JAK3 (IC50 = 1 nM); JAK2 (IC50 = 20 nM); JAK1 (IC50 = 112 nM); Rock-II (IC50 = 3400 nM); Lck (IC50 = 3870 nM)

在 2.2 nM 和 5 nM (Kd) 下，托法替布 (CP-690550) 柠檬酸盐可能与 JAK3 和 JAK2 结合。据报道，以下位点与托法替布有额外的结合：Camk1（Kd 为 5,000 nM）、DCamkL3（Kd 为 4.5 nM）、Mst2（Kd 为 4,300 nM）、Pkn1（Kd 为 200 nM）、Rps6ka2 (Kin.Dom.2) -C-末端）（Kd 为 1,400 nM）、Rps6ka6（Kin.Dom.2-C-末端）（Kd 为 1,200 nM）、Snark（Kd 为 420 nM）、Tnk1（Kd 为 640 nM）和 Tyk2（ Kd 为 620 nM)[1]。为了测量酪氨酸激酶抑制剂 (TKI) 活性，将 K562、KCL22 和 THP-1 细胞用不同剂量的 STI571 或 JAK 抑制剂处理 72 小时。然后使用 MTT 测定来评估细胞生长的抑制情况。 IMA 以浓度依赖性方式抑制 K562 和 KCL22 细胞增殖，但不抑制 THP-1 细胞增殖。 IMA 对 K562 和 KCL22 的 IC50 值分别为 0.28 μM 和 0.17 μM。托法替尼 (TOF) 和 INCB018424 一起增加 K562 和 KCL22 对 IMA 的敏感性，即使它们本身不会降低细胞生长 [4]。

与 PEG 治疗的对照小鼠相比，用托法替布治疗的动物表现出抗药物抗体 (ADA) 的产生显着减少（初次免疫后五周内，p<0.01，n=8）。此外，第 28 天是 ADA 首次引人注目的时候。从第 21 天到第 35 天，SS1P 的效价分别有 1000 到 200 倍的显着差异。注射匙孔血蓝蛋白 (KLH) 的小鼠比注射 SS1P 的小鼠产生抗体的速度更快。然而，与对照组相比，托法替布治疗降低了抗 KLH 滴度（分别在第 21 天 p<0.05 和第 28 天 p<0.01，n = 5）。在第 21 天和第 28 天之间，滴度分别下降了 5000 至 250 倍[2]。根据先前的剂量反应研究，选择托法替布每日剂量 6.2 mg/kg，以便对后爪体积和血浆暴露产生 80% 的抑制，从而抑制 JAK1 和 JAK3 信号通路超过 4 小时[3 ]。

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初次免疫后五周（p<0.01，n=8），与 PEG 治疗的对照小鼠相比，用tofacitinib/托法替尼治疗的动物表现出抗药物抗体 (ADA) 的发育显着下降。此外，第 28 天是 ADA 变得引人注目的时候。 SS1P 滴度从第 21 天到第 35 天分别显示出 1000 到 200 倍的变化。注射匙孔血蓝蛋白 (KLH) 的动物比接受 SS1P 治疗的动物更快地产生抗体反应。然而，与对照组相比，tofacitinib/托法替尼剂量降低了抗 KLH 滴度（分别在第 21 天 p<0.05 和第 28 天 p<0.01，n = 5）。从第 21 天到第 28 天，滴度降低了 5000 到 250 倍[2]。每日剂量为 6.2 mg/kg 的tofacitinib/托法替尼可以抑制 JAK1 和 JAK3 信号通路 4 小时以上，该剂量是根据之前的剂量反应实验选择的，对后爪体积和血浆暴露有 80% 的抑制作用[3 ]。

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口服tofacitinib/托法替尼可抑制LPS诱导的气道中性粒细胞增多、BALF中某些细胞因子的水平以及肺组织中STAT3的磷酸化。 结论和意义：总之，本研究表明JAK抑制改善了LPS诱导的大鼠吸入性气道炎症，表明JAK/STAT3信号至少参与了LPS诱导肺中性粒细胞增多症的建立。应进一步研究JAKs抑制剂作为呼吸道炎症性疾病的潜在治疗方法。[4]

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免疫原性仍然是基于蛋白质的疗法的“阿喀琉斯之踵”。针对蛋白质治疗产生的抗药物抗体会严重限制这类不断扩大的药物的安全性和有效性。在这篇文章中，我们报告了用tofacitinib/托法替尼（JAK抑制剂）对小鼠进行单一治疗，可以抑制对细菌蛋白假单胞菌外毒素A衍生的免疫毒素以及对银钥匙孔血蓝蛋白模型的抗体反应。免疫后21天，观察到两种Ag的IgG1滴度降低了数千倍。事实上，所有IgG同种型和IgM都明显受到抑制。胸腺非依赖性II型抗原的IgG3产生也减少。机制研究表明，tofacitinib/托法替尼治疗导致CD127+pro-B细胞数量减少。此外，我们观察到用tofacitinib/托法替尼治疗的小鼠生发中心B细胞减少，生发中心形成受损。由于托法替尼治疗期间仍存在正常的Ig水平，因此该药物特异性降低了抗药物Abs，从而保留了生物疗法的潜在疗效，包括用作癌症疗法的疗效[2]。

激酶谱由CRO公司利用KINOMEscan™进行。通过与专有标签融合的选定激酶的竞争结合分析记录活性。在存在和不存在测试化合物的情况下，对结合到固定的活性位点导向配体的激酶量的测量提供了配体结合的DMSO对照百分比。选择0至10之间的活性进行Kd测定。树状图表示是由名为PhyloChem的内部可视化工具生成的。树状图聚类和顶点基于人类系统发育激酶数据，可在http://kinase.com/human/kinome1.

B细胞分化和增殖的特征[2]
从BALB/c小鼠制备脾细胞和骨髓细胞悬浮液，并计数总细胞。细胞（1×106）用以下抗小鼠抗体的各种组合染色：CD3、B220、CD43、IgM、Fas、GL-7、CD24、BP-1、CD127或IgG1与FITC、PE或APC结合，并在FACSCalibur流式细胞仪上分析。至少获得了10000个现场活动。为了评估体外B细胞增殖，根据制造商的说明，将CD43-脾细胞纯化为MACS，并用1μM CFSE标记。在0、0.1、0.3或1.0μM的托法替尼存在下，用25μg/mL的LPS（大肠杆菌0111:B4）和5ng/mL的IL-4激活标记细胞48小时。培养后，洗涤细胞，表面染色，并用流式细胞术检查。

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体外人破骨细胞分化和功能。[3]
通过磁激活细胞分选（MACS）细胞分离技术从白细胞包中阴性选择CD14+细胞，获得原代人单核细胞。将细胞以1×105个细胞/孔的速度接种在96孔黑色组织培养板上，在含有5%胎牛血清（FBS）和10单位/ml青霉素-链霉素的高糖Dulbecco改良Eagle培养基中。每隔一天用25ng/ml重组人巨噬细胞集落刺激因子（M-CSF）处理培养的细胞14天，用于巨噬细胞分化，或在100ng/ml重组人RANKL存在下用M-CSF处理破骨细胞分化。在分化细胞因子的同时，还用或不用0.2%DMSO中不同浓度的托法替尼处理细胞。使用ELF-97荧光磷酸酶底物定量TRAP活性。然后根据制造商的建议，使用白细胞酸性磷酸酶试剂盒固定细胞并染色。[3]
通过溶骨试验测定人破骨细胞的功能性骨吸收活性。将人破骨细胞前体细胞 以1×104个细胞/孔的速度接种在含有33 ng/ml M-CSF和66 ng/ml RANKL的培养基中，然后接种在预涂有铕结合的人I型胶原的96孔OsteoLyse细胞培养板上。在分化阶段（第0-6天），细胞用不同浓度的托法替尼处理或不处理。培养6天后，加入含有M-CSF和RANKL的新鲜培养基，并以相同浓度替换或加入先前未处理的细胞中。此外，将阿仑膦酸钠添加到未处理的细胞中作为阳性对照。将细胞再培养4天，以允许功能活性破骨细胞释放胶原蛋白，并使用OsteoLyse荧光细胞释放试剂检测培养上清液中的铕荧光，在340 nm激发和615 nm发射下测量400μs间隔内的时间分辨荧光。

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体外人T淋巴细胞RANKL的产生。[3]
使用MACS细胞分离技术从leukpak中阴性选择CD4+T淋巴细胞，并在含有葡萄糖、10%FBS和10单位/ml青霉素-链霉素的RPMI 1640培养基中，在圆底96孔组织培养板中以2.5×105个细胞/孔的速度培养。细胞在0.2%DMSO中用或不用不同浓度的托法替尼处理，并用1μg/ml抗人CD3和0.1μg/ml抗人类CD28抗体以及50ng/ml重组人IL-2活化5天。使用人LincoPlex测定法测量分泌到培养基中的RANKL。

Drug treatment and immunizations[2]
Mice received tofacitinib in PEG300 (100 mg/ml) or vehicle alone (PEG300) by osmotic pump infusion (Alzet Model 2004, 0.25 μl/hour, 28 days. Four days prior to immunization, mice were anesthetized and their dorsal surface was shaved. A one cm incision was made on the back to create a subcutaneous pocket and insert the pump. The incision site was closed with wound clips. Mice were injected weekly (i.p.) with SS1P recombinant immunotoxin (RIT; 5 μg/mouse) beginning on day 0; control mice received injections of saline alone. Every week before SS1P or vehicle immunization, ~50 μl of blood was drawn to obtain serum samples. Sera were stored at −80°C until analyzed.

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Animals and tofacitinib administration.[3]
AIA was induced in female Lewis rats as previously described. Rats were randomized according to hind paw volume and assigned to tofacitinib or vehicle treatment regimens. Groups of 7–8 rats per treatment group, and normal naive rats (n = 4 per group), were euthanized either 4 hours, 4 days, or 7 days after beginning treatment (days 16, 20, and 23 after immunization, respectively). Tofacitinib was suspended in 0.5% methylcellulose/0.025% Tween 20 for in vivo studies or in DMSO for in vitro use. Once-daily oral administration of vehicle or tofacitinib (6.2 mg/kg) was initiated on day 16 following immunization and continued through day 23. Paw volumes were reassessed 4 and 7 days after the beginning of treatment (days 20 and 23 after immunization, respectively). For micro–computed tomography (micro-CT) imaging, as well as tartrate-resistant acid phosphatase (TRAP) staining in paw tissue, AIA was induced in a separate cohort of Lewis rats.

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Rats were exposed to an aerosol of LPS (0.1 mg/ml) or phosphate-buffered saline (PBS) during 40 min. Bronchoalveolar lavage fluid (BALF) and lung samples were collected 4 h after PBS or LPS exposure. Neutrophils in BALF were counted and a panel of cytokines were measured in BALF. Phosphorylation of STAT3 was studied in lung homogenates by ELISA and localization of phospho-STAT3 (pSTAT3) in lung tissue was also evaluated by immunohistochemistry. In order to assess the effect of JAK inhibition, tofacitinib was administered 1 h before challenge at doses of 3, 10 and 30 mg/kg p.o.[4]

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Formulated in PEG 300; 0-136 ng/mL; Given through osmotic minipump infusion

DBA/2 and C57/BL6 mice

Absorption, Distribution and Excretion
Absorption
74% oral absorption (absolute bioavailability), with peak plasma concentrations (T max) achieved in 0.5-1 hour. Administration with fatty meals does not alter AUC but reduces Cmax by 32%.

Route of Elimination
70% metabolized in the liver by CYP3A4 (major) and CYP2C19 (minor). Metabolites produced are inactive. 30% renally eliminated as unchanged drug.

Volume of Distribution
Vd= 87L after intravenous administration. Distribution is equal between red blood cells and plasma.

The protein binding of tofacitinib is approximately 40%. Tofacitinib binds predominantly to albumin and does not appear to bind to a1-acid glycoprotein. Tofacitinib distributes equally between red blood cells and plasma.

The absolute oral bioavailability of tofacitinib is 74%. Coadministration of Xeljanz with a high-fat meal resulted in no changes in AUC while Cmax was reduced by 32%. In clinical trials, Xeljanz was administered without regard to meals.

Clearance mechanisms for tofacitinib are approximately 70% hepatic metabolism and 30% renal excretion of the parent drug. The metabolism of tofacitinib is primarily mediated by CYP3A4 with minor contribution from CYP2C19. In a human radiolabeled study, more than 65% of the total circulating radioactivity was accounted for by unchanged tofacitinib, with the remaining 35% attributed to 8 metabolites, each accounting for less than 8% of total radioactivity. The pharmacologic activity of tofacitinib is attributed to the parent molecule.

Following oral administration of Xeljanz /to humans/, peak plasma concentrations are reached within 0.5-1 hour, elimination half-life is approximately 3 hours and a dose-proportional increase in systemic exposure was observed in the therapeutic dose range. Steady state concentrations are achieved in 24-48 hours with negligible accumulation after twice daily administration.

/MILK/ Tofacitinib was secreted in milk of lactating rats. It is not known whether tofacitinib is excreted in human milk.

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Metabolism / Metabolites
Metabolized in the liver by CYP3A4 and CYP2C19. Metabolites produced are inactive.

Clearance mechanisms for tofacitinib are approximately 70% hepatic metabolism and 30% renal excretion of the parent drug. The metabolism of tofacitinib is primarily mediated by CYP3A4 with minor contribution from CYP2C19. In a human radiolabeled study, more than 65% of the total circulating radioactivity was accounted for by unchanged tofacitinib, with the remaining 35% attributed to 8 metabolites, each accounting for less than 8% of total radioactivity. The pharmacologic activity of tofacitinib is attributed to the parent molecule.

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Biological Half-Life: ~3 hours
The elimination half-life of tofacitinib /in humans/ is approximately 3 hours.

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Protein Binding: 40%, mostly bound to albumin.

Toxicity Summary
IDENTIFICATION AND USE: Tofacitinib is a yellow foam. As the drug Xeljanz, it is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to methotrexate. It may be used as monotherapy or in combination with methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs). HUMAN EXPOSURE AND TOXICITY: According to epidemiological studies, the overall risk of infection (including serious infection) and mortality rates in RA patients treated with tofacitinib appear to be similar to those observed in RA patients treated with biologic agents. The rates of serious infection were stable over time. Within the global tofacitinib RA development program, tuberculosis was the most common opportunistic infection reported but was rare in regions of low and medium TB incidence. In a genotoxicity study, increases in chromosomal abnormalities were observed in a human lymphocyte in vitro cytogenetic assay, at high cytotoxic concentrations with metabolic activation, but no effects were observed without metabolic activation. ANIMAL STUDIES: In cynomolgus monkeys, emesis and decreased activity were observed as a result of acute exposure. Xeljanz caused death in rats at single oral doses of >/= 500 mg/kg. Immune and hematopoietic organ systems were identified as main targets in repeat-dose toxicity studies on animals. In a peri/postnatal development study in rats, Xeljanz decreased the number of delivered and live born pups, and reduced pup survival at oral doses of 50 mg/kg/day. Xeljanz was teratogenic (external, visceral and skeletal abnormalities) in rabbits and rats at oral doses of 30 and 100 mg/kg/day, respectively. Xeljanz was not mutagenic in the bacterial reverse mutation assay. Xeljanz was not mutagenic in mammalian cells (in vitro CHO/HGPRT assay) and did not induce primary DNA damage in an in vivo/in vitro rat hepatocyte unscheduled DNA synthesis assay. Xeljanz was also negative in the in vivo rat micronucleus test. In a 2-year rat carcinogenicity study, Xeljanz induced benign Leydig cell tumors and malignant hibernomas at oral doses of >/= 30 mg/kg/day and benign thymomas at 100/75 mg/kg/day. In a 39-week repeat-dose toxicity study in adult monkeys, lymphomas were observed at the high dose of 5 mg/kg twice daily, but not at the lower dose of 1 mg/kg twice daily (approximately equivalent to human exposure).

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Hepatotoxicity
In large registration clinical trials, serum aminotransferase elevations occurred in 28% to 34% of tofacitinib treated subjects compared to 25% in comparator arms and 10% in placebo recipients. These elevations were typically mild and transient, but values above 3 times the upper limit of normal (ULN) occurred in 1% to 2% of patients on tofacitinib compared to less than 1% on placebo. The elevations occasionally led to early discontinuations, but more often resolved even without dose adjustment. In prelicensure studies, there were no instances of clinically apparent liver injury attributed to tofacitinib. Since approval and more wide scale availability of tofacitinib, there have been no published reports of hepatotoxicity associated with its use but a proportion of patients do develop serum aminotransferase elevations which in some cases leads to drug discontinuation. While other Janus kinase inhibitors such as ruxolitinib have been associated with episodes of reactivation of hepatitis B, spontaneous reports of clinically apparent reactivation of hepatitis during tofacitinib therapy have not been reported. On the other hand, retrospective studies on patients with HBsAg and inactive liver disease who were treated with tofacitinib have been reported to develop rising levels of HBV DNA and modest elevations in serum aminotransferase levels without symptoms. In contrast, studies of patients with anti-HBc without HBsAg in serum have shown no evidence of HBV DNA rises and appearance of HBsAg. Thus, reactivation of hepatitis B during therapy can occur, although it is generally mild and self-limited in course. Whether reactivation of hepatitis B can arise after therapy of susceptible patients with tofacitinib for severe COVID-19 pneumonia is unknown, but there have been no such reports to date.
Likelihood score: E* (suspected but unproven rare cause of clinically apparent liver injury with the potential to cause reactivation of hepatitis B).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Data from 2 mothers indicate that the amount in milk is relatively low and no adverse effects were seen in infants who were exclusively breastfed during maternal tofacitinib use. Until more data become available, tofacitinib should be used with caution during breastfeeding, especially while nursing a newborn or preterm infant. The manufacturer and an expert panel recommend that breastfeeding be discontinued during tofacitinib therapy and for 18 hours after the last dose of the immediate-release product or 36 hours after the last dose of the sustained-release product.

◉ Effects in Breastfed Infants
Two mothers took tofacitinib during pregnancy while exclusively breastfeeding. One infant whose mother was taking a dose of 5 mg twice daily was breastfed for 14 weeks. The other infant whose mother was taking a dose of 10 mg twice daily was breastfed for 6 weeks. These infants were followed up at 3.5 and 14 months of age, respectively. They had normal growth and psychomotor development at the time of follow-up and no negative safety signals were seen. Both received the mandatory non-live vaccinations without complications.
A woman was taking tofacitinib 10 mg twice daily for ulcerative proctocolitis. She reduced the dose to 5 mg twice daily at week 23 of pregnancy and continued it for the rest of her pregnancy and while breastfeeding (extent not stated). At 12 weeks of age, the infant underwent a thorough immunologic evaluation that was normal. The infant was given two doses of the live rotavirus vaccine (Rotarix, GlaxoSmithKline) at weeks 13 and 20 of age. No adverse events were reported following immunization, including severe vomiting, diarrhea or intussusception, with active and passive surveillance. The infant was healthy at 12 months of age.

◉ Effects on Lactation and Breastmilk

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◈ What is tofacitinib?
Tofacitinib is a medication that has been used to treat rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis. You can find more information on these conditions in the MotherToBaby fact sheets at https://mothertobaby.org/fact-sheets/rheumatoid-arthritis/, https://mothertobaby.org/fact-sheets/psoriasis-and-pregnancy/ and https://mothertobaby.org/fact-sheets/inflammatory-bowel-disease-pregnancy/. A brand name of tofacitinib is Xeljanz® and Xeljanz XR®.Tofacitinib is also being studied to treat severe COVID-19. Since there is little information about tofacitinib in pregnancy and breastfeeding, it is not currently recommended for treatment of COVID-19 in people who are pregnant or breastfeeding if other recommended treatment options are available. However, the National Institutes of Health (NIH) also state that necessary COVID-19 treatments should not be withheld from people just because they are pregnant or breastfeeding. More information on COVID-19 can be found in our fact sheet here: https://mothertobaby.org/fact-sheets/covid-19/.Sometimes when people find out they are pregnant, they think about changing how they take their medication, or stopping their medication altogether. However, it is important to talk with your healthcare providers before making any changes to how you take your medication. Your healthcare providers can talk with you about the benefits of treating your condition and the risks of untreated illness during pregnancy.

◈ I take tofacitinib. Can it make it harder for me to get pregnant?
It is not known if tofacitinib can make it harder to get pregnant.

◈ Does taking tofacitinib increase the chance of miscarriage?
Miscarriage is common and can occur in any pregnancy for many different reasons. Studies have not been done to see if tofacitinib increases the chance of miscarriage. Reports of people exposed to tofacitinib during early pregnancy have not suggested an increased chance of miscarriage.

◈ Does taking tofacitinib increase the chance of birth defects?
Every pregnancy starts out with a 3-5% chance of having a birth defect. This is called the background risk. It is not known if tofacitinib increases the chance of birth defects above the background risk. Animal studies showed an increase in birth defects with the use of tofacitinib at much higher doses than those used in humans. No increased chance of birth defects has been reported in cases of people exposed to tofacitinib during early pregnancy.

◈ Does taking tofacitinib in pregnancy increase the chance of other pregnancy-related problems?
Studies have not been done to see if tofacitinib increases the chance of pregnancy-related problems, such as preterm delivery (birth before week 37) or low birth weight (weighing less than 5 pounds, 8 ounces [2500 grams] at birth).

◈ Does taking tofacitinib in pregnancy affect future behavior or learning for the child?
Studies have not been done to see if tofacitinib can cause behavior or learning issues for the child.

◈ Breastfeeding while taking tofacitinib:
Tofacitinib has not been well studied for use during breastfeeding. The manufacturer and an expert panel recommend that breastfeeding be stopped while using tofacitinib and for 18 hours after the last dose. For the extended release form (Xeljanz® XR), they recommend waiting 36 hours after the last dose before breastfeeding again. Be sure to talk to your healthcare provider about all your breastfeeding questions.

◈ If a male takes tofacitinib, could it affect fertility or increase the chance of birth defects?
Studies have not been done to see if tofacitinib could affect male fertility (ability to get partner pregnant) or increase the chance of birth defects above the background risk. In general, exposures that fathers or sperm donors have are unlikely to increase risks to a pregnancy. For more information, please see the MotherToBaby fact sheet Paternal Exposures at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

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Interactions
In healthy individuals, the CYP3A inducer rifampin (600 mg orally once daily for 7 days) decreased peak plasma concentrations and AUC of tofacitinib (single oral dose of 30 mg) by 74 and 84%, respectively. Concomitant use of rifampin may decrease efficacy of tofacitinib.

There is a risk of added immunosuppression when Xeljanz is coadministered with potent immunosuppressive drugs (e.g., azathioprine, tacrolimus, cyclosporine). Combined use of multiple-dose Xeljanz with potent immunosuppressants has not been studied in rheumatoid arthritis. Use of Xeljanz in combination with biologic disease-modifying antirheumatic drugs (DMARDS) or potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

Concomitant use of tofacitinib with potent immunosuppressive agents (e.g., azathioprine, cyclosporine, tacrolimus) increases the risk of immunosuppression and is not recommended. Concomitant use of tofacitinib with such agents in patients with rheumatoid arthritis has not been studied to date. In healthy individuals, cyclosporine (200 mg orally every 12 hours for 5 days) decreased the clearance of tofacitinib (single oral dose of 10 mg), resulting in a 73% increase in the AUC of tofacitinib, accompanied by a 17% decrease in peak plasma tofacitinib concentrations. In healthy individuals, tacrolimus (5 mg orally every 12 hours for 7 days) slightly decreased the clearance of tofacitinib (single oral dose of 10 mg), resulting in a 21% increase in the AUC of tofacitinib, accompanied by a 9% decrease in peak plasma tofacitinib concentrations.

Tofacitinib exposure is decreased when Xeljanz is coadministered with potent CYP3A4 inducers (e.g., rifampin).

[1]. Examining the chirality, conformation and selective kinase inhibition of 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (CP-690,550). J Med Chem. 2008 Dec 25;51(24):8012-8.

[2]. Tofacitinib suppresses antibody responses to protein therapeutics in murine hosts. J Immunol. 2014 Jul 1;193(1):48-55.

[3]. JAK inhibition with tofacitinib suppresses arthritic joint structural damage through decreased RANKL production. Arthritis Rheum. 2012 Nov;64(11):3531-42.

[4]. Pharmacological inhibition of JAK3 enhances the antitumor activity of STI571 in human chronic myeloid leukemia. Eur J Pharmacol. 2018 Apr 15;825:28-33.

Tofacitinib citrate is a citrate salt obtained by combining equimolar amounts of tofacitinib and citric acid. Used to treat moderately to severely active Rheumatoid Arthritis. It has a role as an EC 2.7.10.2 (non-specific protein-tyrosine kinase) inhibitor and an antirheumatic drug. It contains a tofacitinib.
Tofacitinib Citrate is the citrate salt form of tofacitinib, an orally bioavailable inhibitor of Janus kinases (JAK), with immunomodulatory and anti-inflammatory activities. Upon oral administration, tofacitinib binds to JAK and prevents the activation of the JAK-signal transducers and activators of transcription (STAT) signaling pathway. This may decrease the production of pro-inflammatory cytokines, such as interleukin (IL)-6, -7, -15, -21, interferon-alpha (IFN-a) and -beta (IFN-b), and may prevent both an inflammatory response and the inflammation-induced damage caused by certain immunological diseases. JAK kinases are intracellular enzymes involved in signaling pathways affecting hematopoiesis, immunity and inflammation.
See also: Tofacitinib (has active moiety).

C22H28N6O8

504.4931

504.196

C, 52.38; H, 5.59; N, 16.66; O, 25.37

540737-29-9

Tofacitinib;477600-75-2;Tofacitinib-d3 citrate;2701680-77-3;(3S,4S)-Tofacitinib;1092578-47-6;(3R,4S)-Tofacitinib;1092578-46-5;(3S,4R)-Tofacitinib;1092578-48-7

10174505

White to off-white solid powder

0.234

221.04

5

12

8

36

716

2

C[C@@H]1CCN(C[C@@H]1N(C)C2=NC=NC3=C2C=CN3)C(=O)CC#N.C(C(=O)O)C(CC(=O)O)(C(=O)O)O

SYIKUFDOYJFGBQ-YLAFAASESA-N

InChI=1S/C16H20N6O.C6H8O7/c1-11-5-8-22(14(23)3-6-17)9-13(11)21(2)16-12-4-7-18-15(12)19-10-20-16;7-3(8)1-6(13,5(11)12)2-4(9)10/h4,7,10-11,13H,3,5,8-9H2,1-2H3,(H,18,19,20);13H,1-2H2,(H,7,8)(H,9,10)(H,11,12)/t11-,13+;/m1./s1

2-hydroxypropane-1,2,3-tricarboxylic acid;3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropanenitrile

CP-690550; CP690550; CP 690550; Tasocitinib; Tofacitinib; Xeljanz (Trade name); CP-690550-10; Tofacitinib citrate; 540737-29-9; Tasocitinib citrate; Xeljanz; CP-690550 citrate; Tofacitinib (CP-690550) Citrate; Tofacitinib (citrate); Xeljanz Xr; CP-690,550-10; CP-690550 citrate;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中（例如氮气保护），避免吸湿/受潮和光照。

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

DMSO: 100 mg/mL (198.2 mM) Water:<1 mg/mL Ethanol:<1 mg/mL

配方 1 中的溶解度: ≥ 2.5 mg/mL (4.96 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 25.0 mg/mL澄清DMSO储备液加入到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: ≥ 2.5 mg/mL (4.96 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 25.0 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: ≥ 2.5 mg/mL (4.96 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 25.0 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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配方 4 中的溶解度: ≥ 1.43 mg/mL (2.83 mM) (饱和度未知) in 5% DMSO + 95% (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。
*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 5 中的溶解度: 0.5% methylcellulose:30mg/mL

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配方 6 中的溶解度: 2.5 mg/mL (4.96 mM) in 50% PEG300 50% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶.
*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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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。