Tacrolimus (formerly also known as FK-506), a macrocyclic lactone isolated from the culture broth of a strain of Streptomyces tsukubaensis, is an immunosuppressive agent used mainly after allogeneic organ transplant to reduce the activity of the patient's immune system and to lower the risk of organ rejection. It is also used in a topical preparation in the treatment of atopic dermatitis (eczema), severe refractory uveitis after bone marrow transplants, exacerbations of minimal change disease, TH2-mediated diseases such as Kimura's disease, and the skin condition vitiligo. FK-506 has strong immunosuppressive activity in vivo and prevents the activation of T-lymphocytes in response to antigenic or mitogenic stimulation in vitro.
理化性质和储存条件
| Molecular Weight (MW) | 822.05 |
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| Formula | C44H71NO13 |
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| CAS No. | 04987-11-3 (free base); 109581-93-3 (hydrate) |
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| Storage | -20℃ for 3 years in powder form |
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| -80℃ for 2 years in solvent |
| Solubility (In vitro) | DMSO:>100 mg/mL |
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| Water: <1 mg/mL |
| Ethanol: 83 mg/mL (103.2 mM) |
| SMILES | CO[C@@H]1C[C@H](/C=C([C@H]2OC([C@@H]3CCCCN3C(C([C@@]4(O[C@@H]([C@@H](OC)C[C@H]4C)[C@@H](OC)C[C@H](C/C(C)=C/[C@H](C(C[C@@H]([C@H]2C)O)=O)CC=C)C)O)=O)=O)=O)\C)CC[C@H]1O.O |
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| Synonyms | FR900506 hydrate; FR 900506 monohydrate; FR-900506; FK 506, FK-506, FK506, fujimycin, Prograf, Protopic, Advagraf; Astagraf XL; LCP-Tacro; |
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实验参考方法
| In Vitro | Kinase Assay: Tacrolimus (FK506) inhibits calcium-dependent events, such as IL-2 gene transcription, NO synthase activation, cell degranulation, and apoptosis. Tacrolimus also potentiates the actions of glucocorticoids and progesterone by binding to FKBPs contained within the hormone receptor complex, preventing degradation. The agent may enhance expression of the TGFβ-1 gene in a fashion analogous to that demonstrated for CsA. T cell proliferation in response to ligation of the T cell receptor is inhibited by Tacrolimus. Treatment with a low concentration of Tacrolimus (FK506,10 μg/L) does not significantly affect the proliferation of MH3924A cells (P=0.135). Upon treatment with higher concentrations of Tacrolimus (100-1,000 μg/L), the proliferation of MH3924A cells is significantly enhanced (P<0.01). 50='' 100='' treatment='' with='' amd3100='' at='' any='' concentration='' or='' has='' no='' obvious='' effect='' on='' mh3924a='' cell='' proliferation='' p=''>0.05). However, when different concentrations of AMD3100 are combined with 100 μg/L Tacrolimus, the in vitro proliferation of MH3924A cells is increased (P<0.01).
Cell Assay: FK-506 and cyclosporin A block translocation of the cytoplasmic component without affecting synthesis of the nuclear subunit in T lymphocytes. FK-506 prevents T-cell proliferation by inhibiting a Ca(2+)-dependent event required for induction of interleukin-2 transcription. FK 506 binds to distinct families of intracellular proteins (immunophilins) termed cyclophilins and FK 506-binding proteins (FKBPs). FK-506 specifically inhibits cellular calcineurin at drug concentrations that inhibit interleukin 2 production in activated T cells. FK-506 and CsA exert nearly identical biological effects in cells by inhibiting the same subset of early calcium-associated events involved in lymphokine expression, apoptosis, and degranulation. FK-506 binds to a family of intracellular receptors termed the FK-506 binding proteins (FKBPs). |
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| In Vivo | FK-506 results in increase in the paw and tail withdrawal threshold as revealed by behavioral pain assessment in rats against hyperalgesic and allodynic stimuli. FK-506 also leads to a decrease in the serum nitrate and thiobarbituric acid reactive substance (TBARS) levels along with reduction in tissue myeloperoxidase (MPO) and total calcium levels, whereas, rise in tissue reduced glutathione levels in rats. FK-506 ameliorates the increase in the neuronal edema and axonal degeneration in rats with ischemia reperfusion (I/R). |
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| Animal model | Six-week-old male C57BL/6J mice are maintained in a temperature- and humidity-controlled room with a 12-h light-dark cycle. For the multiple dosing study, colitic mice (n=10) are orally administered Tacrolimus at 30 mg/kg for 7 d (Days 10 to 16) or 14 d (Days 10 to 23). Control (n=10) and normal groups (n=5) are administered placebo using the same regimen. Tacrolimus or placebo is administered at 10 mL/kg. Mice are euthanized by CO2 inhalation on the day following the final dosing. For the single dosing study, colitic mice are orally administered Tacrolimus at 30 mg/kg or placebo (n=8) once on Day 7, 10, 17, or 24. Normal mice (n=4) are administered placebo using the same regimen. Mice are euthanized by CO2inhalation eight hours after dosing |
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| Formulation & Dosage | 30 mg/kg; oral |
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| References | Nature. 1991 Aug 29;352(6338):803-7; Nature. 1992 Jun 25;357(6380):692-4. |
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