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Record Information
Version2.0
Creation Date2014-09-11 05:13:51 UTC
Update Date2014-12-24 20:26:56 UTC
Accession NumberT3D4732
Identification
Common NameTacrolimus
ClassSmall Molecule
DescriptionTacrolimus (also FK-506 or Fujimycin) is an immunosuppressive drug whose main use is after organ transplant to reduce the activity of the patient's immune system and so the risk of organ rejection. It is also used in a topical preparation in the treatment of severe atopic dermatitis, severe refractory uveitis after bone marrow transplants, and the skin condition vitiligo. It was discovered in 1984 from the fermentation broth of a Japanese soil sample that contained the bacteria Streptomyces tsukubaensis. Tacrolimus is chemically known as a macrolide. It reduces peptidyl-prolyl isomerase activity by binding to the immunophilin FKBP-12 (FK506 binding protein) creating a new complex. This FKBP12-FK506 complex interacts with and inhibits calcineurin thus inhibiting both T-lymphocyte signal transduction and IL-2 transcription.
Compound Type
  • Amide
  • Amine
  • Drug
  • Ester
  • Ether
  • Organic Compound
  • Synthetic Compound
Chemical Structure
Thumb
Synonyms
Synonym
(-)-FK 506
8-DEETHYL-8-[but-3-enyl]-ascomycin
Advagraf
FK 506
FK506
Hecoria
Prograf
Protopic
Tacrolimus anhydrous
Chemical FormulaC44H69NO12
Average Molecular Mass804.018 g/mol
Monoisotopic Mass803.482 g/mol
CAS Registry Number104987-11-3
IUPAC Name(1R,9S,12S,13R,14S,17R,18Z,21S,23S,24R,25S,27R)-1,14-dihydroxy-12-[(1E)-1-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]prop-1-en-2-yl]-23,25-dimethoxy-13,19,21,27-tetramethyl-17-(prop-2-en-1-yl)-11,28-dioxa-4-azatricyclo[22.3.1.0^{4,9}]octacos-18-ene-2,3,10,16-tetrone
Traditional Name(1R,9S,12S,13R,14S,17R,18Z,21S,23S,24R,25S,27R)-1,14-dihydroxy-12-[(1E)-1-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]prop-1-en-2-yl]-23,25-dimethoxy-13,19,21,27-tetramethyl-17-(prop-2-en-1-yl)-11,28-dioxa-4-azatricyclo[22.3.1.0^{4,9}]octacos-18-ene-2,3,10,16-tetrone
SMILES[H]\C(=C(\C)[C@@]1([H])OC(=O)[C@]2([H])CCCCN2C(=O)C(=O)[C@]2(O)O[C@@]([H])([C@]([H])(C[C@@]2([H])C)OC)[C@]([H])(C[C@@]([H])(C)CC(C)=C([H])[C@@]([H])(CC=C)C(=O)C[C@]([H])(O)[C@@]1([H])C)OC)[C@]1([H])CC[C@@]([H])(O)[C@@]([H])(C1)OC
InChI IdentifierInChI=1S/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
InChI KeyInChIKey=QJJXYPPXXYFBGM-LJIGMGMYSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as macrolide lactams. These are cyclic polyketides containing both a cyclic amide and a cyclic ester group.
KingdomOrganic compounds
Super ClassPhenylpropanoids and polyketides
ClassMacrolide lactams
Sub ClassNot Available
Direct ParentMacrolide lactams
Alternative Parents
Substituents
  • Macrolide lactam
  • Alpha-amino acid ester
  • Macrolide
  • Alpha-amino acid or derivatives
  • Cyclohexanol
  • Oxane
  • Piperidine
  • Cyclic alcohol
  • Tertiary carboxylic acid amide
  • Cyclic ketone
  • Secondary alcohol
  • Carboxamide group
  • Carboxylic acid ester
  • Hemiacetal
  • Ketone
  • Lactam
  • Lactone
  • Organoheterocyclic compound
  • Azacycle
  • Carboxylic acid derivative
  • Oxacycle
  • Dialkyl ether
  • Ether
  • Monocarboxylic acid or derivatives
  • Organopnictogen compound
  • Alcohol
  • Organic oxygen compound
  • Carbonyl group
  • Organooxygen compound
  • Organonitrogen compound
  • Organic nitrogen compound
  • Hydrocarbon derivative
  • Organic oxide
  • Aliphatic heteropolycyclic compound
Molecular FrameworkAliphatic heteropolycyclic compounds
External DescriptorsNot Available
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Membrane
Biofluid LocationsNot Available
Tissue LocationsNot Available
PathwaysNot Available
ApplicationsNot Available
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite powder.
Experimental Properties
PropertyValue
Melting Point126°C
Boiling PointNot Available
SolubilityInsoluble
LogP3.3
Predicted Properties
PropertyValueSource
Water Solubility0.004 g/LALOGPS
logP3.19ALOGPS
logP5.59ChemAxon
logS-5.3ALOGPS
pKa (Strongest Acidic)9.96ChemAxon
pKa (Strongest Basic)-2.9ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count11ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area178.36 ŲChemAxon
Rotatable Bond Count7ChemAxon
Refractivity215.62 m³·mol⁻¹ChemAxon
Polarizability88.14 ųChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyView
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TMS_1_1) - 70eV, PositiveNot AvailableJSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TMS_1_2) - 70eV, PositiveNot AvailableJSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TMS_1_3) - 70eV, PositiveNot AvailableJSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TMS_1_4) - 70eV, PositiveNot AvailableJSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (TMS_1_5) - 70eV, PositiveNot AvailableJSpectraViewer
LC-MS/MSLC-MS/MS Spectrum - Linear Ion Trap , negativesplash10-0gvo-0000192300-507c8bb18631e452a484JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - Linear Ion Trap , positivesplash10-066r-0000119030-65296f545a06c11d017bJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - Linear Ion Trap , positivesplash10-001i-0000009120-d1952a63d681e01b0eecJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 40V, Negativesplash10-0gb9-0973261100-2ee28926fa74ad5bfbf7JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 20V, Negativesplash10-0udi-0225271390-6837305c39f6b65c92faJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - 10V, Negativesplash10-0udi-0220030290-ceafe80295758dda73b4JSpectraViewer | MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0f79-0200001930-3416d86dc0d61354fd20JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-014u-1400003900-1705b8ca1b5858186d96JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-00rf-5200008900-20683c9798305f220c92JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0udi-0000000490-b536a515071aa91b3d99JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0uei-0000000920-face0da2f9f0fced4ae7JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0a4r-3000001900-75ecdc7e12ec9d9989ccJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-0udi-0100000950-1c5a13554e5f7c0cb19dJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-0udj-0000000910-da1939239c06f39a19e5JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-03di-6100001900-2b571619b8d121a40470JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0udi-0000000490-edb714c334df2df2491bJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0udi-0000001940-b4cff31e71a4daf5e13fJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0nmi-2000009410-12aa8c80b0c1ed3b8a6bJSpectraViewer
Toxicity Profile
Route of ExposureAbsorption of tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable. The absolute bioavailability in adult kidney transplant patients is 17Њ±10%; in adults liver transplant patients is 22Њ±6%; in healthy subjects is 18Њ±5%. The absolute bioavailability in pediatric liver transplant patients was 31Њ±24%. Tacrolimus maximum blood concentrations (Cmax) and area under the curve (AUC) appeared to increase in a dose-proportional fashion in 18 fasted healthy volunteers receiving a single oral dose of 3, 7, and 10 mg. When given without food, the rate and extent of absorption were the greatest. The time of the meal also affected bioavailability. When given immediately after a meal, mean Cmax was reduced 71%, and mean AUC was reduced 39%, relative to the fasted condition. When administered 1.5 hours following the meal, mean Cmax was reduced 63%, and mean AUC was reduced 39%, relative to the fasted condition.
Mechanism of ToxicityThe mechanism of action of tacrolimus in atopic dermatitis is not known. While the following have been observed, the clinical significance of these observations in atopic dermatitis is not known. It has been demonstrated that tacrolimus inhibits T-lymphocyte activation by first binding to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin is inhibited. This prevents the dephosphorylation and translocation of nuclear factor of activated T-cells (NF-AT), a nuclear component thought to initiate gene transcription for the formation of lymphokines. Tacrolimus also inhibits the transcription for genes which encode IL-3, IL-4, IL-5, GM-CSF, and TNF-, all of which are involved in the early stages of T-cell activation. Additionally, tacrolimus has been shown to inhibit the release of pre-formed mediators from skin mast cells and basophils, and to downregulate the expression of FceRI on Langerhans cells.
MetabolismHepatic, extensive, primarily by CYP3A4. The major metabolite identified in incubations with human liver microsomes is 13-demethyl tacrolimus. In in vitro studies, a 31-demethyl metabolite has been reported to have the same activity as tacrolimus. Route of Elimination: In man, less than 1% of the dose administered is excreted unchanged in urine. When administered IV, fecal elimination accounted for 92.6±30.7%, urinary elimination accounted for 2.3±1.1%. Half Life: The elimination half life in adult healthy volunteers, kidney transplant patients, liver transplants patients, and heart transplant patients are approximately 35, 19, 12, 24 hours, respectively. The elimination half life in pediatric liver transplant patients was 11.5±3.8 hours, in pediatric kidney transplant patients was 10.2±5.0 (range 3.4-25) hours.
Toxicity ValuesLD50=134-194 mg/kg (rat).
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesFor use 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.
Minimum Risk LevelNot Available
Health EffectsNot Available
SymptomsSide effects can be severe and include blurred vision, liver and kidney problems (it is nephrotoxic), seizures, tremors, hypertension, hypomagnesemia, diabetes mellitus, hyperkalemia, itching, insomnia, confusion.
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00864
HMDB IDNot Available
PubChem Compound ID445647
ChEMBL IDCHEMBL269732
ChemSpider IDNot Available
KEGG IDC01375
UniProt IDNot Available
OMIM ID
ChEBI ID61049
BioCyc IDNot Available
CTD IDNot Available
Stitch IDNot Available
PDB IDNot Available
ACToR IDNot Available
Wikipedia LinkTacrolimus
References
Synthesis Reference

Pan Sup Chang, Hoon Cho, “Water soluble polymer-tacrolimus conjugated compounds and process for preparing the same.” U.S. Patent US5922729, issued April, 1997.

MSDST3D4732.pdf
General References
  1. Kino T, Hatanaka H, Hashimoto M, Nishiyama M, Goto T, Okuhara M, Kohsaka M, Aoki H, Imanaka H: FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics. J Antibiot (Tokyo). 1987 Sep;40(9):1249-55. [2445721 ]
  2. Pritchard DI: Sourcing a chemical succession for cyclosporin from parasites and human pathogens. Drug Discov Today. 2005 May 15;10(10):688-91. [15896681 ]
  3. Liu J, Farmer JD Jr, Lane WS, Friedman J, Weissman I, Schreiber SL: Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell. 1991 Aug 23;66(4):807-15. [1715244 ]
  4. Fukatsu S, Fukudo M, Masuda S, Yano I, Katsura T, Ogura Y, Oike F, Takada Y, Inui K: Delayed effect of grapefruit juice on pharmacokinetics and pharmacodynamics of tacrolimus in a living-donor liver transplant recipient. Drug Metab Pharmacokinet. 2006 Apr;21(2):122-5. [16702731 ]
  5. Hanifin JM, Paller AS, Eichenfield L, Clark RA, Korman N, Weinstein G, Caro I, Jaracz E, Rico MJ: Efficacy and safety of tacrolimus ointment treatment for up to 4 years in patients with atopic dermatitis. J Am Acad Dermatol. 2005 Aug;53(2 Suppl 2):S186-94. [16021174 ]
  6. FDA label
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

General Function:
Type i transforming growth factor beta receptor binding
Specific Function:
Keeps in an inactive conformation TGFBR1, the TGF-beta type I serine/threonine kinase receptor, preventing TGF-beta receptor activation in absence of ligand. Recruites SMAD7 to ACVR1B which prevents the association of SMAD2 and SMAD3 with the activin receptor complex, thereby blocking the activin signal. May modulate the RYR1 calcium channel activity. PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides.
Gene Name:
FKBP1A
Uniprot ID:
P62942
Molecular Weight:
11950.665 Da
References
  1. Labrande C, Velly L, Canolle B, Guillet B, Masmejean F, Nieoullon A, Pisano P: Neuroprotective effects of tacrolimus (FK506) in a model of ischemic cortical cell cultures: role of glutamate uptake and FK506 binding protein 12 kDa. Neuroscience. 2006;137(1):231-9. Epub 2005 Nov 10. [16289353 ]
  2. Masri M, Rizk S, Barbari A, Stephan A, Kamel G, Rost M: An assay for the determination of sirolimus levels in the lymphocyte of transplant patients. Transplant Proc. 2007 May;39(4):1204-6. [17524933 ]