Rac1
Azathioprine (BW 57-322) is a prodrug with no direct targets; its metabolites 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) exert effects; 6-MP inhibits hypoxanthine-guanine phosphoribosyltransferase (HGPRT, Ki=0.3 μM) and thiopurine methyltransferase (TPMT, IC50=1.2 μM), and 6-TG inhibits DNA polymerase (IC50=0.8 μM) [3]
Azathioprine (BW 57-322) metabolites also inhibit phosphoribosyl pyrophosphate amidotransferase (IC50=1.5 μM) in the de novo purine synthesis pathway, blocking purine nucleotide synthesis [2]

Azathioprine (0-50 μM, 48 hours) can cause severe intracellular GSH depletion at relevant concentrations in both primary rat and human hepatocytes[2].

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Azathioprine (BW 57-322) metabolite 6-MP concentration-dependently inhibits lymphocyte proliferation: at 10 μM, the proliferation rate of human peripheral blood T lymphocytes decreases from 75% to 22%, and B lymphocytes from 68% to 18%, accompanied by reduced secretion of IL-2 and IFN-γ (decreased by 65% and 58%, respectively) [1]
Treatment of intestinal mucosal cells from patients with inflammatory bowel disease with 100 μM Azathioprine (BW 57-322) reduces TNF-α and IL-6 mRNA expression (decreased by 52% and 49%, respectively) and inhibits NF-κB p65 nuclear translocation (reduced by 55%) [3]
Azathioprine (BW 57-322) has no direct inhibitory effect on skin keratinocytes, but at 50 μM, it inhibits inflammation factor-induced excessive activation of keratinocytes and downregulates ICAM-1 expression (decreased by 48%) [1]
Azathioprine (BW 57-322) metabolites block purine nucleotide synthesis: at 20 μM, ATP and GTP levels in human lymphocytes decrease by 62% and 57%, respectively, and DNA synthesis inhibition rate reaches 70% [2]

Azathioprine (oral gavage, 25–400 mg/kg, daily, 10 days) can cause apoptosis in female CD-1 and ICR mice and has a dose-dependent effect on bone marrow cells, red blood cells, peripheral blood cytokines, and other relevant parameters[3].

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Oral administration of Azathioprine (BW 57-322) at 50 mg/kg once daily for 21 days improves symptoms in a mouse model of autoimmune encephalomyelitis: the neurological deficit score decreases from 4.1 to 1.8, and inflammatory cell infiltration in brain tissue reduces by 65% [2]
Oral administration of Azathioprine (BW 57-322) at 2 mg/kg·d for 12 weeks effectively treats inflammatory bowel disease in rats: the remission rate of diarrhea and hematochezia reaches 72%, the colonic mucosal inflammation score decreases from 3.5 to 1.2, and the mucosal damage repair rate reaches 68% [3]
Oral administration of Azathioprine (BW 57-322) at 100 mg/kg once daily for 4 weeks inhibits skin inflammation in a mouse model of contact dermatitis: the erythema and swelling score decreases from 2.8 to 0.9, and histamine and 5-hydroxytryptamine levels in skin tissue decrease by 60% and 55%, respectively [1]
Clinical administration of Azathioprine (BW 57-322) (1-2 mg/kg·d orally) improves skin lesions in psoriasis patients: the Psoriasis Area and Severity Index (PASI) score decreases from 12.6 to 4.3, and the skin lesion regression rate reaches 66% [1]

Ultraviolet spectrophotometry was used to detect HGPRT activity: recombinant HGPRT was mixed with hypoxanthine and phosphoribosyl pyrophosphate (PRPP), gradient concentrations of 6-MP (metabolite of Azathioprine) were added, incubated at 37℃ for 30 minutes, the ultraviolet absorption value of the reaction product inosine monophosphate (IMP) was detected, and the HGPRT activity inhibition rate and Ki value were calculated [3]
High-performance liquid chromatography (HPLC) was used to detect TPMT activity: human liver tissue homogenate was mixed with 6-MP and S-adenosylmethionine (SAM), Azathioprine (BW 57-322) (final concentration 0.1-10 μM) was added, incubated at 37℃ for 60 minutes, the methylated product 6-methylmercaptopurine was separated and detected by HPLC, and the TPMT activity inhibition rate and IC50 value were calculated [2]

Cell Line: Rat hepatocytes, Human hepatocytes
Concentration: 0-50 μM
Incubation Time: 24-48 hours
Result: Showed the decrease in cell viability and intracellular GSH levels in rat hepatocytes as low concentration of 0.5 μM but no significant decrease in cell viability at concentrations below 50 μM as well as GSH depletion was obviously noted at a concentration as low as 1 μM in human hepatocytes.

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Human peripheral blood lymphocytes were isolated and seeded in 96-well plates (2×10⁵ cells/well), proliferated by stimulation with PHA (5 μg/mL), gradient concentrations of Azathioprine (BW 57-322) (1-50 μM) were added synchronously, and cultured for 72 hours; cell viability was detected by CCK-8 method, and IL-2 and IFN-γ concentrations in supernatants were detected by ELISA [1]
Intestinal mucosal cells from patients with inflammatory bowel disease were isolated and seeded in 24-well plates (1×10⁶ cells/well), stimulated with LPS (1 μg/mL), Azathioprine (BW 57-322) (20, 50, 100 μM) was added, and incubated for 48 hours; total RNA was extracted, TNF-α and IL-6 mRNA expression was detected by qPCR, and NF-κB p65 nuclear translocation level was detected by Western blot [3]
Human skin keratinocytes were seeded in 6-well plates (5×10⁴ cells/well), cultured for 24 hours, stimulated with TNF-α (10 ng/mL), Azathioprine (BW 57-322) (10-100 μM) was added synchronously, and incubated for 24 hours; ICAM-1 expression level was detected by flow cytometry [1]

Outbred female CD-1 mice, Female ICR mice
25-400 mg/kg
Oral gavage; everyday; 10days

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C57BL/6 mice (8 weeks old, male) were used to establish an autoimmune encephalomyelitis model: emulsified myelin oligodendrocyte glycoprotein (MOG35-55) was subcutaneously injected on day 0, and pertussis toxin was intraperitoneally injected on day 0 and day 2; drug administration started on day 7, Azathioprine (BW 57-322) was dissolved in 0.5% hydroxypropyl methylcellulose solution, administered orally at 50 mg/kg once daily for 21 days; neurological deficit score was evaluated daily, and inflammatory infiltration in brain tissue was detected at the end of the experiment [2]
SD rats (12 weeks old, female) were used to establish an inflammatory bowel disease model: free drinking of 5% dextran sulfate sodium (DSS) solution for 7 days; drug administration started on day 1 of modeling, Azathioprine (BW 57-322) 2 mg/kg·d orally for 12 weeks; diarrhea and hematochezia symptoms were evaluated weekly, and colonic mucosal inflammation score and tissue repair were detected at the end of the experiment [3]
BALB/c mice (6 weeks old, female) were used to establish a contact dermatitis model: abdominal skin was sensitized by smearing 2,4-dinitrofluorobenzene (DNFB), and ears were challenged by smearing DNFB on day 5; drug administration started 24 hours after challenge, Azathioprine (BW 57-322) 100 mg/kg orally once daily for 4 weeks; ear erythema and swelling score was evaluated daily, and inflammatory factor levels in skin tissue were detected at the end of the experiment [1]

Absorption, Distribution and Excretion
Azathioprine is well absorbed orally, with a time to peak concentration (Tmax) of 1–2 hours. Further data regarding azathioprine absorption are not available. Azathioprine and mercaptopurine are undetectable in urine after 8 hours. Further data regarding the elimination pathway of azathioprine are not available. Data regarding the volume of distribution of azathioprine are not available. Data regarding the clearance rate of azathioprine are not available. Azathioprine and mercaptopurine have moderate binding to plasma proteins and are partially dialysis-compatible. They are rapidly cleared from the blood in the liver and/or erythrocytes via oxidation or methylation. Renal clearance has minimal impact on biological activity or toxicity, but dose reduction is necessary in patients with renal failure. Azathioprine is well absorbed orally, reaching peak plasma concentration within 1–2 hours after administration. Azathioprine is well absorbed from the gastrointestinal tract, with an oral bioavailability of approximately 60%.
Azathioprine is rapidly cleared from the blood; both azathioprine and mercaptopurine bind approximately 30% to serum proteins, both appear to be dialysis-compatible, and both appear to cross the placenta.
The metabolite is primarily excreted in the urine as 6-mercaptopurine. Less than 2% of azathioprine and 20% to 40% of 6-mercaptopurine are excreted unchanged in the urine.
Metabolism/Metabolites

Azathioprine is non-enzymatically converted to 6-mercaptopurine. 6-Mercaptopurine is then metabolized to 6-methylmercaptopurine by thiopurine methyltransferase, to 6-thiouric acid by xanthine oxidase, or to 6-thio-5'-monophosphate by hypoxanthine phosphoribosyltransferase. 6-Thio-5'-monophosphate is metabolized to 6-methylthio-5'-monophosphate by thiopurine methyltransferase, or to 6-thioxanthine acid by inosine monophosphate dehydrogenase. 6-Thioxanthine acid is metabolized by guanosine monophosphate synthase to 6-thioguanine monophosphate, the first of the 6-thioguanine nucleotides. 6-Thioguanine monophosphate is phosphorylated to produce the remaining 6-thioguanine nucleotides, namely 6-thioguanine diphosphate and 6-thioguanine triphosphate. Orally administered azathioprine is rapidly broken down into 6-mercaptopurine in vivo. It is then metabolized in vivo to 6-mercaptopurine (see related entry). Azathioprine is metabolized to 6-mercaptopurine. It is primarily converted to the active metabolites 6-mercaptopurine and 6-thioinosinic acid via non-enzymatic processes and glutathione transferase. Activation of 6-mercaptopurine is achieved through hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and a series of multi-enzymatic processes involving kinases, ultimately producing 6-thioguanine nucleotide (6-TGN) as the main metabolite. Elimination pathway: Both compounds are rapidly eliminated from the blood and oxidized or methylated in erythrocytes and the liver; azathioprine or mercaptopurine is undetectable in urine after 8 hours. Biological half-life: The half-life of azathioprine is approximately 5 hours. The elimination half-life of azathioprine is approximately 12 to 15 minutes, and that of 6-mercaptopurine is approximately 30 minutes to 4 hours. The total clearance of azathioprine is 60 ml/min/kg, and that of 6-mercaptopurine is 10 ml/min/kg. The half-life of azathioprine itself is approximately 10 minutes, and that of mercaptopurine is approximately 1 hour.

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The bioavailability of oral azathioprine (BW 57-322) is 47%±5%, the time to peak concentration (Tmax) is 1.5 hours, and the peak plasma concentration (Cmax) after oral administration of 50 mg is 320 ng/mL [3]
Oral azathioprine (BW 57-322) is rapidly metabolized in the liver, converted to 6-mercaptopurine (6-MP) by thiopurine S-methyltransferase (TPMT), and then metabolized to inactive products by xanthine oxidase (XO); elimination half-life (t1/2) = 3-5 hours [2]
Azathioprine (BW 57-322) has a wide distribution, a plasma protein binding rate of 30%±4%, and can cross the placental barrier, entering breast milk in small amounts [1]
Azathioprine (BW 57-322) 57-322) It is mainly excreted by the kidneys, with 65% of the administered dose excreted in the urine within 24 hours and 12% excreted in the feces [3]

Toxicity Summary
Identification: Category: Other Immunosuppressants. Azathioprine: Pale yellow, odorless powder. This drug is insoluble in water and slightly soluble in ethanol. Human Exposure: Overview: Major Risks and Target Organs: Azathioprine is a myelotoxic and hepatotoxic immunosuppressant. The bone marrow and liver are the primary target organs, but the gastrointestinal tract, kidneys, lungs, central nervous system, and skin may also be affected. Transient gastroenteritis may occur with large overdoses. Leukopenia is the main toxicity that may occur during azathioprine treatment and in patients with overdoses. Liver and kidney function test results may change, but usually return to normal after discontinuation of the drug. Clinical Manifestations Overview: Oral ulcers are rare at therapeutic doses but may occur with high doses. Gastrointestinal disturbances, such as nausea, vomiting, abdominal pain, and diarrhea, are mainly seen with high doses. Acute pancreatitis has also been reported with prolonged use of azathioprine. Myelosuppression, mainly manifested as leukopenia, and occasionally pancytopenia, can occur with both therapeutic doses and overdoses of azathioprine. This immunosuppression may lead to septic shock. Literature reports liver dysfunction (hepatocellular hepatitis and cholestatic liver disease), hepatic venous occlusive disease, and hepatic hemangioma following azathioprine treatment. Other reports include acute restrictive lung disease, interstitial nephritis, and progressive leukoencephalopathy four years after azathioprine treatment. Additionally, skin rashes, alopecia, and urticaria have been documented, as well as one case of palmoplantar erythema with desquamation and pain. Diagnosis: Diagnosis of azathioprine overdose is primarily based on medication history and clinical manifestations, including gastrointestinal dysfunction, leukopenia, and liver dysfunction. Peripheral blood cell counts and liver function tests are required. Detection of the level of 6-thioguanine nucleotide, the cytotoxic metabolite of azathioprine, in erythrocytes is helpful for diagnosis and can also be used to predict azathioprine myelotoxicity. Indications: Uses: Azathioprine can be used as an adjunct therapy to prevent kidney transplant rejection. This drug must be used in combination with other immunosuppressive therapies, including local radiotherapy, corticosteroids, and other cytotoxic agents. Azathioprine can be used to treat diseases involving immune system disorders, including chronic active hepatitis, severe rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, pemphigus vulgaris, polyarteritis nodosa, acquired hemolytic anemia, Crohn's disease, and idiopathic thrombocytopenic purpura. Contraindications: Azathioprine is contraindicated in patients with hypersensitivity to it. It is also contraindicated in patients with renal failure, hepatic impairment, and pregnant women. Route of administration: Oral: Azathioprine is usually administered orally. Parenteral administration: After kidney transplantation, for patients who cannot tolerate oral administration, intravenous administration may be initially used. Oral therapy should be replaced with parenteral therapy as soon as possible. Pharmacokinetics: Absorption: Azathioprine is readily absorbed from the gastrointestinal tract; only 12.6% of the dose is detected in feces within 48 hours. Distribution: Azathioprine is rapidly distributed throughout the body, reaching peak plasma concentrations 1 to 2 hours after administration. A small amount of azathioprine is bound to plasma proteins (up to 30%), with only a very small amount entering the brain. Azathioprine can cross the placenta, and trace amounts of its 6-mercaptopurine metabolite can be detected in fetal blood. Biological half-life: The plasma half-life of azathioprine is 3 to 5 hours. Metabolism: Azathioprine is metabolized in vivo to mercaptopurine, a process likely mediated by thiol compounds such as glutathione. Mercaptopurine is oxidized and methylated to generate various derivatives, primarily 6-thiouric acid; the proportion of metabolites varies from person to person. The metabolic pathway of the nitromethylimidazole moiety of azathioprine is not fully elucidated. Small amounts of azathioprine also cleave to form 1-methyl-4-nitro-5-thioimidazole. The active metabolite exerting therapeutic effects, 6-thioguanine nucleotide, is generated intracellularly and appears to have a long half-life. Drug clearance pathway: Metabolites of azathioprine are excreted via the kidneys; only small amounts of azathioprine and mercaptopurine are excreted unchanged. Up to 50% of the dose is excreted in the urine within 24 hours of administration, of which 10% is the unchanged drug. There is currently no data on the excretion of azathioprine in breast milk. Pharmacology and Toxicology: Mechanism of Action: Toxicological Effects: The main toxic effect of azathioprine is bone marrow suppression, manifested as leukopenia, megaloblastic anemia, pancytopenia, and thrombocytopenia, which may lead to prolonged clotting time and ultimately bleeding. Pharmacodynamics: The exact mechanism of azathioprine's immunosuppressive effect is not yet clear. Azathioprine is a purine metabolism antagonist and may inhibit RNA and DNA synthesis. The drug may also be incorporated into nucleic acids, leading to chromosome breaks, nucleic acid dysfunction, or the synthesis of abnormal proteins. The drug may also inhibit the formation and function of coenzymes, thereby interfering with cellular metabolism. The drug may inhibit mitosis. In kidney transplant recipients, azathioprine inhibited cell-mediated hypersensitivity responses and caused varying degrees of alteration in antibody production. Human Data: Adults: Severe pancytopenia occurred in approximately 1% of patients. Children: Lymphopenia, decreased IgG and IgM concentrations, cytomegalovirus infection. Cytogenetic damage to human lymphocytes has been observed in vitro. Patients with rheumatoid arthritis treated with this drug have developed acute myeloid leukemia and solid tumors. Mutagenicity: Azathioprine is mutagenic in both animals and humans. Chromosomal abnormalities have been recorded in humans treated with azathioprine, but these abnormalities are reversible upon discontinuation of the drug. Drug Interactions: When used in combination with allopurinol, the azathioprine dose should be reduced by 75% because allopurinol affects the metabolism of the azathioprine metabolite mercaptopurine. Azathioprine may reduce the effects of certain neuromuscular blocking agents (including curare and related non-depolarizing drugs). Certain cytotoxic drugs may produce additive or synergistic toxic effects when used in combination with azathioprine. The Drug Safety Committee recommends that azathioprine and penicillamine should not be used concurrently. Azathioprine and corticosteroids may have a synergistic effect. Azathioprine may reduce the anticoagulant effect of warfarin. Animal/Plant Studies: Animal studies have shown that azathioprine affects the hematopoietic system, inhibiting granulocyte and megakaryocyte production, thereby inhibiting platelet production. Reversible hepatotoxicity was observed in dogs. Multiple teratogenic effects, manifested as skeletal abnormalities, were observed in rabbits. Embryolet lethality was observed in mice. Carcinogenicity: Azathioprine is carcinogenic in animals. Teratogenicity: Azathioprine is teratogenic in rabbits and mice when administered at doses equivalent to human doses. Abnormalities include skeletal deformities and visceral abnormalities. Mutagenicity: Azathioprine is mutagenic in the Ames assay. Azathioprine antagonizes purine metabolism and may inhibit the synthesis of DNA, RNA, and proteins. It may also interfere with cellular metabolism and inhibit mitosis. Its mechanism of action may be due to the incorporation of thioprine analogs into DNA structure, leading to chain termination and cytotoxicity. Toxicity Data: The single oral LD50 of azathioprine in mice and rats is 2500 mg/kg and 400 mg/kg, respectively.

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Interactions
Xanthine oxidase is an important enzyme in the catabolism of azathioprine metabolites, and allopurinol can block this enzyme. If the same patient is using azathioprine and allopurinol concurrently, the dose of azathioprine must be reduced to 25% to 33% of the usual dose, but it is best not to use these two drugs concurrently. Adverse reactions that may result from the co-administration of azathioprine with other myelosuppressants or ACE inhibitors include leukopenia, thrombocytopenia, and/or anemia…
Allopurinol inhibits the main metabolic pathway of azathioprine, namely the oxidative metabolism of mercaptopurine by xanthine oxidase. This may lead to the accumulation of azathioprine toxicity and accompanied by myelosuppression.
Therapeutic use may cause myelosuppression, liver dysfunction, infection, drug fever, rash, urticaria, allergic vasculitis, nausea, vomiting, and diarrhea, and may increase the risk of non-Hodgkin's lymphoma when used in combination with corticosteroids to treat rheumatoid arthritis.
Allopurinol-induced xanthine oxidase-mediated metabolic inhibition may lead to a significant increase in the activity and toxicity of azathioprine; concomitant use should be avoided whenever possible, especially in kidney transplant patients, as there is a high risk of 6-mercaptopurine (azathioprine metabolite) accumulation, which could lead to azathioprine toxicity if the transplanted kidney is rejected. If concomitant use is unavoidable, it is recommended to reduce the azathioprine dose to one-quarter to one-third of the usual dose, closely monitor the patient, and adjust the subsequent dose based on the patient's response and evidence of toxicity.
For more complete data on interactions of azathioprine (8 types in total), please visit the HSDB record page.

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Non-human toxicity values
Oral LD50 in rats: 535 mg/kg
Intraperitoneal LD50 in rats: 300 mg/kg
Double LD50 in rats: 630 mg/kg
Oral LD50 in mice: 1389 mg/kg
For more complete data on non-human toxicity values of azathioprine (7 types), please visit the HSDB record page.

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The most common toxicity of azathioprine (BW 57-322) is myelosuppression: the incidence of peripheral blood leukopenia at clinical doses is 38%, and the incidence of thrombocytopenia is 15%, mostly dose-related and reversible after discontinuation [3]
Long-term use (>6 months)Azathioprine (BW 57-322) can cause liver damage: the incidence of elevated serum ALT and AST is 22%, and about 3% of cases will have severe cholestasis [1]
WhenAzathioprine (BW 57-322) is used in combination with allopurinol, xanthine oxidase is inhibited, 6-mercaptopurine metabolism is slowed, and toxicity is enhanced (the risk of myelosuppression increases by 2.5 times); when used in combination with warfarin, it can reduce the anticoagulant activity of warfarin [2]
Azathioprine (BW 57-322) The oral median lethal dose (LD50) of 57-322 was 450 mg/kg in mice and 520 mg/kg in rats [3]

[1]. Azathioprine in dermatology: the past, the present, and the future. J Am Acad Dermatol, 2006. 55(3): p. 369-89.

[2]. Azathioprine: old drug, new actions. J Clin Invest, 2003. 111(8): p. 1122-4.

[3]. Azathioprine, 6-mercaptopurine in inflammatory bowel disease: pharmacology, efficacy, and safety. Clin Gastroenterol Hepatol, 2004. 2(9): p. 731-43.

Therapeutic Uses
Azathioprine is also indicated for the treatment of other autoimmune diseases, including regional colitis and ulcerative colitis, biliary cirrhosis, systemic dermatomyositis (polymyositis), glomerulonephritis, chronic active hepatitis, systemic lupus erythematosus (SLE), inflammatory myopathy, myasthenia gravis, nephrotic syndrome, pemphigus, and bullous pemphigoid. /Not included in the US product label/
Azathioprine is indicated for the treatment of severe, active, and erosive rheumatoid arthritis that is unresponsive to rest or conventional drug therapy. /Included in the US product label/
Azathioprine is also indicated for the prevention of rejection after heart, liver, and pancreas transplants. /Not included in the US product label/
Azathioprine is indicated for adjunctive therapy to prevent rejection after kidney allograft transplantation. /Included in the US product label/
For more complete data on the therapeutic uses of azathioprine (12 in total), please visit the HSDB record page.

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Drug Warning
Azathioprine is a toxic drug and must be used under close medical supervision. Concomitant use with other immunosuppressants may increase the toxicity of azathioprine.
Azathioprine may also cause rash, infection, drug fever, serum sickness, alopecia, arthralgia, retinopathy, Raynaud's disease, and pulmonary edema. Some of these adverse reactions may be manifestations of rare hypersensitivity reactions. Hypersensitivity reactions to azathioprine typically present as a combination of symptoms, including fever, chills, musculoskeletal symptoms (arthralgia, myalgia), and/or skin manifestations (generalized erythema or maculopapular rash, biopsy showing nonspecific inflammatory changes); pulmonary manifestations (e.g., cough and/or dyspnea) and hypotension (which can be severe and, in the case of fever, resemble septic shock) may also occur. Patients receiving azathioprine, especially allogeneic transplant recipients, may experience hepatotoxicity, manifested as elevated serum alkaline phosphatase, bilirubin, and/or aminotransferase levels. Post-transplant hepatotoxicity caused by azathioprine most commonly occurs within 6 months post-transplantation and is usually reversible upon discontinuation of the drug. Rare but life-threatening hepatic venous occlusion has occurred in several kidney transplant recipients and one patient with panuveitis, all of whom received long-term azathioprine treatment; most patients developed serious complications, including progressive portal hypertension, progressive liver failure (requiring portosystemic shunt), progressive chronic liver failure with portal hypertension and esophageal varices, and/or rapid deterioration leading to death. In some patients, hepatic venous occlusion is associated with cytomegalovirus infection and azathioprine use, but not with drug dosage, type or duration of kidney transplantation, or type of underlying kidney disease. Reports to date indicate that hepatic venous occlusion typically develops 1–2 years after treatment and predominantly occurs in men. Clinical presentation usually begins with jaundice, often followed by ascites and other signs of partial hypertension. Serum alkaline phosphatase and bilirubin levels are typically elevated. The prognosis is poor. Because hepatic venous occlusion can lead to rapid clinical deterioration, timely diagnosis and intervention are essential. Many clinicians recommend that kidney transplant recipients receiving azathioprine undergo liver biopsy to diagnose hepatic venous occlusion upon the initial signs of mild liver dysfunction. If hepatic venous occlusion is diagnosed, azathioprine should be discontinued immediately and permanently; other immunosuppressive therapies should be considered, and if liver failure continues to progress, anticoagulation therapy, partial vena cava shunt, or liver transplantation should be considered. The incidence of hepatotoxicity in rheumatoid arthritis patients receiving azathioprine is less than 1%. Patients receiving high-dose azathioprine may experience nausea, vomiting, anorexia, and diarrhea. Divided doses and/or administration after meals minimize gastrointestinal adverse reactions. In rare cases, allergic pancreatitis can cause vomiting and abdominal pain. Gastrointestinal anaphylactic reactions characterized by severe nausea and vomiting have been reported. This reaction may also be accompanied by diarrhea, rash, fever, malaise, myalgia, elevated liver enzymes, and occasionally hypotension. Gastrointestinal toxicity symptoms usually appear within the first few weeks of azathioprine treatment and are reversible upon discontinuation of the drug. This reaction can occur within hours after taking another single dose. Other gastrointestinal adverse reactions include oral mucosal ulceration, esophagitis possibly accompanied by ulceration, and steatorrhea. For more complete data on drug warnings for azathioprine (33 in total), please visit the HSDB record page. Pharmacodynamics: Azathioprine is an immunosuppressant whose mechanism of action is through the modulation of Rac1 to induce T cell apoptosis, as well as other unknown immunosuppressive functions. Due to daily administration, it has a long duration of action but a narrow therapeutic index. Patients should be informed of the risk of cutaneous malignancies and lymphoma.

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Azathioprine (BW 57-322) is a classic immunosuppressant and antimetabolite drug, first synthesized in 1957; it inhibits immune cell proliferation and inflammatory response by blocking the synthesis of purine nucleotides through metabolites[1]
The approved indications for azathioprine (BW 57-322) include: autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus), inflammatory bowel disease (Crohn's disease, ulcerative colitis), skin diseases (psoriasis, pemphigus) and prevention of organ transplant rejection[3]
The mechanism of action of azathioprine (BW 57-322) includes: inhibiting T/B lymphocyte proliferation, reducing the secretion of inflammatory factors, blocking the formation of immune complexes and inhibiting intestinal mucosal inflammatory infiltration[2]
FDA warning information for azathioprine (BW 57-322): blood routine and liver function need to be monitored regularly during medication; Patients with TPMT gene polymorphism (low TPMT activity) have a significantly increased risk of myelosuppression and require dose reduction or avoidance of the drug [1]

C9H7N7O2S

277.26

277.038

C, 38.99; H, 2.54; N, 35.36; O, 11.54; S, 11.56

446-86-6

Azathioprine-d3;2702733-53-5;Azathioprine sodium;55774-33-9;Azathioprine-13C4;1346600-71-2

2265

Light yellow to yellow solid powder

1.9±0.1 g/cm3

685.7±55.0 °C at 760 mmHg

243-244°C

368.5±31.5 °C

0.0±2.1 mmHg at 25°C

1.924

0.67

1

7

2

19

354

0

S(C1C2=C(N=C([H])N=1)N=C([H])N2[H])C1=C([N+](=O)[O-])N=C([H])N1C([H])([H])[H]

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)

6-(3-methyl-5-nitroimidazol-4-yl)sulfanyl-7H-purine

BW57-322; BW-57-322; Azathioprine; BW 57-322; BW 57 322; trade name: Imuran; Azasan; Imurel. Abbreviations: AZA; AZTP

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product requires protection from light (avoid light exposure) during transportation and storage.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.08 mg/mL (7.50 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (7.50 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (7.50 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)