Tacrolimus (FK506)
(Synonyms: 他克莫司; FK506; Fujimycin; FR900506) 目录号 : GC16233
他克莫司 (FK506) 是一种具有强效免疫抑制作用的大环内酯类抗生素，从筑波链霉菌中分离出来，以前曾用于预防人类同种异体移植和治疗自身免疫性疾病。
Cas No.:104987-11-3
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.90%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
| Cell experiment [1]: | |
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Cell lines |
Human lung fibroblasts (HLFs) |
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Preparation Method |
Cells were incubated with the indicated concentrations of FK506 for 24 h. The cells were then washed 3 times with PBS and incubated for 3 h in serum free medium to accumulate secreted collagen. |
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Reaction Conditions |
0-2 µM Tacrolimus (FK506);24 h |
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Applications |
Tacrolimus (FK506) reduces synthesis of type I collagen protein. |
| Animal experiment [1]: | |
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Animal models |
Male inbred alki Wistar rats weighing 150-200 g |
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Preparation Method |
At the start of the study, drinking water was replaced by 5% ethanol as the only source of liquid and the rats were allowed to drink at will. Carbon tetrachloride (CCl4) was administered intraperitoneally (i.p.) at 0.5 µl/g of CCl4 in mineral oil twice a week for 4 weeks. Tacrolimus (FK506) was dissolved in 200 µL of Cremaphor and injected at daily dose of 4 mg/kg for 4 weeks (28 days). Control animals received by i.p. injections the Cremaphor vehicle. The groups were as follows: group 1:5% ethanol liquid+CCl4 injections; group 2:5% ethanol liquid+CCl4 injections+FK506 treatment; group 3: FK506 treatment only; group 4: vehicle only. |
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Dosage form |
4 mg/kg;4 weeks (28 days);i.p. |
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Applications |
Tacrolimus (FK506) treatment inhibited activation of hepatic stellate cells (HSC) or reduced their number in the liver. In vivo, administration of FK506 at a dose of 4 mg/kg completely prevented development of alcohol/carbon tetrachloride induced liver fibrosis in rats. |
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References: [1].Manojlovic Z, Blackmon J, et,al. Tacrolimus (FK506) prevents early stages of ethanol induced hepatic fibrosis by targeting LARP6 dependent mechanism of collagen synthesis. PLoS One. 2013 Jun 3;8(6):e65897. doi: 10.1371/journal.pone.0065897. PMID: 23755290; PMCID: PMC3670911. |
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Tacrolimus (FK506), a macrolide antibiotic with potent immunosuppressive effects was isolated from Streptomyces tsukubaensis and has been previously used to prevent allograft and for treatment of autoimmune disorders in humans[1-3].
Tacrolimus(FK506) (0-2 μM;24 h)reduces synthesis of type I collagen protein without affecting expression of collagen mRNAs in Human lung fibroblasts (HLFs)[8]. T cell proliferation in response to ligation of the T cell receptor is inhibited by tacrolimus(FK506) [4]. Ttacrolimus(FK506) (concentration gradient;48 h)inhibited oral squamous cell carcinoma (OSCC) progression in vitro [9].
Tacrolimus (FK506) was given intramuscularly at the dose of 0.5 and 1.0 mg/kg for three days before burn injury. Thermal trauma to the skin caused a statistically significant increase in MPO activity and MDA content in remote organs. Tacrolimus (FK506) was effective in reducing lipid peroxidation and neutrophil infiltration especially at 24 h postinjury in lung, liver and kidney[5]. Tacrolimus (FK506) has the ability to down-regulate free radical levels in severe ischemia-reperfusion liver, and tachlimus has also been shown to be an effective inhibitor of cytokine response[6]. A study on pulmonary fibrosis in mice suggested that FK506 can be a potent antifibrotic agent [7]. Tacrolimus (FK506) treatment inhibited activation of HSCs or reduced their number in the liver. In vivo, administration of Tacrolimus (FK506) at a dose of 4 mg/kg(i.p.; 4 weeks) completely prevented development of alcohol/carbon tetrachloride induced liver fibrosis in rats[8].
References:
[1]. Wiederrecht G, Lam E, et,al. The mechanism of action of FK-506 and cyclosporin A. Ann N Y Acad Sci. 1993 Nov 30;696:9-19. doi: 10.1111/j.1749-6632.1993.tb17137.x. PMID: 7509138.
[2]. Kino T, Hatanaka H, et,al. FK-506, a novel immunosuppressant isolated from a Streptomyces. II. Immunosuppressive effect of FK-506 in vitro. J Antibiot (Tokyo). 1987 Sep;40(9):1256-65. doi: 10.7164/antibiotics.40.1256. PMID: 2445722.
[3]. Kondo H, Abe T, et,al. Efficacy and safety of tacrolimus (FK506) in treatment of rheumatoid arthritis: a randomized, double blind, placebo controlled dose-finding study. J Rheumatol. 2004 Feb;31(2):243-51. PMID: 14760792.
[4]. Thomson AW, Bonham CA, et,al.Mode of action of tacrolimus (FK506): molecular and cellular mechanisms. Ther Drug Monit. 1995 Dec;17(6):584-91. doi: 10.1097/00007691-199512000-00007. PMID: 8588225.
[5]. Cetinkale O, Konuko?lu D, et,al. Modulating the functions of neutrophils and lipid peroxidation by FK506 in a rat model of thermal injury. Burns. 1999 Mar;25(2):105-12. doi: 10.1016/s0305-4179(98)00147-8. PMID: 10208383.
[6]. Garcia-Criado FJ, Palma-Vargas JM, et,al.Tacrolimus (FK506) down-regulates free radical tissue levels, serum cytokines, and neutrophil infiltration after severe liver ischemia. Transplantation. 1997 Aug 27;64(4):594-8. doi: 10.1097/00007890-199708270-00008. PMID: 9293871.
[7]. Nagano J, Iyonaga K, et,al.Use of tacrolimus, a potent antifibrotic agent, in bleomycin-induced lung fibrosis. Eur Respir J. 2006 Mar;27(3):460-9. doi: 10.1183/09031936.06.00070705. PMID: 16507844.
[8]. Manojlovic Z, Blackmon J, et,al.Tacrolimus (FK506) prevents early stages of ethanol induced hepatic fibrosis by targeting LARP6 dependent mechanism of collagen synthesis. PLoS One. 2013 Jun 3;8(6):e65897. doi: 10.1371/journal.pone.0065897. PMID: 23755290; PMCID: PMC3670911.
[9]: Li Y, Wang Y, et,al. Tacrolimus inhibits oral carcinogenesis through cell cycle control. Biomed Pharmacother. 2021 Jul;139:111545. doi: 10.1016/j.biopha.2021.111545. Epub 2021 Apr 16. PMID: 33873145.
他克莫司 (FK506) 是一种具有强效免疫抑制作用的大环内酯类抗生素,从筑波链霉菌中分离出来,以前曾用于预防人类同种异体移植和治疗自身免疫性疾病[1-3]。\n
他克莫司 (FK506)（0-2 μM；24 小时）减少 I 型胶原蛋白的合成,而不影响人肺成纤维细胞 (HLF) 中胶原蛋白 mRNA 的表达[8]。他克莫司 (FK506) 抑制响应于 T 细胞受体连接的 T 细胞增殖 [4]。 Ttacrolimus(FK506)（浓度梯度；48 h）体外抑制口腔鳞状细胞癌（OSCC）进展[9]。
在烧伤前三天,他克莫司 (FK506) 以 0.5 和 1.0 mg/kg 的剂量肌肉注射。皮肤的热损伤导致远端器官中 MPO 活性和 MDA 含量显着增加。他克莫司 (FK506) 可有效减少肺、肝和肾损伤后 24 小时的脂质过氧化和中性粒细胞浸润[5]。他克莫司 (FK506) 具有下调严重缺血再灌注肝脏中自由基水平的能力,而且他克莫司也被证明是一种有效的细胞因子反应抑制剂[6]。一项针对小鼠肺纤维化的研究表明,FK506 可能是一种有效的抗纤维化药物[7]。他克莫司 (FK506) 治疗可抑制 HSC 的激活或减少其在肝脏中的数量。在体内,以 4 mg/kg（i.p.；4 周）的剂量给予他克莫司 (FK506) 可完全阻止酒精/四氯化碳诱导的大鼠肝纤维化的发展[8]。
他克莫司 (FK506)（0-2 μM；24 小时）减少 I 型胶原蛋白的合成,而不影响人肺成纤维细胞 (HLF) 中胶原蛋白 mRNA 的表达[8]。他克莫司 (FK506) 抑制响应于 T 细胞受体连接的 T 细胞增殖 [4]。 Ttacrolimus(FK506)（浓度梯度；48 h）体外抑制口腔鳞状细胞癌（OSCC）进展[9]。
在烧伤前三天,他克莫司 (FK506) 以 0.5 和 1.0 mg/kg 的剂量肌肉注射。皮肤的热损伤导致远端器官中 MPO 活性和 MDA 含量显着增加。他克莫司 (FK506) 可有效减少肺、肝和肾损伤后 24 小时的脂质过氧化和中性粒细胞浸润[5]。他克莫司 (FK506) 具有下调严重缺血再灌注肝脏中自由基水平的能力,而且他克莫司也被证明是一种有效的细胞因子反应抑制剂[6]。一项针对小鼠肺纤维化的研究表明,FK506 可能是一种有效的抗纤维化药物[7]。他克莫司 (FK506) 治疗可抑制 HSC 的激活或减少其在肝脏中的数量。在体内,以 4 mg/kg（i.p.；4 周）的剂量给予他克莫司 (FK506) 可完全阻止酒精/四氯化碳诱导的大鼠肝纤维化的发展[8]。
| Cas No. | 104987-11-3 | SDF | |
| 别名 | 他克莫司; FK506; Fujimycin; FR900506 | ||
| Canonical SMILES | CO[C@@H]1C[C@H](/C=C(C)/[C@@H](OC([C@]2([H])CCCCN2C(C([C@]3(O)O[C@H]([C@@H](OC)C[C@H](C/C(C)=C/4)C)[C@@H](OC)C[C@H]3C)=O)=O)=O)[C@H](C)[C@H](CC([C@@H]4CC=C)=O)O)CC[C@H]1O | ||
| 分子式 | C44H69NO12 | 分子量 | 804.02 |
| 溶解度 | ≥ 26.6mg/mL in DMSO, ≥ 84.5 mg/mL in EtOH | 储存条件 | 4°C, protect from light |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 1.2438 mL | 6.2188 mL | 12.4375 mL |
| 5 mM | 0.2488 mL | 1.2438 mL | 2.4875 mL |
| 10 mM | 0.1244 mL | 0.6219 mL | 1.2438 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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Tacrolimus - Pharmacokinetic Considerations for Clinicians
Background: The calcineurin inhibitor tacrolimus (Tac) is an integral part of the standard immunosuppressive regimen after renal transplantation (RTx). However, clinical management of Tac therapy can be challenging because of its narrow therapeutic window and because many factors interfere with its metabolism. Therefore, therapeutic drug monitoring is used to adjust the dosage. Method: Recently, we were able to classify patients receiving tacrolimus into two major metabolism groups by simple calculation of the C/D ratio (expressed as the blood concentration normalized by the dose). Results: We showed that the C/D ratio is significantly associated with the (renal) outcome of recipients after kidney and liver transplantation. Conclusion: These findings are interesting and relevant to transplant physicians and physicians interested in immunosuppressive therapy. We therefore review current state of the art aspects of tacrolimus pharmacokinetics including genetics or different tacrolimus formulations (twice-daily immediate-release tacrolimus capsules, once-daily extended- release tacrolimus capsules; novel once-daily tacrolimus tablets) and their possible clinical impact including practical considerations for clinicians.
Pharmacokinetics, Pharmacodynamics and Pharmacogenetics of Tacrolimus in Kidney Transplantation
Background: Tacrolimus (Tac, or FK506), a calcineurin inhibitor (CNI), is the first-line immunosuppressant which consists of the footstone as immunosuppressive regimens in kidney transplantation. However, the drug toxicity and the significant differences of pharmacokinetics (PK) and pharmacodynamics (PD) among individuals are hidden troubles for clinical application. Recently, emerging evidences of Tac pharmacogenetics (PG) regarding drug absorption, metabolism, disposition, excretion and response are discovered for better understanding of this drug.
Method: We reviewed the published articles regarding the Tac PG and its effects on PK and PD in kidney transplantation. In addition, we summarized information on polygenic algorithms.
Results: The polymorphism of genes encoding metabolic enzymes and transporters related to Tac were largely investigated, but the results were inconsistent. In addition to CYP3A4, CYP3A5 and P-gp (also known as ABCB1), single nucleotide polymorphisms (SNPs) might also affect the PK and PD parameters of Tac.
Conclusion: The correlation between Tac PK, PD and PG is very complex. Although many factors need to be verified, it is envisaged that thorough understanding of PG may assist clinicians to predict the optimal starting dosage, help adjust the maintenance regimen, as well as identify high risk patients for adverse effects or drug inefficacy.
Clinical pharmacokinetics of tacrolimus
Tacrolimus, a novel macrocyclic lactone with potent immunosuppressive properties, is currently available as an intravenous formulation and as a capsule for oral use, although other formulations are under investigation. Tacrolimus concentrations in biological fluids have been measured using a number of methods, which are reviewed and compared in the present article. The development of a simple, specific and sensitive assay method for measuring concentrations of tacrolimus is limited by the low absorptivity of the drug, low plasma and blood concentrations, and the presence of metabolites and other drugs which may interfere with the determination of tacrolimus concentrations. Currently, most of the pharmacokinetic data available for tacrolimus are based on an enzyme-linked immunosorbent assay method, which does not distinguish tacrolimus from its metabolites. The rate of absorption of tacrolimus is variable with peak blood or plasma concentrations being reached in 0.5 to 6 hours; approximately 25% of the oral dose is bioavailable. Tacrolimus is extensively bound to red blood cells, with a mean blood to plasma ratio of about 15; albumin and alpha 1-acid glycoprotein appear to primarily bind tacrolimus in plasma. Tacrolimus is completely metabolised prior to elimination. The mean disposition half-life is 12 hours and the total body clearance based on blood concentration is approximately 0.06 L/h/kg. The elimination of tacrolimus is decreased in the presence of liver impairment and in the presence of several drugs. Various factors that contribute to the large inter- and interindividual variability in the pharmacokinetics of tacrolimus are reviewed here. Because of this variability, the narrow therapeutic index of tacrolimus, and the potential for several drug interactions, monitoring of tacrolimus blood concentrations is useful for optimisation of therapy and dosage regimen design.
The Rise of Molecular Glues
2021 marks the 30th anniversary of the revelation that cyclosporin A and FK506 act in a way previously not seen-as "molecular glues" that induce neo-protein-protein associations. As a torrent of new molecular-glue probes and medicines are fueling interest in this field, I explore the arc of this story.
FK506 (tacrolimus), a novel immunosuppressant in organ transplantation: clinical, biomedical, and analytical aspects
The macrolide immunosuppressant FK506 (tacrolimus) is a powerful and selective anti-T-lymphocyte agent that was discovered in 1984. This agent, isolated from the fungus Streptomyces tsukubaensis, has a mechanism of action similar to that of cyclosporine. Experimental data were first published in 1987, and clinical trials were started 2 years later in Pittsburgh. The drug has a potent hepatotrophic effect, which could explain its success in liver transplantation. Particularly encouraging results were obtained in liver allograft recipients, suggesting a lower risk/benefit ratio than with other immunosuppressants. However, recent data show that the drug is not devoid of toxicity (mainly nephrotoxicity), which should the percent the need for careful blood monitoring. Several methods of analysis have been described, some satisfactory, others inadequate for routine monitoring. There is still a lack of specific methods to determine routinely the parent drug concentrations in biological fluids for clinical pharmacokinetics purposes. Despite greater experience in therapeutic drug monitoring, the correlation between FK506 concentrations and efficacy or toxicity is still unclear. More investigations are required to better understand and determine the appropriate use of FK506 in organ transplantation and treating autoimmune diseases.