresses the formation of antibodies
An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of ...
when given to rabbits together with antigen
In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune respon ...
s. Following the work done by Sir Peter Medawar
Sir Peter Brian Medawar (; 28 February 1915 – 2 October 1987) was a Brazilian-British biologist and writer, whose works on graft rejection and the discovery of acquired immune tolerance have been fundamental to the medical practice of tissu ...
and Gertrude Elion in discovering the immunological basis of rejection of transplanted tissues and organs, and Schwartz's researches on 6-MP, Sir Roy Calne
Sir Roy Yorke Calne, FRCP, FRCS, FRS (born 30 December 1930) is a British surgeon and pioneer in organ transplantation.
Career
His most notable achievements are the world's first liver, heart, and lung transplant together with John Wallwork ...
, the British pioneer in transplantation, introduced 6-MP as an experimental immunosuppressant for kidney
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blo ...
and heart transplants. When Calne asked Elion for related compounds to investigate, she suggested azathioprine, which was subsequently found out to be superior (as effective and less toxic to the bone marrow) by Calne.
On 5 April 1962, with regimens consisting of azathioprine and prednisone, the transplantation of kidneys to unrelated recipients (allotransplantation) was successful for the first time. For many years, this kind of dual therapy with azathioprine and glucocorticoids was the standard antirejection regimen, until ciclosporin was introduced into clinical practice (by Calne as well) in 1978.
Ciclosporin has now replaced some of the azathioprine use due to a longer survival time, especially in heart-related transplantations. Moreover, despite being considerably more expensive, mycophenolate mofetil is also increasingly being used in place of azathioprine in organ transplantation, as it is associated with less bone marrow suppression, fewer opportunistic infection
An opportunistic infection is an infection caused by pathogens (bacteria, fungi, parasites or viruses) that take advantage of an opportunity not normally available. These opportunities can stem from a variety of sources, such as a weakened immun ...
s, and a lower incidence of acute rejection.
References
Further reading
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External links
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