生物活性

• 描述The immunophilin FKBP12 is one of the most abundant and conserved proteins in biology. It is the primary receptor for the immunosuppressant actions of ascomycin in whose presence FKBP12 binds to and inhibits CaN, disrupting IL formation in lymphocytes. Tacrolimus(FK-506) block early events in T lymphocyte activation by its immunosuppressive effects such as phosphoinositide turnover, reducing peptidyl-prolyl isomerase activity in T cells by binding to the FKBP12 which will create a new complex. FK-506 inhibited FKBP12 for activity with IC50 of 3nM. Furthermore, FK-506 Inhibited secretion of IL-1, IL-2 (IC50 = 1 nM), IL-3, IL-4, IL-6 (IC50 = 35 nM), GM-CSF, TNFα (IC50 = 10 nM), IFNγ and Myc from activated T cells. In terms of anti-inflammatory activity in rat RBL2H3 cells, the inhibition of FK506 to DNP-BSA-induced TNF-alpha production pre-incubated for 15 mins with IC50 of 0.25 nM. FK-506 can decrease the serum nitrate and thiobarbituric acid reactive substance (TBARS) levels along with reduction in tissue myeloperoxidase (MPO) and total calcium levels. FK-506 ameliorates the increase in the neuronal edema and axonal degeneration in rats with ischemia reperfusion (I/R) . In the presence of 10ng/mL FK-506, nuclear extracts from Jurkat cells that had been stimulated for 2 hours with PMA and ionomycin transcribe the IL-2 G-less template in amounts nearly equivalent to extracts from fully stimulated Jurkat cells . Overexpression of FKBP12 by transfection enhanced the ability of FK-506 to inhibit calcineurin phosphatase activity with IC50 of 2nM, compared with cells transfected with the expression vector alone (IC50 > 30 nM). The IC50 value for FK-506 inhibition of IgE activation-induced transcripts for TNF-α decreased from 40nM to 10nM in FKBP12 transfectants. Similarly, the IC50 value for inhibition of IL-6 transcripts decreased from > 1000 nM to 35 nM, suggesting FKBP12 is the dominant cytosolic protein that mediates FK506 inhibition of TNF-α and IL-6 transcripts.
• 作用机制FK506 selectively inhibits the enzymatic activity of the calcium/calmodulin-dependent protein phosphatase CaN
• 细胞研究
• Cell Data

  Cell Lines	Concentration	Assay Type	Time	Activity Description	Data Sources
  human T-cell	-	Proliferation assay	-	In vitro inhibitory activity against human T-cell proliferation, IC50=0.5 nM	7537331
  human U251 cells	-	Function assay	-	Inhibition of SAP130 in VEGF-stimulated human U251 cells by PLAP reporter gene assay, IC50=13.8 nM	17643112
  human WiDr cells	-	Growth inhibition assay	-	Inhibition of SAP130 mediated cell growth in human WiDr cells, IC50=10.9 nM	17643112

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• 动物研究
  剂量	Mice: 0.3 mg/kg - 3 mg/kg[1] (p.o.) Rat: 1.25 mg/kg - 5 mg/kg[1] (p.o.)
  给药途径	p.o.
  动物药代数据	Animal Rats[2] Dose 1 mg/kg (i.v. or p.o.) Administration i.v. p.o. F 4.8% (p.o.) Vd 15.0 L/kg (i.v.) T1/2 5.6 h (i.v.) 7.0 h (p.o.) Tmax 0.25 h (p.o.) CL 3.9 L/h·kg (i.v.) Cmax 2.9 ng/ml (p.o.) AUC0→∞ 228.0 ng·h/ml(i.v.) 10.9 ng·h/ml(p.o.)

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT03762473	Renal Transplant Infection	Phase 2	Not yet recruiting	June 30, 2021	United States, Alabama ... more >> University of Alabama at Birmingham Not yet recruiting Birmingham, Alabama, United States, 35294 Contact: Graham C Towns, MD    205-934-9045    gtowns@uabmc.edu    Contact: Tina W Ayer, BS    205-996-2577    tayer@uabmc.edu Collapse <<
  NCT00535691	Dermatitis, Atopic	Phase 2	Completed	-	Canada ... more >> Halifax, Canada Vancouver, Canada Waterloo, Canada Finland Helsinki, Finland Ireland Drogheda, Ireland Dublin, Ireland Latvia Riga, Latvia United Kingdom London, United Kingdom Collapse <<
  NCT01410747	-	-	Active, not recruiting	January 2020	Japan ... more >> Chubu, Japan Hokkaido, Japan Kansai, Japan Kantou, Japan Kyusyu, Japan Shagoku, Japan Shikoku, Japan Touhoku, Japan Collapse <<

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• 参考文献

• [1] FK 506

  [2] Prograf