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English name: Tacrolimus
CAS number:104987-11-3
Molecular formula: C44H69NO12
Molecular weight: 804.02
EINECS No:1308068-626-2
Related categories: microbial metabolites; signal transduction pathway kinase inhibitors; Dermatosis skin beauty; drug substance; macrocyclic lactam antibiotics; antibiotics; immunosuppressive; small molecule inhibitors; drug standard; pharmaceutical intermediates; impurities control; antiviral.
The Mol file: 104987-11-3.mol.
Structural formula:
Tacrolimus nature
Melting point: 113-115℃
Boiling point: 871.7 ± 75.0 ℃ (Predicted)
Density: 1.19±0.1g/cm3 (Predicted)
flash point of: 2℃
Storage conditions: SealediChemicalbookndry, Storeinfreezer, under-20℃
Solubility: dimethyl sulfoxide:> 3 mg/mL
Form: solid
Aciity coefficient (pK a): 9.97 ± 0.70 (Predicted)
Color: white
Optical rotation (optical activity): + 62.223 (CHCl 3)
Water solubility:Freely soluble in DMSO or ethanol. Poorly soluble in water.Soluble in dimethyl sulfoxide, ethanol, water, acetone, chloroform, ethyl acetate, ether, methanol and dimethyl formamide.
BCS Class:2
Stability: Hold in DMSO or ethanol solution at-20℃ for up to 2 months.
InChIKey:QJJXYPPXXYFBGM-LFZNUXCKSA-N
CAS database: 104987-11-3 (CAS DataBase Reference)
Tacrolimus use and synthesis method
Summary
Tacrolimus is a macrolide isolated from Streptomyces, which has a strong immunosuppressive effect, which can specifically bind and inhibit calmodulin phosphatase activity and inhibit IL-2 signaling transcription, thus inhibiting T cell activation, inhibition of ChemicalbookTNF- α, IL-1 β and IL-6 production and T cell-dependent B cell proliferation. Compared with cyclosporin, tacrolimus inhibited T cell activation more strongly than another calmodulin phosphatase inhibitor, with fewer adverse effects.
Tacrolimus (also known as FK506, trade name: FK506) is widely used in anti-rejection therapy after organ transplantation, but also in the treatment of autoimmune diseases, kidney disease, blood Chemicalbook fluid system diseases, etc. However, the medication of tacrolimus varies very greatly, and various drugs and foods may affect the blood concentration of tacrolimus in each link of medication.
Immunosuppressive action
Tacrolimus (Tarolimus, Tac, or FK506), a calcineurin inhibitor (CNI), became the cornerstone of most immunosuppressive programs in the field of transplantation in the 1990s. The mechanism of tacrolimus is mainly combined with FK506Chemicalbook receptor binding protein-12 (FKBP-12) in T lymphocytes to form the Tac-FKBP-12 complex, which binds to calcineurin and suppresses the activation of the latter, interferes with and suppresses the synthesis of interleukin 2 (IL-2) at the molecular level, and suppresses the infiltration of cytotoxic T lymphocytes into the graft, so as to prevent and treat rejection.
The use of tacrolimus has revolutionized the future of kidney transplantation compared to cyclosporine because the drug has higher graft survival, higher drug tolerance, lower incidence of rejection, and fewer side effects. KDIGO has recommended tacrolimus as first-line CNI for kidney transplant Chemicalbook as a medication for initial and long-term maintenance immunosuppressive therapy. However, tacrolimus concentration monitoring is still complex, increasing the risk of rejection, while excessive dosage increases the risk of side effects, mainly nephrotoxicity, neurotoxicity, infections, malignancy, diabetes, and gastrointestinal discomfort.
Drug monitoring
Oral intake of tacrolimus is incomplete absorbed in the gastrointestinal tract and has large individual differences. Some patients absorb rapidly after oral administration, reaching the highest plasma concentration at 0.5h, and some patients can peak at 1 – 3h. After absorption of tacrolimus, Chemicalbook can be widely distributed in vivo, and the blood concentration is high in heart, liver and kidney. Tacrolimus is mainly metabolized through the liver, and at least nine metabolites have been found, among which the methyl deficiency group is considered to be the main metabolites of liver microsomes, which is mainly excreted by bile through feces.
The treatment window of tacrolimus is narrow, its therapeutic dose is close to the toxic dose, and the pharmacokinetic characteristics and bioavailability of different individuals vary greatly. Therefore, it is necessary to monitor the blood concentration of tacrolimus and adjust the administered dose according to the monitoring results, so as to reach the target blood concentration as soon as possible within a certain period of time.
Drug interaction
Tacrolimus is mainly metabolized by the hepatic CYP enzyme system and is also an inhibitor of CYP enzyme. Therefore, drugs also metabolized by CYP enzyme or drugs affecting CYP enzyme can fluctuate the concentration of tacrolimus.
-- Antifungal drugs (ketoconazole, fluconazole, itraconazole, voriconazole), macrolide antibiotics (erythromycin, clarithromycin), calcium channel blockers (diltiazem Chemicalbook) can significantly increase the blood concentration of tacrolimus; various aluminum and magnesium drugs such as aluminum hydroxide, aluminum phosphate, magnesium hydroxide, magnesium oxide can increase the exposure of tacrolimus and should be avoided.
Reduce the blood concentration of -- rifampicin, glucocorticoids and other liver drug enzyme inducers will significantly reduce the blood concentration of tacrolimus. Five flavor methyl element (the main component of five ester capsule), berberine (berberine hydrochloride), rhubarb, compound glycyrrhizin (licorice), mulberry yellow, biphenyl diester, Chemicalbook forsythia and other Chinese medicine ingredients can affect the concentration of tacrolimus, should be avoided at the same time.
Therefore, during the administration of tacrolimus, the concentration of tacrolimus should be closely monitored with any western medicine or Chinese patent medicine. In addition, because of the complex composition of Chinese herbal medicine, we should try to avoid taking Chinese herbal medicine, cream prescription, etc.
Untoward effect
Tacrolimus can cause neurotoxicity, nephrotoxicity, glucose metabolism disorders and other adverse reactions, and is higher than cyclosporine, and can also lead to adverse reactions such as infection, hypertension, hypercholesterolemia and hairy, but lower than cyclosporine. Adverse effects were related to the drug dose. After intravenous administration can cause hypertension, tremor, headache, insomnia, perceptual disorder, visual Chemicalbook (such as cataract, amblyopia), abnormal renal function (such as blood creatinine, urea nitrogen and urine volume), constipation, diarrhea, nausea, high blood calcium, high blood sugar, hyperglycemia, low blood phosphorus, white blood cell hyperplasia. Occasionally, leukopenia, anemia, allergic reaction, and increase the possibility of infection. Oral administration is better tolerance to this product, and adverse effects are correspondingly reduced.
Chemical properties of the single
Hydrate: C44H69NO12? H2O. Colorless prism crystals from acetonitrile, melting point from 127 to 129℃.[α] D20-84.4 (C=1.02, chloroform). Solsoluble in methanol, ethanol, acetone, ethyl acetate, chloroform or Chemicalbook ethyl ether, insoluble in hexane or petroleum ether, insoluble in water. Acute toxic LD50 mice (mg / kg):> 200 i. p. Acute toxic LD50 male and female rats (mg / kg): 57.0,23.6 IV; 134,194 orally.
Use
Tacrolimus is a macrolide antibiotic.immunosuppressant. The mechanism of action is the same as cyclosporin, mainly due to the inhibition of interleukin-2 synthesis. For organ transplantation, better efficacy for acute rejection.
A macrolide that binds to the FK506-binding protein (FKBP) to form a complex, thereby reducing the peptidyl-prolyl isomerase activity in T cells.
Methods of production
Was obtained from the Streptomyces tsukubaensis fermentation. The fermentation process is performed as follows:
Transfer 100m1 seed solution (containing 1% glycerol, 1% cornstarch, 0.5% glucose, 1% cotton seed powder, 0.5% corn dip and 0.2% calcium carbonate, pH=6.5) into a 500ml bottle and disinfect at 120℃ for 30min. A circle of S.TsukubaensisNo.9993 seeds were accessed and grown for 4 days at 30℃. This culture was transferred to cells loaded with 201. In a 30L Chemicalbook yeast tank, which is stored at 120℃, sterilized for 30min, drum the human air for 2 L/min and stirring for 300 r/min.16L of this culture was implanted in 2000L of 1600L of broth (containing 4.5% soluble starch, 1% corn extract, 1% dry yeast, 0.1% calcium carbonate and 0.1%Adekancd, 0 = 6.8), incubated for 30℃, 170 r/min agitation and 1600 L/min of air flow for 4 days.
Separation: 1500L of fermentation broth was filtered with the assistance of 25kg of diatomite. The filter cake was extracted with 500L of acetone, and the extract and filtrate (1350L) were combined by containing 100LDiaionHP-20 non-ionic absorbing resin (Mitsubishi (2hemicalIndustriesLtd,. Japan products) of the pillar. After washing with 300L of water and 300 L of 50% aqueous acetone, they was eluted with 75% aqueous acetone. The eluent was concentrated under reduced pressure to about 300L aqueous solution and extracted three times with 20L ethyl acetate. Extracts were pooled and concentrated to the remaining oil material under reduced pressure. The oil residue was mixed with 2 times the weight of acid silicone (specialsilicagelgrade12, Fuji (9evisionCo, Japanese product) and immersed in human ethyl acetate. The solvent was steamed and the remaining dry powder was analyzed with 8L of the same acidic silicone column and eluted with 30L hexane, 30L hexane and ethyl acetate (4:1) mixture, Chemicalbook30L ethyl acetate. The eluate containing fugidicins was collected and concentrated under reduced pressure. The oil residue was mixed with 2 times the weight of acid silica gel and immersed in ethyl acetate. The solvent was steamed, and the dry powder was separated with a 3.5L acidic silica gel column and eluted with 10L hexane, 10L hexane and ethyl acetate (4:1) mixture, 10L ethyl acetate. The eluate containing fugidicins was collected and concentrated under reduced pressure. The resulting yellow oil residue was dissolved in 300ml of hexane and ethyl acetate (1:1) with 2L silica gel (230~400μm,MerckCo.,Ltd.IJSA product) and eluted with hexane and ethyl acetate (10L1:1, then 6L1:2), 6L of ethyl acetate. The eluate containing fugemimycin was collected and concentrated under reduced pressure to yield 34g of white powdered fumimycin. They were dissolved in acetonitrile and concentrated under reduced pressure. The concentrate was placed at 5℃ overnight to yield 22.7g angular crystals. Then recrystallized with acetonitrile to obtain pure fumimycin with 13.6g colorless prism.
Security information
Hazmat signs: T, Xi, Xn, F
Hazard category code: 25-36 / 37 / 38-36-20 / 21 / 22-11
Safety description: 45-36-26-36 / 37-16-60-20
Dangerous goods transport No.: UN 2811 6.1 / PG 3
WGK Germany:3
RTECS number: KD4201200
Hazard level: 6.1
Customs code: 29349990
Toxic substance data: 104987-11-3 (Hazardous Substances Data)
MSDS information
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