104987-11-3 Usage
Uses
Used in Organ Transplantation:
Tacrolimus is used as an immunosuppressant for patients who have undergone allogeneic organ transplant to reduce the activity of their immune system and the risk of organ rejection. It has been effective in prolonging the survival of hepatic, renal, cardiac, small intestine, pancreatic, and skin allografts and reversing cardiac and renal allograft rejection.
Used in Dermatology:
Tacrolimus is used in a topical preparation for the treatment of severe atopic dermatitis, severe refractory uveitis after bone marrow transplants, and the skin condition vitiligo. Its discovery has led to a greater understanding of skin pathology, particularly in atopic dermatitis.
Used in the Treatment of Cushing's Syndrome:
Tacrolimus is also used in the treatment of Cushing's syndrome, a hormonal disorder caused by prolonged exposure to high levels of cortisol.
Used in Autoimmune Diseases:
Tacrolimus has potential applications in multiple sclerosis, psoriasis, rheumatoid arthritis, and uveitis associated with Behcet's disease due to its immunosuppressive properties.
Chemical Properties:
Tacrolimus is a white crystalline solid and is available under the brand names Prograf (Astellas) and Protopic (Astellas).
Indication and administrations
It is used after allogenic organ transplant to reduce the activity of the patient's immune system and so the risk of organ rejection. It was first approved by the FDA in 1994 for use in liver transplantation, this has been extended to include kidney, heart, small bowel, pancreas, lung, trachea, skin, cornea, and limb transplants. It has also been used in a topical preparation in the treatment of severe atopic dermatitis.
Pharmacodynamics
Tacrolimus was absorbed topically by intact skin at rates of 3.1, 4.9 and 6.8 ng/cm2 per hour, for the 0.03%, 0.1% and 0.3% ointment concentrations, respectively.[1,2] Interestingly, tacrolimus was absorbed regardless of occlusion at significantly higher rates in damaged skin, with percutaneous penetration of 40 ng/cm2 per hour. Thus, while on topical therapy, the patient’s skin will absorb progressively lower quantities of the agent as the lesions heal. This self-regulatory property of tacrolimus is a major advantage, as it should result in fewer adverse effects over the course of treatment.[4] In one randomized, double-blind study, a 3-week course of twice daily, topically applied tacrolimus ointment 0.03%, 0.1% and 0.3% resulted in blood concentrations below 0.25 ng/mL in most patients.[5] This low systemic absorption rate is typical of the majority of clinical cases. The mean time taken to attain the highest blood concentration of tacrolimus is between 5 and 6 h after application in adults and 2.5 h in children.[6] In another study, the bioavailability of topical tacrolimus was found to be lower than 0.5%. 6 Furthermore, tacrolimus does not seem to
accumulate, either in the skin or blood, following repeated applications.[7] When taken orally, the absorption of tacrolimus is erratic and poor. The bioavailability of the drug ranges from 5% to 67%. 8 Intravenous administration of tacrolimus has resulted in the highest relative tissue concentrations in the spleen, lung and kidneys, followed by heart, skin and muscle, then fat and bone marrow and finally by liver, bone and blood.[9]
During topical administration, there is no evidence of cutaneous metabolism. Systemically, tacrolimus metabolism is mediated by the cytochrome P450 3A4 isoenzyme. It is metabolized in the liver, by CYPIA and CYPIIIA.[8] In vitro studies have identified eight different metabolites. When SMS 201-995 is administered via the intraperitoneal route, the effects of tacrolimus are enhanced and thus may enable lower doses of the latter to be used.[10]
When administered systemically, tacrolimus is eliminated in bile. It is cleared at 2.25 L/h, with a half-life of 40 h. 1 It has been found that paediatric transplant patients under 6 years old have higher weight-normalized clearance of tacrolimus, as compared with older children and adults.
Mode of action
Tacrolimus is a prodrug that enters the T cells and binds to immunophilins, forming a complex that binds competitively and blocks calmodulin.[2] This has the spin-off effect of not activating phosphatase calcineurin, which disables the dephosphorylation of NF-AT and subsequently inhibits entry of NF-AT into the nucleus, suppressing gene transcription. The final result is a decreased responsiveness of T cells to antigens.
Tacrolimus can also exert a broad range of immunomodulatory effects on various skin disorders by binding to cell surface steroid receptors and inhibiting mast cell adhesion, inhibiting the release of mediators from mast cells and basophils, decreasing intercellular adhesion molecule-1 and E-selectin lesional blood vessel expression, and downregulating the expression of IL-8 receptor and Fcε RI on Langerhans cells.[11-13] Langerhans cells are considered to be important in the pathophysiology of many inflammatory diseases.[14] There is speculation that the features involved in the activation of Langerhans cells are common with T-cell activation; in other words, there is a dependence on calcineurin in the activation of Fcε RI-specific transcription factor.[15] Tacrolimus may downregulate the expression of FcεRI. Langerhans cells and other CD1a+ skin dendritic cells are important targets of tacrolimus.[14]
It has also been suggested that tacrolimus is able to increase levels of p53.2 Topical tacrolimus has been shown to decrease cytokine mRNA levels of IL-1α, IL-1β and macrophage inflammatory protein (MIP)-2, which results in lymph node cell proliferation.16,17 Tacrolimus inhibits the transcription and release of cytokines, for example, IL-2, Il-3, IL-4, IL-5, interferon-γ, tumor necrosis factor-α, and granulocyte-monocyte colony stimulating factor.[18] Additionally, the production of T-helper 1 (Th1) and Th2 cytokines is inhibited by tacrolimus.[18]
Side effects
Owing to its potent activity as an immunosuppressant, tacrolimus has a number of adverse effects when administered orally or intravenously following transplant operations. Nephrotoxicity, represented by elevated creatinine, blood urea nitrogen, hyperkalaemia and reduction of the glomerular filtration rate, as well as vasoconstrictive effects, such as hypertension are among the most serious adverse effects.[19-22] There are also various neurotoxic adverse effects that can occur with systemic therapy. The major ones include mutism, aphasia, encephalopathy, seizures, psychosis, coma and focal disturbances. These reactions have an incidence of 5–10%. [23,24] Minor adverse effects such as headaches, transient, tremors, paraesthesias, photophobias, somnolence and insomnia occur in approximately 20% of individuals.[25,26] Systemic tacrolimus can also cause adverse reactions in the gastrointestinal system, causing diarrhoea, nausea, constipation, anorexia and vomiting. Respiratory disorders such as dyspnoea, pleural effusion and atelectasis, and cutaneous disorders, such as pruritus or a rash may develop. Other adverse effects include fever, pain, peripheral oedema, arthralgia and asthenia. Hypersensitivity reactions may also occur and may be due castor oil derivatives in the parenteral formulation.[24]
Side effects
Local irritant reactions (burning, stinging, erythema)
are a common side effect, but these usually resolve
within the first few days of treatment. The major
benefit of topical tacrolimus over topical corticosteroids
is that tacrolimus does not cause atrophy, striae, or
telangiectasia, even with chronic use.
References
1 Ruzicka T, Assmann T, Homey B. Tacrolimus: The drug for the turn of the millennium? Arch Dermatol 1999; 135: 574–580.
Lawrence ID. Tacrolimus (FK506): experience in dermatology. Dermatol Ther 1998; 5: 74–84.
Michel G, Kemeny L, Homey B, Ruzicka T. FK506 in the treatment of inflammatory skin disease: promises and perspectives. Immunol Today 1996; 17: 106–108.
Bieber T. Topical tacrolimus (FK506): a new milestone in the management of atopic dermatitis. J Allergy Clin Immunol 1998; 102: 555–557.
Ruzicka T, Bieber T, Schopf E et al. A short-term trial of tacrolimus ointment for atopic dermatitis. N Engl J Med 1997; 337: 816–821.
Alaiti S, Kang S, Fiedler VC et al. Tacrolimus (FK506) ointment for atopic dermatitis: a phase I study in adults and children. J Am Acad Dermatol 1998; 38: 69–76.
Hanifin JM, Chan S. Biochemical and immunologic mechanisms in atopic dermatitis: New targets for emerging therapies. J Am Acad Dermatol 1999; 41: 72–77.
Laurema AI, Granlund H, Reitamo S. Use of the newer immunosuppressive agents in dermatology. Bio Drugs 1997; 8: 96–106.
Shirbacheh MV, Jones JW, Harralson TA et al. Pharmacokinetics of intra-arterial delivery of tacrolimus to vascularly isolated rabbit forelimb. J Pharmacol Exp Ther 1999; 289: 1196–1201.
Perego C, Lattuada D, Casnici C et al. Evidence that SMS 201–995 enhances the immunosuppressive effect of FK506. Int J Immunopharmacol 1998; 20: 479–490.
Fleischer AB. Treatment of atopic dermatitis: Role of tacrolimus ointment as a topical noncorticosteroid therapy. J Allergy Clin Immunol 2000; 104: S126–S130.
Wollenberg A, Bieber T. FK-506/Tacrolimus. In: Burg G, Dummer RG, editors. Strategies for Immunointerventions in Dermatology. Springer-Verlag, Heidelberg, 1997: 53–57.
Columbo M, Bochner BS, Marone G. Human skin mast cells express functional beta1 integrins that mediate adhesion to extracellular martix proteins. J Immunol 1995; 154: 6058–6064.
Panhans-Gro? A, Novak N, Kraft S et al. Human epidermal Langerhans’ cells are targets for the immnosuppressive macrolide tacrolimus (FK506). J Allergy Clin Immunol 2001; 107: 345–352.
Reitamo S. Tacrolimus: a new topical immunomodulatory therapy for atopic dermatitis. J Allergy Clin Immunol 2001; 107: 445–448.
Nagai H, Hiyama H, Matsuo A et al. FK-506 and cyclosporin A potentiate the IgE antibody production by contact sensitization with hapten in mice. J Pharmacol Exp Ther 1997; 283: 321–327.
Homey B, Assmann T, Vohr H-W et al. Topical FK506 suppresses cytokine and costimulatory molecule expression in epidermal and local draining lymph node cells during primary skin immune responses. J Immunol 1998; 160: 5331–5340.
Leung DYM, Soter NA. Cellular and immunologic mechanisms in atopic dermatitis. J Am Acad Dermatol 2001; 44: S1–S12.
Nash RA, Etzioni R, Storb R et al. Tacrolimus (FK506) alone or in combination with methotrexate or methylprednisolone for the prevention of acute graft-versus-host disease after marrow transplantation from HLA-matched siblings: a single-center study. Blood 1995; 85: 3746–3753.
Nielsen FT, Leyssac PP, Kemp E et al. Nephrotoxicity of FK-506 in the rat. Studies on glomerular and tubular function, and on the relationship between efficacy and toxicity. Nephrol Dial Transplant 1995; 10: 334–340.
Nasr IS. Topical tacrolimus in dermatology. Clin Exp Dermatol 2000; 25: 250–254.
Compendium of Pharmaceuticals Specialties, 35th edn. Webcom Limited, Toronto, 2000: 1287–1292.
Manez R, Jain A, Marino IR, Thomson AW. Comparative evaluation of tacrolimus (FK506) and cyclosporin A as immunosuppressive agents. Transplant Rev 1995; 9: 63–76.
Nousari Hossein C, Sragovich A, Kimyai-Asadi A et al. Mycophenolate mofetil in autoimmune and inflammatory skin disorders. J Am Acad Dermatol 1999; 40: 265–268.
Ohashi Y, Minegishi M, Fujie H et al. Successful treatment of steroid-resistant severe acute GVHD with 24-h continuous infusion of FK506. Bone Marrow Transplant 1997; 19: 625–627.
Jegasothy BV, Ackerman CD, Todo S et al. Tacrolimus (FK506) – A new therapeutic agent for severe recalcitrant psoriasis. Arch Dermatol 1992; 128: 781–785.
References
1) Yu et al. (2006), Effects of cyclosporine A, FK506 and rapamycin on calcineurin phosphatase activity in mouse brain; IUBMB Life, 58 429
Originator
Fujisawa (Japan)
Indications
Tacrolimus is a macrolide lactone originally derived
from Streptomyces tsukubaensis. Although structurally
unrelated to cyclosporine, tacrolimus has a very similar
mechanism of action; that is, it blocks the production of
proinflammatory cytokines by T lymphocytes by inhibiting
calcineurin.Tacrolimus, however, appears to be
10 to 100 times as potent as an immunosuppressive.
Oral tacrolimus (FK506) is used for prevention of organ
rejection in recipients of renal and hepatic transplants.
Indications
Tacrolimus (Prograf) is a second-generation immunosuppressive
agent that has been approved for use in
liver transplantation. Its efficacy for other transplantations
is being evaluated. It has properties similar to
those of cyclosporine except that weight for weight it is
10 to 100 times more potent. It is a macrolide antibiotic
that selectively inhibits transcription of a specific set of
lymphokine genes in T lymphocytes (e.g., IL-2, IL-4, and
interferon-) and binds to cytoplasmic proteins in lymphocytes.
Although the binding proteins (cytophilins)
for cyclosporine and tacrolimus are different, they share
similar functions in that the cytophilins are important
for the intracellular folding of proteins. It is speculated
that these proteins are important in regulating gene expression
in T lymphocytes and that both drugs somehow
interfere in this process.
Absorption of tacrolimus from the gastrointestinal
(GI) tract is variable. It is extensively metabolized in
the liver and excreted in the urine.As with cyclosporine,
nephrotoxicity is its principal side effect.
Manufacturing Process
The novel 17-allyl-1,14-dihydroxy-12-[2-(4-hydroxy-3-methoxycyclohexyl)-1-
methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-
azatrcyclo[22.3.1.04,9]octacos-18-ene-2,3,10,16-tetraone (FR-900506),
substance can be produced by culturing a FR-900506 substance(s)-producing
strain belonging to the genus Streptomyces (e.g. Streptomyces tsukubaensis
No. 9993, FERM BP-927) in a nutrient medium.FermentationA culture medium (160 ml) containing glycerin (1%), corn starch (1%),
glucose (0.5%), cottonseed meal (1%), dried yeast (0.5%), corn steep liquor
(0.5%) and calcium carbonate (0.2%) (adjusted to pH 6.5) was poured into
each of ten 500 ml-Erlenmeyer flasks and sterilized at 120°C for 30 min. A
loopful of slant culture of Streptomyces tsukubaensis No. 9993 was inoculated
to each of the medium and cultured at 30°C for 4 days on a rotary shaker.
The resultant culture was inoculated to a medium containing soluble starch
(5%), peanut powder (0.5%), dried yeast (0.5%), gluten meal (0.5%),
calcium carbonate (0.1%) and Adekanol (deforming agent, Trade Mark, maker
Asasi Denka Co.) (0.1%) (150 liters) in a 200-liter jar-fermentor, which had
been sterilized at 120°C for 20 min in advance, and cultured at 30C for 4 days
under aeration of 150 liters/minutes and agitation of 250 rpm.Isolation and PurificationThe cultured broth thus obtained was filtered with an aid of diatomaseous
earth (5 kg). The mycelial cake was extracted with acetone (50 liters),
yielding 50 liters of the extract. The acetone extract from mycelium and the
filtrate (135 L) were combined and passed through a column of a non-ionic
adsorption resin "Diaion HP-20" (Trade Mark, maker Mitsubishi Chemical
Industries Ltd.) (10 L). After washing with water (30 L) and 50 % aqueous
acetone (30 L), elution was carried out with 75 aqueous acetone. The eluate
(30 liters) was evaporated under reduced pressure to give residual water (2
L). This residue was extracted with ethyl acetate (2 L) three times. The ethyl
acetate extract was concentrated under reduced pressure to give an oily
residue. The oily residue was mixed with twice weight of acidic silica gel
(special silica gel grade 12, maker Fuji Devison Co.), and this mixture was
slurried in ethyl acetate. After evaporating the solvent, the resultant dry
powder was subjected to column chromatography of the same acidic silica gel
(800 ml) which was packed with n-hexane. The column was developed with nhexane
(3 L), a mixture of n-hexane and ethyl acetate (4:1 v/v, 3 L) and
ethyl acetate (3 L). The fractions containing the object compound were
collected and concentrated under reduced pressure to give an oily residue.
The oily residue was dissolved in a mixture of n-hexane and ethyl acetate
(1:1 v/v, 30 ml) and subjected to column chromatography of silica gel (maker
Merck Co., Ltd. 230-400 mesh) (500 ml) packed with the same solvents
system. Elution was carried out with a mixture of n-hexane and ethyl acetate (1:1 v/v, 2 liters and 1:2 v/v, 1.5 L) and ethyl acetate (1.5 L). Fractions
containing the first object compound were collected and concentrated under
reduced pressure to give crude FR-900506 substance (3 g) in the form of
yellowish powder.This powder of the FR-900506 substance could be transformed into a form of
white crystals by recrystallization thereof from acetonitrile. Melting point:
127°-129°C.
Therapeutic Function
Immunosuppressive
Biochem/physiol Actions
Product does not compete with ATP.
Clinical Use
A topical formulation (Protopic) has recently been approved
for treatment of moderate to severe atopic dermatitis
in children and adults who have not responded
to other therapies. Levels of systemic absorption are
low even when applied to a relatively large body surface
area.
Veterinary Drugs and Treatments
Tacrolimus has recently been studied at the University of Tennessee
College of Veterinary Medicine where investigators found it equally
effective as cyclosporine and effective for cyclosporine-resistant
cases of KCS. It exerts its effects through a mechanism similar to
that of cyclosporine, however exact mechanisms of action in causing
tear production are still being determined.
Veterinary Drugs and Treatments
Tacrolimus ointment may be of benefit in veterinary patients in the adjunctive treatment of atopic dermatitis, discoid lupus erythematosus,
pemphigus erythematosus or foliaceous, pinnal vascular disease, alopecia areata, vitiligo and for perianal fistulas (terminal phase or
maintenance treatment after cyclosporine therapy). Unlike topical corticosteroids, tacrolimus or pimecrolimus do not have atrophogenic
or metabolic effects associated with long-term or large area treatment.
Tacrolimus acts similarly as cyclosporine, namely inhibiting T-lymphocyte activation primarily by inhibiting the phosphatase activity
of calcineurin. It also inhibits the release of inflammatory cytokines and mediators from mast cells and basophils.
in vitro
tacrolimus (fk506) has been reported to inhibit the interleukin 2(il-2) production and the response of mixed lymphocyte culture. in addition, tacrolimus (fk506) added to the cell cultures has been revealed to inhibit murine or human mixed lymphocyte reactivity and the generation of cytotoxic t cells. furermor, tacrolimus (fk506) has also been reported to dose-dependently suppress the production of various cytokines including il-2, il-3, il-4, and γ-interferon, in response to different stimulis. besides, tacrolimus has shown its efficacy in the prevention of allograft rejection in animal transplant models. tacrolimus has been found to be significantly efficient in experimental hepatic allografts, and has hepatotrophic properties [1].
Drug interactions
Potentially hazardous interactions with other drugs
Ciclosporin: may increase the half-life of ciclosporin
and exacerbate any toxic effects. The two should not
be prescribed concomitantly. Care should be taken
when converting from ciclosporin to tacrolimus.
Tacrolimus levels increased by: amlodipine,
atazanavir, basiliximab, boceprevir, bromocriptine,
chloramphenicol, cimetidine, cortisone, danazol,
dapsone, diltiazem, ergotamine, ethinyloestradiol,
felodipine, fosamprenavir, gestodene, grapefruit
juice, imidazole and triazole antifungals, lidocaine,
lansoprazole, possibly levofloxacin, macrolides,
midazolam, nicardipine, nifedipine, norethisterone,
omeprazole, pantoprazole, posaconazole, ranolazine;
ritonavir, saquinavir, Chinese herbal remedies
containing extracts of Schisandra sphenanthera,
tamoxifen, theophylline, verapamil and voriconazole.
Tacrolimus levels decreased by: carbamazepine,
caspofungin, fosphenytoin, isoniazid, phenobarbital,
phenytoin (fosphenytoin and phenytoin levels
possibly increased), primidone, rifampicin, possibly
rifabutin and St John’s wort. Increased nephrotoxicity with: aminoglycosides,
amphotericin, NSAIDs, sulfamethoxazole,
trimethoprim and vancomycin.
Increased risk of hyperkalaemia with: potassiumsparing-diuretics and potassium salts.
Anticoagulants: possibly increases concentration of
dabigatran - avoid.
Antipsychotics: avoid with droperidol, increased risk
of ventricular arrhythmias.
Antivirals: increased risk of nephrotoxicity with
acyclovir, ganciclovir, valaciclovir and valganciclovir;
concentration affected by efavirenz; concentration of
both drugs increased with telaprevir; concomitant
use with dasabuvir and ombitasvir/paritaprevir/
ritonavir is not recommended unless the benefits
outweigh the risks, if used concomitantly, tacrolimus
should not be administered on the day dasabuvir
and ombitasvir/paritaprevir/ritonavir are initiated.
Beginning the day after dasabuvir and ombitasvir/
paritaprevir/ritonavir are initiated; reinitiate
tacrolimus at a reduced dose based on tacrolimus
levels. The recommended tacrolimus dosing is 0.5
mg every 7 days, monitor levels at initiation and
throughout treatment.
Clotrimazole: more than doubles the bioavailability
of tacrolimus (US-based researchers report that
concomitant clotrimazole substantially increases
the relative oral bioavailability of tacrolimus in renal
transplant recipients. Inpharma. 2005 Dec 10; 1517:
15).
Cytotoxics: concentration of afatinib possibly
increased - separate dose by 6-12 hours; use
crizotinib with caution; concentration increased by
imatinib.
Metabolism
Tacrolimus is extensively bound to erythrocytes in the
blood, and variations in red cell binding account for much
of the variability in pharmacokinetics. It is extensively
metabolised in the liver, mainly by cytochrome P450
isoenzyme CYP3A4, and excreted, primarily in bile,
almost entirely as metabolites. Considerable metabolism
also occurs in the intestinal wall.There are several metabolites identified. Only one of
these has been shown in vitro to have immunosuppressive
activity similar to that of tacrolimus. The other
metabolites have only weak or no immunosuppressive
activity. In systemic circulation only one of the inactive
metabolites is present at low concentrations. Therefore,
metabolites do not contribute to pharmacological activity
of tacrolimus.
Check Digit Verification of cas no
The CAS Registry Mumber 104987-11-3 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,0,4,9,8 and 7 respectively; the second part has 2 digits, 1 and 1 respectively.
Calculate Digit Verification of CAS Registry Number 104987-11:
(8*1)+(7*0)+(6*4)+(5*9)+(4*8)+(3*7)+(2*1)+(1*1)=133
133 % 10 = 3
So 104987-11-3 is a valid CAS Registry Number.
InChI:InChI=1/C44H69NO12/c1-10-13-31-19-25(2)18-26(3)20-37(54-8)40-38(55-9)22-28(5)44(52,57-40)41(49)42(50)45-17-12-11-14-32(45)43(51)56-39(29(6)34(47)24-35(31)48)27(4)21-30-15-16-33(46)36(23-30)53-7/h10,19,21,26,28-34,36-40,46-47,52H,1,11-18,20,22-24H2,2-9H3/b25-19-,27-21+/t26-,28+,29+,30-,31+,32-,33+,34-,36+,37-,38-,39+,40+,44+/m0/s1
104987-11-3Relevant articles and documents
Synthesis and characterization of an epimer of tacrolimus, an immunosuppressive drug
Skytte, Dorthe M.,Frydenvang, Karla,Hansen, Liselotte,Nielsen, Peter G.,Jaroszewski, Jerzy W.
, p. 776 - 779 (2010)
8-Epitacrolimus (2), a new l-pipecolic acid macrolide lactone, was obtained by base-catalyzed epimerization of tacrolimus (FK-506, 1), an important immunosuppressive drug, and its structure determined by a single-crystal X-ray diffraction method. The compound was fully characterized by spectroscopic techniques. The epimer is of importance due to its potential biological effects as well as because of its possible formation during formulation, handling, and use of tacrolimus products.
Some transformations of tacrolimus, an immunosuppressive drug
Skytte, Dorthe M.,Jaroszewski, Jerzy W.,Johansen, Kenneth T.,Hansen, Steen Honore,Hansen, Liselotte,Nielsen, Peter G.,Frydenvang, Karla
, p. 514 - 522 (2013/05/21)
Transformations of the macrocyclic lactone tacrolimus (1), an important immunosuppressive drug produced by Streptomyces species, are described. These transformation products are primarily of interest as reference substances for drug impurity analyses. Upon action of acid (p-toluenesulfonic acid in toluene), tacrolimus is dehydrated by loss of water from the b-hydroxyketone moiety with partial inversion of configuration at C-8, resulting in formation of 5-deoxy-D5,6-tacrolimus and 5-deoxy-δ5,β-8-epitacrolimus. The structure of the latter was determined by single-crystal X-ray crystallography. The same products are formed upon action of free radicals (iodine in boiling toluene), along with formation of 8- epitacrolimus. The latter is converted by p-toluenesulfonic acid to 5-deoxy-D5,6-8-epitacrolimus. Treatment of tacrolimus with weak base (1,5-diazabicyclo[4.3.0]nonene) gives, in addition to 8-epitacrolimus, the open-chain acid corresponding to 5-deoxy-Δ5,β-tacrolimus, a rare non-cyclic derivative of tacrolimus. Strong base (t-butoxide) causes pronounced degradation of the molecule. Thermolysis of tacrolimus leads to ring expansion by an apparent [3,3]-sigmatropic rearrangement of the allylic ester moiety with subsequent loss of water from the b-hydroxyketone moiety. 1H and 13C NMR spectra of the obtained compounds, complicated by the presence of amide bond rotamers and ketal moiety tautomers, were assigned by extensive use of 2D NMR techniques.
Characterization of FK506 biosynthetic intermediates involved in post-PKS elaboration
Ban, Yeon Hee,Shinde, Pramod B.,Hwang, Jae-Yeon,Song, Myoung-Chong,Kim, Dong Hwan,Lim, Si-Kyu,Sohng, Jae Kyung,Yoon, Yeo Joon
, p. 1091 - 1098 (2013/07/26)
The post-PKS modification steps of FK506 biosynthesis include C9-oxidation and 31-O-methylation, but the sequence of these reactions and the exact route have remained unclear. This study details the post-PKS modification pathways in FK506 biosynthesis thr
PROCESS FOR PURIFICATION OF MACROLIDES
-
Page/Page column 2; 3, (2008/12/05)
The invention is a novel process for purification of macrolides such as Tacrolimus using a new polymer resin and copper salts containing cupric ions. The novel polymer resin contains polyvinyl pyrrolidone, metha acrylate, divinyl benzene based compounds. In the said process manufacturing of new polymer resin and use of cupric salt is very much cost effective. The same metal salts can also be used along with other neutral non-ionic adsorption resins of polyethylene i e HP2O, HP2OSS, Sepabeads SP207 and the like. The concentration of copper ions may be generally 0.20 to 1.5 mol/L, preferably 0.30 to 0.40 mol/L. As an aqueous medium for the copper ion containing aqueous solvent, an aqueous acetone, an aqueous alcohol, an aqueous acetonitrile or the like. The invention covers Tacrolimus having a purity of more than 99.7%.
A PROCESS FOR PURIFICATION OF MACROLIDES
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Page/Page column 5-6, (2008/06/13)
The present invention relates to a process for separating a macrolide from a mixture comprising homologs, analogs or isomers thereof by using silver-impregnated silica gel chromatography.
METHOD OF PURIFYING MACROLIDES
-
Page/Page column 10-15, (2008/06/13)
A method for purifying macrolide is provided in which a loading charge of macrolide is placed in juxtaposition with a bed of wet sorption resin, the loading charge and bed are eluted at a temperature greater than 30°C with an eluent of an organic solvent selected from the group consisting of THF, acetonitrile, n-propyl alcohol, iso-propyl alcohol, ethyl alcohol, and acetone, the heart cut of the eluent is collected, and purified macrolide is collected.
METHOD OF PURIFYING MACROLIDES
-
Page 13-14, (2008/06/13)
Provided is a method of purifying a macrolide, especially tacrolimus, that includes loading macrolide onto a bed of sorption resin and elting with a suitable eluent such as a combination of water and tetrahydrofuran.
A PROCESS FOR THE RECOVERY OF SUBSTANTIALLY PURE TRICYCLIC MACROLIDE
-
Page/Page column 8-9, (2008/06/13)
Process for the recovery of a macrolide in substantially pure form comprising: a) treating the macrolide with water immiscible solvent followed by concentration, b) mixing with water, water miscible solvent or mixture thereof, c) performing hydrophobic interaction chromatography and collecting the fractions, d)extracting the fraction containing macrolide with water immiscible solvent followed by concentration, e) adding water miscible solvent to effect separation of impurities from the macrolide compound, f) performing silica gel chromatography and collecting the fractions, g) isolating the macrolide compound in substantially pure form. The macrolide is preferably rapamycin, tacrolimus or immunomycin.
CRYSTALLIZATION AND PURIFICATION OF MACROLIDES
-
Page 8-9, (2008/06/13)
Provided is a method for crystallization and purification of a macrolide such as tacrolimus, sirolimus, pimecrolimus, or everolimus that includes the step of providing a combination of a macrolide, and a polar solvent, dopolar aprotic solvent, or hydrocarbon solvent at pH of 7 or above.
Rapid synthesis of 11C-labeled FK506 for positron emission tomography
Murakami, Yoshihiro,Kuroda, Akio,Osoda, Kazuhiko,Nishimura, Shintaro
, p. 641 - 644 (2007/10/03)
The present study describes a rapid synthesis method for labeled [11C]FK506 for positron emission tomography (PET). A one-pot reaction from [11C]CH3I, involving a Wittig reaction as the key carbon-carbon bond formation was developed. The chemical process was accomplished using a designed, fully automated synthetic apparatus, and an injectable solution of [11C]FK506 was obtained in only 34 min from [11C]CH3I. The decay-corrected radiochemical yield based on [11C]CH3I was 11.9%, and the specific activity was 39.8 GBq/μmol.
