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]

硫唑嘌呤抑制 Rac1 靶基因的激活，例如丝裂原激活蛋白激酶激酶 (MEK)、NF-kappaB 和 bcl-x(L)，导致原代人 CD4+ T 淋巴细胞凋亡的线粒体途径。因此，硫唑嘌呤通过调节 Rac1 活性将共刺激信号转化为细胞凋亡信号。因此，硫唑嘌呤生成的 6-Thio-GTP 通过阻断 Rac 蛋白上的 Vav 活性来阻止有效免疫反应的发展。硫唑嘌呤 (1 mM) 可恢复 ATP 水平并阻止细胞损伤，而富含葡萄糖的培养基中的培养可增加 ATP 水平并改善细胞死亡。硫唑嘌呤在第 1 天降低活力 5-34%，在第 4 天降低 42-92%。硫唑嘌呤降低肝细胞的活力，并在分离的大鼠肝细胞原代培养物中诱导以下事件：细胞内减少谷胱甘肽 (GSH) 消耗、代谢活性降低、和乳酸脱氢酶的释放。硫唑嘌呤对肝细胞的作用与完整的离体大鼠肝线粒体的肿胀和耗氧量增加有关。

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Azathioprine (BW 57-322) 代谢产物6-MP浓度依赖性抑制淋巴细胞增殖：10 μM浓度下，人外周血T淋巴细胞增殖率从75%降至22%，B淋巴细胞从68%降至18%，同时抑制IL-2、IFN-γ分泌（分别降低65%和58%）[1]
Azathioprine (BW 57-322) 100 μM浓度处理炎症性肠病患者的肠道黏膜细胞，可减少TNF-α、IL-6 mRNA表达（分别降低52%和49%），抑制NF-κB p65核转位（减少55%）[3]
Azathioprine (BW 57-322) 对皮肤角质形成细胞无直接抑制作用，但50 μM浓度下可抑制炎症因子诱导的角质形成细胞过度活化，下调ICAM-1表达（降低48%）[1]
Azathioprine (BW 57-322) 代谢产物可阻断嘌呤核苷酸合成：20 μM浓度下，人淋巴细胞中ATP和GTP水平分别降低62%和57%，DNA合成抑制率达70% [2]

在小鼠-大鼠脑异种移植物中，硫唑嘌呤联合环孢菌素 A 和泼尼松龙可使 15 个移植物中的 14 个存活（93%），而单独使用环孢菌素 A 治疗组中的 14 个移植物中只有 11 个存活（79%）。

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Azathioprine (BW 57-322) 以50 mg/kg口服，每日1次，持续21天，可改善小鼠自身免疫性脑炎模型症状：神经功能缺损评分从4.1分降至1.8分，脑组织炎性细胞浸润减少65% [2]
Azathioprine (BW 57-322) 口服2 mg/kg·d，持续12周，可有效治疗大鼠炎症性肠病：腹泻、便血症状缓解率达72%，结肠黏膜炎症评分从3.5分降至1.2分，黏膜损伤修复率达68% [3]
Azathioprine (BW 57-322) 以100 mg/kg口服，每日1次，持续4周，可抑制小鼠接触性皮炎模型的皮肤炎症：红斑肿胀评分从2.8分降至0.9分，皮肤组织中组胺、5-羟色胺水平分别降低60%和55% [1]
Azathioprine (BW 57-322) 临床给药（1-2 mg/kg·d口服）可改善银屑病患者皮损：银屑病面积和严重程度指数（PASI）评分从12.6分降至4.3分，皮损消退率达66% [1]

采用紫外分光光度法检测HGPRT活性：将重组HGPRT与次黄嘌呤、磷酸核糖焦磷酸（PRPP）混合，加入梯度浓度的6-MP（Azathioprine代谢产物），37℃孵育30分钟，检测反应产物次黄嘌呤核苷酸（IMP）的紫外吸收值，计算HGPRT活性抑制率及Ki值 [3]
采用高效液相色谱（HPLC）法检测TPMT活性：将人肝组织匀浆与6-MP、S-腺苷甲硫氨酸（SAM）混合，加入Azathioprine（终浓度0.1-10 μM），37℃孵育60分钟，HPLC分离检测甲基化产物6-甲基巯基嘌呤，计算TPMT活性抑制率及IC50值 [2]

细胞系：大鼠肝细胞、人肝细胞
浓度：0-50 μM
孵育时间：24-48 小时
结果：低浓度0.5时，大鼠肝细胞的细胞活力和细胞内GSH水平下降μM，但在浓度低于 50 μM 时细胞活力没有显着降低，并且在人肝细胞中浓度低至 1 μM 时明显注意到 GSH 消耗。

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人外周血淋巴细胞分离后接种于96孔板（2×10⁵个/孔），加入PHA（5 μg/mL）刺激增殖，同步加入梯度浓度的Azathioprine (BW 57-322)（1-50 μM），培养72小时；CCK-8法检测细胞活力，ELISA法检测上清中IL-2、IFN-γ浓度 [1]
炎症性肠病患者肠道黏膜细胞分离后接种于24孔板（1×10⁶个/孔），加入LPS（1 μg/mL）刺激，加入Azathioprine (BW 57-322)（20、50、100 μM），孵育48小时；提取总RNA，qPCR检测TNF-α、IL-6 mRNA表达，Western blot检测NF-κB p65核转位水平 [3]
人皮肤角质形成细胞接种于6孔板（5×10⁴个/孔），培养24小时后加入TNF-α（10 ng/mL）刺激，同步加入Azathioprine (BW 57-322)（10-100 μM），孵育24小时；流式细胞仪检测ICAM-1表达水平 [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
Oral azathioprine is well absorbed, with a Tmax of 1-2h. Further data regarding the absorption of azathioprine is not readily available.
Azathioprine and mercaptopurine are not detectable in urine after 8 hours. Further data regarding the route of elimination of azathioprine are not available.
Data regarding the volume of distribution of azathioprine is not readily available.
Data regarding the clearance of azathioprine is not readily available.
Azathioprine and mercaptopurine are moderately bound to plasma proteins and are partially dialyzable. They are rapidly removed from the blood by oxidation or methylation in the liver and/or erythrocytes. Renal clearance is of little impact in biological effectiveness or toxicity, but dose reduction is practiced in patients with renal failure.
Azathioprine is well absorbed orally and reaches maximum blood levels within 1 to 2 hours after administration.
Azathioprine is well absorbed from the gastrointestinal tract and has an oral bioavailibility of approximately 60%.
Azathioprine is rapidly cleared from the blood; both azathioprine and mercaptopurine are approximately 30% bound to serum proteins, both appear dialyzable, and both appear to cross the placenta.
The metabolites are excreted in the urine, largely as 6-mercaptopurine. Less than 2% of azathioprine and 20 to 40% of 6-mercaptopurine are excreted as unchanged drugs in the urine.

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Metabolism / Metabolites
Azathioprine is converted to 6-mercaptopurine nonenzymatically. 6-mercaptopurine is then metabolized to 6-methylmercaptopurine by thiopurine methyltransferase, 6-thiouric acid by xanthine oxidase, or 6-thiosine-5'-monophosphate by hypoxanthine phosphoribosyltransferase. 6-thiosine-5'-monophosphate is metabolized to 6-methylthiosine-5'-monophosphate by thiopurine methyltransferase or 6-thioxanthylic acid by inosine monophosphate dehydrogenase. 6-thioxanthylic acid is metabolized by guanosine monophosphate synthetase to 6-thioguanine monophosphate, the first of the 6-thioguanine nucleotides. 6-thioguanine monophosphate is phosphorylated to produce the remaining 6-thioguanine nucleotides, 6-thioguanine diphosphate and 6-thioguanine triphosphate.
Orally administered azathioprine is rapidly divided in vivo to form 6-mercaptopurine.
Metabolized in vivo to 6-mercaptopurine, q.v.
Azathioprine is metabolized to 6-mercaptopurine.
Primarily converted to the active metabolites 6-mercaptopurine and 6-thioinosinic acid via a non-enzymatica process and glutathione transferases. 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
Route of Elimination: 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.

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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 boby clearance of azathioprine is 60 ml/min/kg, and that of 6-mercaptopurine, 10 ml/min/kg.
The half-life of azathioprine itself is about 10 minutes, and that for mercaptopurine is about an hour.

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

Toxicity Summary
IDENTIFICATION: Group: Other Immunosuppressive agents. Azathioprine: pale yellow, odorless powder. The drug is insoluble in water and very slightly soluble in ethanol. HUMAN EXPOSURE: Summary: Main risks and target organs: Azathioprine is a myelotoxic and hepatotoxic immunosuppressive agent. Bone marrow and liver are the main targets but gastrointestinal tract, kidney, lungs, CNS and skin may also be affected. Transient gastroenteritis may be observed with massive overdose. Leukopenia is the main toxic effect which may occur during azathioprine therapy and in the overdose patient. Liver and kidney function tests may be altered but usually returned to normal after discontinuation of the drug. Summary of clinical effects: Oral ulceration occurs rarely with therapeutic doses but may be seen with large doses. Gastrointestinal disturbances such as nausea, vomiting, abdominal pain and diarrhea can appear mainly at higher doses. Acute pancreatitis was also reported following long term azathioprine treatment. Suppression of the bone marrow mainly leukopenia and occasionally pancytopenia may be seen after therapeutic doses and overdoses of azathioprine. Septic shock due to this immunosuppression may occur. Hepatic dysfunction (hepatocellular and cholestatic), venocclusive disease and hemangioma of the liver following azathioprine therapy were documented. Acute restrictive lung disease, interstitial nephritis and a case of progressive leukoencephalopathy after 4 years azathioprine therapy were reported. Skin rash, alopecia and urticaria and a case of palmar-plantar erythema with desquamation and pain were also documented. Diagnosis: Diagnosis of azathioprine overdose is based on history of the drug taken and clinical findings mainly gastrointestinal dysfunction, leukopenia and liver dysfunction. Peripheral cell blood counts and liver function tests are required. Estimation of 6-thioguanine nucleotide, a cytotoxic metabolite of azathioprine in red blood cell may confirm the diagnosis and could also be used to predict bone marrow toxicity of azathioprine. Indications: Uses: Azathioprine is used as an adjunct for the prevention of the rejection of kidney allografts. The drug is used in conjunction with other immunosuppressive therapy including local radiation therapy, corticosteroids, and other cytotoxic agents. Azathioprine may be used for the treatment of conditions which involve derangement of the immune system including chronic active hepatitis, severe rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, pemphigus vulgaris, polyarteritis nodosa, acquired hemolytic anemia, Crohn's disease and idiopathic thrombocytopenia. Contraindications: Azathioprine is contraindicated in patients who are hypersensitive to the drug. Azathioprine is also contraindicated in those patients with renal failure, impaired hepatic function and in pregnant women. Routes of entry: Oral: Azathioprine is usually administered orally. Parenteral: Following renal transplantation, azathioprine may initially be given intravenously to patients unable to tolerate oral medication. Oral therapy should replace parenteral therapy as soon as possible. Kinetics: Absorption by route of exposure: Azathioprine is readily absorbed from the gastrointestinal tract with only 12.6% of the dose being detected in the stool over a 48 hour period. Distribution by route of exposure: Azathioprine is rapidly distributed throughout the body with peak plasma concentrations being reached at 1 to 2 hours after dosing. Small amounts of azathioprine bind to plasma proteins (to a maximum of 30%) and only very small amounts enter the brain. Azathioprine crosses the placenta and trace amounts of the 6-mercaptopurine metabolite have been detected in fetal blood. Biological half-life by route of exposure: The plasma half-life of azathioprine is 3 to 5 hours. Metabolism: Azathioprine is metabolized in vivo to mercaptopurine, apparently by sulfhydryl compounds such as glutathione. Mercaptopurine is oxidized and methylated to several derivatives among which 6-thiouric acid predominates; the proportion of metabolites varies amongst individuals. The fate of the nitromethylimidazole portion of azathioprine has not been completely elucidated. Small amounts of azathioprine are also split to give 1-methyl-4-nitro-5-thioimidazole. The active metabolites, 6-thioguanine nucleotides, responsible for the therapeutic action, are formed intracellularly and appear to have very long half-lives. Elimination by route of exposure: The metabolites of azathioprine are excreted by the kidneys; only small amounts of azathioprine and mercaptopurine are excreted intact. In the 24 hour period after administration up to 50% of the dose is excreted in the urine with 10% as the parent drug. There is no data concerning azathioprine excretion in breast milk. Pharmacology and toxicology: Mode of action: Toxicodynamics: The principal toxic effect of azathioprine is bone marrow depression manifested by leukopenia, macrocytic anemia, pancytopenia, and thrombocytopenia, which may result in prolongation of clotting time and eventual hemorrhage. Pharmacodynamics: The exact mechanism of immunosuppressive activity of azathioprine has not been determined. Azathioprine which is an antagonist to purine metabolism may inhibit RNA and DNA synthesis. The drug may also be incorporated into nucleic acids resulting in chromosome breaks, malfunctioning of the nucleic acids, or synthesis of fraudulent proteins. The drug may also inhibit coenzyme formation and functioning, thereby interfering with cellular metabolism. Mitosis may be inhibited by the drug. In patients who undergo renal transplantation, azathioprine suppresses hypersensitivities of the cell-mediated type and causes variable alterations in antibody production. Human data: Adults: Severe pancytopenia has been observed in about 1% of the patients. Children: Lymphopenia, decreased IgG and IgM concentrations, cytomegalovirus infection. Cytogenetic damage was observed in human lymphocytes in vitro. Acute myelogenous leukemia and solid tumours have occurred in patients with rheumatoid arthritis who received the drug. Mutagenicity: Azathioprine is mutagenic in animals and humans, chromosomal abnormalities have been documented in humans receiving azathioprine, but the abnormalities were reversed following discontinuance of the drug. Interactions: Azathioprine dose should be reduced 75% when administered with allopurinol, as allopurinol affects the metabolism of mercaptopurine, a metabolite of azathioprine. Azathioprine may reduce the effect of certain neuromuscular blocking agents including curare and related non-depolarizing drugs. Certain cytotoxic agents may be additive or synergistic in producing toxicity when used in conjunction with azathioprine. The Committee on Safety of Medicines have advised that azathioprine and penicillamine should not be used concurrently. The effects of azathioprine and corticosteroids could be synergistic. Azathioprine may reduce the anticoagulant effect of warfarin. ANIMAL/PLANT STUDIES: Studies with animals have shown that the haemopoietic system is affected by azathioprine with depression of granulopoiesis, megakaryocytes and, hence, platelet formation. Reversible hepatoxicity has been observed in dogs. Various teratogenic effects have been observed in rabbits, showing skeletal abnormalities. In mice embryolethalite was observed. Carcinogenicity: Azathioprine is carcinogenic in animals. Teratogenicity: Azathioprine is teratogenic in rabbits and mice when given in dosages equivalent to the human dosage. Abnormalities included skeletal malformations and visceral anomalies. Mutagenicity: Azathioprine is mutagenic in the Ames test.
Azathioprine antagonizes purine metabolism and may inhibit synthesis of DNA, RNA, and proteins. It may also interfere with cellular metabolism and inhibit mitosis. Its mechanism of action is likely due to incorporation of thiopurine analogues into the DNA structure, causing chain termination and cytotoxicity.

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Toxicity Data
The oral LD₅₀ for single doses of azathioprine in mice and rats are 2500 mg/kg and 400 mg/kg, respectively.

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Interactions
Xanthine oxidase, an enzyme of major importance in the catabolism of metabolites of azathioprine, is blocked by allopurinol. If azathioprine and allopurinol are used in the same patient, the azathioprine dose must be decreased to 25 to 33% of the usual dose, but it is best not to use these two drugs together. Adverse effects resulting from coadministration of azathioprine with other myelosuppressive agents or ACE inhibitors include leukopenia, thrombocytopenia, and/or anemia ...
Allopurinol inhibits the principal metabolic pathway of azathioprine, the oxidative metabolism of mercaptopurine by xanthine oxidase. This may lead to toxic accumulation of azathioprine with concomitant bone marrow depression.
Therapeutic use may lead to bone marrow depression, hepatic dysfunction infection, drug fever, rash, urticarial eruption, hypersensitivity vasculitis, nausea, vomiting, and diarrhea, and possibly an increase in non-Hodgkin's lymphoma when used with corticosteroids in rheumatoid arthritis.
Allopurinol-induced inhibition of xanthine oxidase-mediated metabolism may result in greatly increased azathioprine activity and toxicity; concurrent use should be avoided if possible, especially in renal transplant patients, because of the high risk of 6-mercaptopurine (azathioprine metabolite) accumulation and consequent azathioprine toxicity if the transplanted kidney is rejected; if concurrent use is essential, it is recommended that azathioprine dosage be reduced to one quarter to one third of the usual dosage, the patient be carefully monitored, and subsequent dosage adjustments be based on patient response and evidence of toxicity.
For more Interactions (Complete) data for AZATHIOPRINE (8 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat oral 535 mg/kg
LD50 Rat intraperitoneal 300 mg/kg
LD50 Rat intraduodenal 630 mg/kg
LD50 Mouse oral 1389 mg/kg
For more Non-Human Toxicity Values (Complete) data for AZATHIOPRINE (7 total), 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 is 38% and thrombocytopenia is 15% at clinical doses, mostly dose-dependent and reversible after drug withdrawal [3]
Long-term administration (>6 months) of Azathioprine (BW 57-322) can cause liver injury: the incidence of elevated serum ALT and AST is 22%, and severe cholestasis occurs in about 3% of cases [1]
When Azathioprine (BW 57-322) is combined with allopurinol, xanthine oxidase is inhibited, 6-MP metabolism is slowed down, and toxicity is enhanced (the risk of myelosuppression increases by 2.5 times); combined with warfarin can reduce the anticoagulant activity of warfarin [2]
The oral median lethal dose (LD50) of Azathioprine (BW 57-322) is 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 also is indicated in the treatment of other immunological diseases including regional and ulcerative colitis, biliary cirrhosis, systemic dermatomyositis (polymyositis), glomerulonephritis, chronic active hepatitis, systemic lupus erythematosus (SLE), inflammatory myopathy, myasthenia gravis, nephrotic syndrome, pemphigus and pemphigoid. /NOT included in US product labeling/
Azathioprine is indicated for the management of severe, active, and erosive rheumatoid arthritis unresponsive to rest or conventional medications. /Included in US product labeling/
It /azathioprine/ is also also indicated in the prevention of rejection in cardiac, hepatic, and pancreatic transplantation. /NOT included in US product labeling/
Azathioprine is indicated as an adjunct for prevention of rejection in renal homotransplantation. /Included in US product labeling/
For more Therapeutic Uses (Complete) data for AZATHIOPRINE (12 total), please visit the HSDB record page.

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Drug Warnings
Azathioprine is a toxic drug and must be used only under close medical supervision. Other immunosuppressive therapy given concomitantly with azathioprine therapy may increase the toxic potential of the drug.
Azathioprine may also cause rash, infection, drug fever, serum sickness, alopecia, arthralgia, retinopathy, Raynaud's disease, and pulmonary edema. Some of these adverse effects can occur as manifestations of rare hypersensitivity reactions. Azathioprine-induced hypersensitivity reactions are often characterized by a combination of symptoms, including fever, rigors, musculuskeletal symptoms (arthralgias, myalgias), and/or cutaneous effects (generalized erythematous or maculopapular rash with nonspecific inflammatory changes demonstrated on biopsy); pulmonary manifestations (eg, cough and/or dyspnea) and hypotension (which may be severe and, in the presence of fever, mimic septic shock) may also occur.
Hepatotoxicity manifested by increased serum alkaline phosphatase, bilirubin, and/or aminotransferase concentrations may occur in patients receiving azathioprine, principally in allograft recipients. Azathioprine-induced hepatotoxicity following transplantation occurs most frequently within 6 months of transplantation and is generally reversible following discontinuance of the drug. Rare, but life-threatening hepatic veno-occlusive disease has occurred during chronic azathioprine therapy in several renal allograft recipients and in a patient with panuveitis; serious complications, including progressive portal hypertension, progressive liver failure requiring a portacaval shunt, progressive chronic liver failure with portal hypertension and esophageal varices, and/or rapid deterioration resulting in death, occurred in most of these patients. Veno-occlusive disease was associated with cytomegalovirus infection in some of these patients and with use of azathioprine but not with dosage of the drug, type or duration of renal allograft, or type of underlying renal disease. Reports to date suggest that the onset of hepatic veno-occlusive disease generally occurs after 1-2 years of therapy and that the disease occur principally in males. The clinical syndrome is usually manifested initially by jaundice, often followed by the development of ascites and other signs of partal hypertension. Serum alkaline phosphatase and bilirubin concentrations are usually elevated. Prognosis is poor. Because hepatic veno-occlusive disease may result in rapid clincial deterioration, prompt diagnosis and therapeutic intervention are necessary. Many clinicians suggest that liver biopsy to diagnose veno-occlusive disease should be performed in renal allograft recipients receiving azathioprine at the first sign of mild hepatic dysfunction. If veno-occlusive disease is evident, azathioprine therapy should be promptly and permanently discontinued; alternative immunosuppressive therapy should be considered and, if liver failure is progressive anticoagulation, a partacaval shunt, or hepatic allotransplantation should be considered. Hepatotoxicity occurs in less than 1% of patients with rheumatoid arthritis who receive azathioprine.
Nausea, vomiting, anorexia, and diarrhea may occur in patients receiving large doses of azathioprine. Adverse GI effects may be minimized by giving the drug in divided doses and/or after meals. Vomiting with abdominal pain may occur rarely with a hypersensitivity pancreatitis. A GI hypersensitivity reaction characterized by severe nausea and vomiting has been reported. This reaction also may be accompanied by diarrhea, rash, fever, malaise, myalgias, elevations in liver enzymes, and, occasionally, hypotension. Symptoms of GI toxicity most often develop within the first several weeks of azathioprine therapy and are reversible upon discontinuance of the drug. The reaction can occur within several hours after rechallange with a single dose of the drug. Other adverse GI effects include ulceration of the mucous membranes of the mouth, esophagitis with possible ulceration, and steatorrhea.
For more Drug Warnings (Complete) data for AZATHIOPRINE (33 total), please visit the HSDB record page.

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Pharmacodynamics
Azathioprine is an immunosuppressive agent which functions through modulation of rac1 to induce T cell apoptosis, as well as other unknown immunosuppressive functions. It has a long duration of action as it is given daily, and has a narrow therapeutic index. Patients should be counselled regarding the risk of malignancies of the skin and lymphomas.

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Azathioprine (BW 57-322) is a classic immunosuppressant and antimetabolite, first synthesized in 1957; it blocks purine nucleotide synthesis through metabolites, inhibiting immune cell proliferation and inflammatory response [1]
Approved indications of Azathioprine (BW 57-322) include: autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus), inflammatory bowel diseases (Crohn's disease, ulcerative colitis), skin diseases (psoriasis, pemphigus), and prevention of organ transplant rejection [3]
The mechanisms of Azathioprine (BW 57-322) include: inhibiting T/B lymphocyte proliferation, reducing inflammatory factor secretion, blocking immune complex formation, and inhibiting intestinal mucosal inflammatory infiltration [2]
FDA warning information for Azathioprine (BW 57-322): regular monitoring of blood routine and liver function is required during medication; patients with TPMT gene polymorphism (low TPMT activity) have a significantly increased risk of myelosuppression and need dose reduction or avoidance [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

143.4

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

注意： 本产品在运输和储存过程中需避光。

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

配方 1 中的溶解度: ≥ 2.08 mg/mL (7.50 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.08 mg/mL (7.50 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.08 mg/mL (7.50 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。