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Statements

Subject Item
n2:DB00864
rdf:type
n3:Drug
n3:description
Tacrolimus (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.
n3:dosage
n4:271B51F8-363D-11E5-9242-09173F13E4C5 n4:271B51E9-363D-11E5-9242-09173F13E4C5 n4:271B51EA-363D-11E5-9242-09173F13E4C5 n4:271B51EB-363D-11E5-9242-09173F13E4C5 n4:271B51EC-363D-11E5-9242-09173F13E4C5 n4:271B51E8-363D-11E5-9242-09173F13E4C5 n4:271B51F5-363D-11E5-9242-09173F13E4C5 n4:271B51F6-363D-11E5-9242-09173F13E4C5 n4:271B51F7-363D-11E5-9242-09173F13E4C5 n4:271B51F1-363D-11E5-9242-09173F13E4C5 n4:271B51F2-363D-11E5-9242-09173F13E4C5 n4:271B51F3-363D-11E5-9242-09173F13E4C5 n4:271B51F4-363D-11E5-9242-09173F13E4C5 n4:271B51F0-363D-11E5-9242-09173F13E4C5 n4:271B51ED-363D-11E5-9242-09173F13E4C5 n4:271B51EE-363D-11E5-9242-09173F13E4C5 n4:271B51EF-363D-11E5-9242-09173F13E4C5
n3:generalReferences
# 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. "Pubmed":http://www.ncbi.nlm.nih.gov/pubmed/2445721 # Pritchard DI: Sourcing a chemical succession for cyclosporin from parasites and human pathogens. Drug Discov Today. 2005 May 15;10(10):688-91. "Pubmed":http://www.ncbi.nlm.nih.gov/pubmed/15896681 # 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. "Pubmed":http://www.ncbi.nlm.nih.gov/pubmed/1715244 # 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. "Pubmed":http://www.ncbi.nlm.nih.gov/pubmed/16702731 # 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. "Pubmed":http://www.ncbi.nlm.nih.gov/pubmed/16021174 # FDA label
n3:group
approved investigational
n3:halfLife
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.
n3:indication
For 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.
n3:manufacturer
n10:271B51D4-363D-11E5-9242-09173F13E4C5 n10:271B51D7-363D-11E5-9242-09173F13E4C5 n10:271B51D8-363D-11E5-9242-09173F13E4C5 n10:271B51D5-363D-11E5-9242-09173F13E4C5 n10:271B51D6-363D-11E5-9242-09173F13E4C5
owl:sameAs
n18:DB00864 n29:DB00864
dcterms:title
Tacrolimus
adms:identifier
n15:D00107 n16:Tacrolimus n19:61049 n22:C01375 n23:0469-0607-73 n24:DB00864 n25:445647 n26:46506004 n27:FK5 n28:PA451578
n3:mechanismOfAction
The 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.
n3:packager
n10:271B51D3-363D-11E5-9242-09173F13E4C5 n10:271B51D1-363D-11E5-9242-09173F13E4C5 n10:271B51D2-363D-11E5-9242-09173F13E4C5 n10:271B51CF-363D-11E5-9242-09173F13E4C5 n10:271B51D0-363D-11E5-9242-09173F13E4C5 n10:271B51CE-363D-11E5-9242-09173F13E4C5 n10:271B51CC-363D-11E5-9242-09173F13E4C5 n10:271B51CD-363D-11E5-9242-09173F13E4C5 n10:271B51CA-363D-11E5-9242-09173F13E4C5 n10:271B51CB-363D-11E5-9242-09173F13E4C5 n10:271B51C8-363D-11E5-9242-09173F13E4C5 n10:271B51C9-363D-11E5-9242-09173F13E4C5 n10:271B51C7-363D-11E5-9242-09173F13E4C5
n3:patent
n9:5260301 n9:2037408 n9:5665727 n9:1338491
n3:routeOfElimination
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%.
n3:synonym
(-)-FK 506 Prograf 8-DEETHYL-8-[but-3-enyl]-ascomycin FK 506 FK506 Tacrolimus anhydrous
n3:toxicity
Side 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. LD<sub>50</sub>=134-194 mg/kg (rat).
n3:volumeOfDistribution
* 2.6 ± 2.1 L/kg [pediatric liver transplant patients] * 1.07 ± 0.20 L/kg [patients with renal impairment, 0.02 mg/kg/4 hr dose, IV] * 3.1 ± 1.6 L/kg [Mild Hepatic Impairment, 0.02 mg/kg/4 hr dose, IV] * 3.7 ± 4.7 L/kg [Mild Hepatic Impairment, 7.7 mg dose, PO] * 3.9 ± 1.0 L/kg [Severe hepatic impairment, 0.02 mg/kg/4 hr dose, IV] * 3.1 ± 3.4 L/kg [Severe hepatic impairment, 8 mg dose, PO]
n11:hasAHFSCode
n13:84-92-00 n13:92-00-00
n3:foodInteraction
The time of the meal affects tacrolimus bioavailability. Take tacrolimus capsules consistently everyday either with or without food. Food, especially food with a high-fat content, decreases the rate and extent of absorption.
n3:proteinBinding
~99% bound to human plasma protein, primarily to albumin and alpha-1-acid glycoprotein. This is independent of concentration over a range of 5-50 ng/mL.
n3:salt
n3:synthesisReference
Pan Sup Chang, Hoon Cho, "Water soluble polymer-tacrolimus conjugated compounds and process for preparing the same." U.S. Patent US5922729, issued April, 1997.
n30:hasConcept
n31:M0025261
foaf:page
n8:tacrolimus.htm n20:tacrolimus.html
n3:IUPAC-Name
n6:271B51FD-363D-11E5-9242-09173F13E4C5
n3:InChI
n6:271B5203-363D-11E5-9242-09173F13E4C5
n3:Molecular-Formula
n6:271B5202-363D-11E5-9242-09173F13E4C5
n3:Molecular-Weight
n6:271B51FF-363D-11E5-9242-09173F13E4C5
n3:Monoisotopic-Weight
n6:271B5200-363D-11E5-9242-09173F13E4C5
n3:SMILES
n6:271B5201-363D-11E5-9242-09173F13E4C5
n3:Water-Solubility
n6:271B51FB-363D-11E5-9242-09173F13E4C5 n6:271B5213-363D-11E5-9242-09173F13E4C5
n3:logP
n6:271B51F9-363D-11E5-9242-09173F13E4C5 n6:271B51FC-363D-11E5-9242-09173F13E4C5 n6:271B5215-363D-11E5-9242-09173F13E4C5
n3:logS
n6:271B51FA-363D-11E5-9242-09173F13E4C5
n11:hasATCCode
n12:L04AD02 n12:D11AH01
n3:H-Bond-Acceptor-Count
n6:271B5209-363D-11E5-9242-09173F13E4C5
n3:H-Bond-Donor-Count
n6:271B520A-363D-11E5-9242-09173F13E4C5
n3:InChIKey
n6:271B5204-363D-11E5-9242-09173F13E4C5
n3:Polar-Surface-Area--PSA-
n6:271B5205-363D-11E5-9242-09173F13E4C5
n3:Polarizability
n6:271B5207-363D-11E5-9242-09173F13E4C5
n3:Refractivity
n6:271B5206-363D-11E5-9242-09173F13E4C5
n3:Rotatable-Bond-Count
n6:271B5208-363D-11E5-9242-09173F13E4C5
n3:absorption
Absorption of tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable. The absolute bioavailability in adult kidney transplant patients is 17±10%; in adults liver transplant patients is 22±6%; in healthy subjects is 18±5%. The absolute bioavailability in pediatric liver transplant patients was 31±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.
n3:affectedOrganism
Humans and other mammals
n3:casRegistryNumber
104987-11-3
n3:clearance
* 0.040 L/hr/kg [healthy subjects, IV] * 0.172 ± 0.088 L/hr/kg [healthy subjects, oral] * 0.083 L/hr/kg [adult kidney transplant patients, IV] * 0.053 L/hr/kg [adult liver transplant patients, IV] * 0.051 L/hr/kg [adult heart transplant patients, IV] * 0.138 ± 0.071 L/hr/kg [pediatric liver transplant patients] * 0.12 ± 0.04 (range 0.06-0.17) L/hr/kg [pediatric kidney transplant patients] * 0.038 ± 0.014 L/hr/kg [patients with renal impairment, 0.02 mg/kg/4 hr dose, IV] * 0.042 ± 0.02 L/hr/kg [Mild Hepatic Impairment, 0.02 mg/kg/4 hr dose, IV] * 0.034 ± 0.019 L/hr/kg [Mild Hepatic Impairment, 7.7 mg dose, PO] * 0.017 ± 0.013 L/hr/kg [Severe hepatic impairment, 0.02 mg/kg/4 hr dose, IV] * 0.016 ± 0.011 L/hr/kg [Severe hepatic impairment, 8 mg dose, PO]
n3:containedIn
n5:271B51E0-363D-11E5-9242-09173F13E4C5 n5:271B51DD-363D-11E5-9242-09173F13E4C5 n5:271B51DE-363D-11E5-9242-09173F13E4C5 n5:271B51E7-363D-11E5-9242-09173F13E4C5 n5:271B51E5-363D-11E5-9242-09173F13E4C5 n5:271B51E6-363D-11E5-9242-09173F13E4C5 n5:271B51DB-363D-11E5-9242-09173F13E4C5 n5:271B51DC-363D-11E5-9242-09173F13E4C5 n5:271B51D9-363D-11E5-9242-09173F13E4C5 n5:271B51DA-363D-11E5-9242-09173F13E4C5 n5:271B51E3-363D-11E5-9242-09173F13E4C5 n5:271B51E4-363D-11E5-9242-09173F13E4C5 n5:271B51E1-363D-11E5-9242-09173F13E4C5 n5:271B51E2-363D-11E5-9242-09173F13E4C5 n5:271B51DF-363D-11E5-9242-09173F13E4C5
n3:Bioavailability
n6:271B520F-363D-11E5-9242-09173F13E4C5
n3:Ghose-Filter
n6:271B5211-363D-11E5-9242-09173F13E4C5
n3:MDDR-Like-Rule
n6:271B5212-363D-11E5-9242-09173F13E4C5
n3:Melting-Point
n6:271B5214-363D-11E5-9242-09173F13E4C5
n3:Number-of-Rings
n6:271B520E-363D-11E5-9242-09173F13E4C5
n3:Physiological-Charge
n6:271B520D-363D-11E5-9242-09173F13E4C5
n3:Rule-of-Five
n6:271B5210-363D-11E5-9242-09173F13E4C5
n3:Traditional-IUPAC-Name
n6:271B51FE-363D-11E5-9242-09173F13E4C5
n3:pKa--strongest-acidic-
n6:271B520B-363D-11E5-9242-09173F13E4C5
n3:pKa--strongest-basic-
n6:271B520C-363D-11E5-9242-09173F13E4C5