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Identification
NameTacrolimus
Accession NumberDB00864  (APRD00276, EXPT01437)
TypeSmall Molecule
GroupsApproved, Investigational
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.

Structure
Thumb
Synonyms
SynonymLanguageCode
(-)-FK 506Not AvailableNot Available
8-DEETHYL-8-[but-3-enyl]-ascomycinNot AvailableNot Available
FK 506Not AvailableNot Available
FK506Not AvailableNot Available
PrografNot AvailableNot Available
Tacrolimus anhydrousNot AvailableNot Available
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Prografcapsule, gelatin coated.5 mgoralAstellas Pharma US, Inc.1998-08-24Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Prografcapsule, gelatin coated1 mgoralAstellas Pharma US, Inc.1994-04-08Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Prografcapsule, gelatin coated5 mgoralAstellas Pharma US, Inc.1994-04-08Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Prografinjection, solution5 mg/mLintravenousAstellas Pharma US, Inc.1994-04-08Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Protopicointment.3 mg/gtopicalAstellas Pharma US Inc.2000-12-08Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Protopicointment1 mg/gtopicalAstellas Pharma US Inc.2000-12-08Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Prografcapsule, gelatin coated1 mgoralRebel Distributors Corp1994-04-08Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Prografcapsule, gelatin coated1 mgoralAphena Pharma Solutions Tennessee, Llc1994-04-08Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimusointment.3 mg/gtopicalPerrigo New York Inc2014-11-20Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimusointment1 mg/gtopicalPerrigo New York Inc2014-11-20Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Protopicointment1 mg/gtopicalPhysicians Total Care, Inc.2008-05-08Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Prografcapsule, gelatin coated1 mgoralCardinal Health1994-04-08Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Prografcapsule5 mgoralAstellas Pharma Canada IncNot AvailableNot AvailableCanada 5f16b84899037e23705f146ff57e3794121879cb055f0954756d94bc690476b4
Prografcapsule1 mgoralAstellas Pharma Canada IncNot AvailableNot AvailableCanada 5f16b84899037e23705f146ff57e3794121879cb055f0954756d94bc690476b4
Prografcapsule0.5 mgoralAstellas Pharma Canada IncNot AvailableNot AvailableCanada 5f16b84899037e23705f146ff57e3794121879cb055f0954756d94bc690476b4
Advagrafcapsule (extended release)0.5 mgoralAstellas Pharma Canada IncNot AvailableNot AvailableCanada 5f16b84899037e23705f146ff57e3794121879cb055f0954756d94bc690476b4
Advagrafcapsule (extended release)1 mgoralAstellas Pharma Canada IncNot AvailableNot AvailableCanada 5f16b84899037e23705f146ff57e3794121879cb055f0954756d94bc690476b4
Advagrafcapsule (extended release)5 mgoralAstellas Pharma Canada IncNot AvailableNot AvailableCanada 5f16b84899037e23705f146ff57e3794121879cb055f0954756d94bc690476b4
Advagrafcapsule (extended release)3 mgoralAstellas Pharma Canada IncNot AvailableNot AvailableCanada 5f16b84899037e23705f146ff57e3794121879cb055f0954756d94bc690476b4
Protopicointment0.1 %topicalAstellas Pharma Canada IncNot AvailableNot AvailableCanada 5f16b84899037e23705f146ff57e3794121879cb055f0954756d94bc690476b4
Protopicointment0.03 %topicalAstellas Pharma Canada IncNot AvailableNot AvailableCanada 5f16b84899037e23705f146ff57e3794121879cb055f0954756d94bc690476b4
Prografsolution5 mgintravenousAstellas Pharma Canada IncNot AvailableNot AvailableCanada 5f16b84899037e23705f146ff57e3794121879cb055f0954756d94bc690476b4
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Hecoriacapsule.5 mgoralNovartis Pharmaceuticals Corporation2011-12-20Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Hecoriacapsule1 mgoralNovartis Pharmaceuticals Corporation2011-12-20Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Hecoriacapsule5 mgoralNovartis Pharmaceuticals Corporation2011-12-20Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimusointment1 mg/gtopicalE. Fougera & Co. a division of Fougera Pharmaceuticals Inc.2014-09-09Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimusointment.3 mg/gtopicalE. Fougera & Co. a division of Fougera Pharmaceuticals Inc.2014-09-09Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimuscapsule1 mgoralKAISER FOUNDATION HOSPITALS2010-12-10Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimuscapsule.5 mgoralMylan Pharmaceuticals Inc.2012-07-23Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimuscapsule1 mgoralMylan Pharmaceuticals Inc.2012-07-23Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimuscapsule5 mgoralMylan Pharmaceuticals Inc.2012-07-23Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimuscapsule5 mgoralWatson Laboratories, Inc.2010-07-06Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimuscapsule.5 mgoralSandoz Inc2009-08-10Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimuscapsule1 mgoralSandoz Inc2009-08-10Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimuscapsule5 mgoralSandoz Inc2009-08-10Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimuscapsule.5 mgoralSandoz Inc2012-01-15Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimuscapsule1 mgoralSandoz Inc2012-01-15Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimuscapsule5 mgoralSandoz Inc2012-01-15Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimuscapsule1 mgoralMajor Pharmaceuticals2015-01-05Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimuscapsule.5 mgoralAccord Healthcare Inc.2011-08-31Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimuscapsule1 mgoralAccord Healthcare Inc.2011-08-31Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimuscapsule5 mgoralAccord Healthcare Inc.2011-08-31Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimuscapsule.5 mgoralIngenus Pharmaceuticals, LLC2012-09-28Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimuscapsule1 mgoralIngenus Pharmaceuticals, LLC2012-09-28Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimuscapsule5 mgoralIngenus Pharmaceuticals, LLC2012-09-28Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimuscapsule5 mgoralUDL Laboratories, Inc.2010-11-04Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimuscapsule.5 mgoralUDL Laboratories, Inc.2010-11-04Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimuscapsule1 mgoralUDL Laboratories, Inc.2010-11-04Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimuscapsule.5 mgoralDr. Reddy's Laboratories Limited2010-05-14Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimuscapsule1 mgoralDr. Reddy's Laboratories Limited2010-05-14Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimuscapsule5 mgoralDr. Reddy's Laboratories Limited2010-05-14Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimuscapsule1 mgoralCardinal Health2011-06-15Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimuscapsule.5 mgoralCardinal Health2011-06-15Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimuscapsule1 mgoralCardinal Health2013-07-17Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimuscapsule1 mgoralCardinal Health2009-08-10Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimuscapsule1 mgoralCardinal Health2009-08-10Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimuscapsule, gelatin coated.5 mgoralKremers Urban Pharmaceuticals Inc.2012-10-30Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimuscapsule, gelatin coated1 mgoralKremers Urban Pharmaceuticals Inc.2012-10-30Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimuscapsule, gelatin coated5 mgoralKremers Urban Pharmaceuticals Inc.2012-10-30Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimuscapsule.5 mgoralStrides Arcolab Limited2014-08-13Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimuscapsule1 mgoralStrides Arcolab Limited2014-08-13Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimuscapsule5 mgoralStrides Arcolab Limited2014-08-13Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimuscapsule.5 mgoralAmerican Health Packaging2013-07-17Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimuscapsule1 mgoralAmerican Health Packaging2013-07-17Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Tacrolimuscapsule5 mgoralAmerican Health Packaging2013-07-17Not AvailableUs 0a2ef1ad1c84951dc1392a8bbe1f3cb241c91ed59e44ad8268635315440d978c
Over the Counter ProductsNot Available
International BrandsNot Available
Brand mixturesNot Available
Salts
Name/CASStructureProperties
Tacrolimus Hydrate
Thumb
  • InChI Key: NWJQLQGQZSIBAF-MLAUYUEBSA-N
  • Monoisotopic Mass: 821.492541363
  • Average Mass: 822.0334
DBSALT000167
CategoriesNot Available
CAS number104987-11-3
WeightAverage: 804.0182
Monoisotopic: 803.481976677
Chemical FormulaC44H69NO12
InChI KeyQJJXYPPXXYFBGM-LFZNUXCKSA-N
InChI
InChI=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
IUPAC Name
(1R,9S,12S,13R,14S,17R,18E,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[22.3.1.0⁴,⁹]octacos-18-ene-2,3,10,16-tetrone
SMILES
CO[C@@H]1C[C@@H](CC[C@H]1O)\C=C(/C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@]2(O)O[C@@H]([C@H](C[C@H]2C)OC)[C@H](C[C@@H](C)C\C(C)=C\[C@@H](CC=C)C(=O)C[C@H](O)[C@H]1C)OC
Taxonomy
DescriptionThis compound 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
  • Macrolide
  • Alpha-amino acid ester
  • Cyclohexanol
  • Piperidine
  • Oxane
  • Tertiary carboxylic acid amide
  • Cyclic alcohol
  • Cyclic ketone
  • Tertiary amine
  • Secondary alcohol
  • Lactone
  • Lactam
  • Ketone
  • Hemiacetal
  • Carboxylic acid ester
  • Carboxamide group
  • Oxacycle
  • Azacycle
  • Organoheterocyclic compound
  • Monocarboxylic acid or derivatives
  • Ether
  • Dialkyl ether
  • Carboxylic acid derivative
  • Hydrocarbon derivative
  • Organooxygen compound
  • Organonitrogen compound
  • Carbonyl group
  • Amine
  • Alcohol
  • Aliphatic heteropolycyclic compound
Molecular FrameworkAliphatic heteropolycyclic compounds
External Descriptors
Pharmacology
IndicationFor 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.
PharmacodynamicsTacrolimus is a macrolide antibiotic. It acts by reducing peptidyl-prolyl isomerase activity by binding to the immunophilin FKBP-12 (FK506 binding protein) creating a new complex. This inhibits both T-lymphocyte signal transduction and IL-2 transcription. Although this activity is similar to cyclosporine studies have shown that the incidence of acute rejection is reduced by tacrolimus use over cyclosporine. Tacrolimus has also been shown to be effective in the topical treatment of eczema, particularly atopic eczema. It suppresses inflammation in a similar way to steroids, but is not as powerful. An important dermatological advantage of tacrolimus is that it can be used directly on the face; topical steroids cannot be used on the face, as they thin the skin dramatically there. On other parts of the body, topical steroid are generally a better treatment.
Mechanism of actionThe 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.
AbsorptionAbsorption 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.
Volume of distribution
  • 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]
Protein binding~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.
Metabolism

Hepatic, 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.

SubstrateEnzymesProduct
Tacrolimus
31-O-DemethyltacrolimusDetails
Tacrolimus
Not Available
13-demethyl tacrolimusDetails
Route of eliminationIn 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 lifeThe 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.
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]
ToxicitySide 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. LD50=134-194 mg/kg (rat).
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug Reactions
Interacting Gene/EnzymeSNP RS IDAllele nameDefining changeAdverse ReactionReference(s)
Multidrug resistance protein 1
Gene symbol: ABCB1
UniProt: P08183
rs2032582 Not AvailableT Allele (G2677T)Increased risk of neurotoxicity12352921
ADMET
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption-0.8264
Blood Brain Barrier-0.9659
Caco-2 permeable-0.5977
P-glycoprotein substrateSubstrate0.7862
P-glycoprotein inhibitor IInhibitor0.8687
P-glycoprotein inhibitor IIInhibitor0.7974
Renal organic cation transporterNon-inhibitor0.8135
CYP450 2C9 substrateNon-substrate0.9116
CYP450 2D6 substrateNon-substrate0.9116
CYP450 3A4 substrateSubstrate0.7435
CYP450 1A2 substrateNon-inhibitor0.8874
CYP450 2C9 substrateNon-inhibitor0.9053
CYP450 2D6 substrateNon-inhibitor0.9402
CYP450 2C19 substrateNon-inhibitor0.8969
CYP450 3A4 substrateNon-inhibitor0.869
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9807
Ames testNon AMES toxic0.6355
CarcinogenicityNon-carcinogens0.9422
BiodegradationNot ready biodegradable0.9698
Rat acute toxicity2.7541 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9817
hERG inhibition (predictor II)Non-inhibitor0.8733
Pharmacoeconomics
Manufacturers
  • Astellas pharma us inc
  • Dr reddys laboratories ltd
  • Sandoz inc
  • Watson laboratories inc
  • Astellas Pharma US
Packagers
Dosage forms
FormRouteStrength
Capsuleoral.5 mg
Capsuleoral0.5 mg
Capsuleoral1 mg
Capsuleoral5 mg
Capsule (extended release)oral0.5 mg
Capsule (extended release)oral1 mg
Capsule (extended release)oral3 mg
Capsule (extended release)oral5 mg
Capsule, gelatin coatedoral.5 mg
Capsule, gelatin coatedoral1 mg
Capsule, gelatin coatedoral5 mg
Injection, solutionintravenous5 mg/mL
Ointmenttopical.3 mg/g
Ointmenttopical0.03 %
Ointmenttopical0.1 %
Ointmenttopical1 mg/g
Solutionintravenous5 mg
Prices
Unit descriptionCostUnit
Tacrolimus micronized powder2800.0USD g
Protopic 0.1% Ointment 60 gm Tube255.34USD tube
Protopic 0.03% Ointment 60 gm Tube251.17USD tube
Prograf 5 mg/ml ampule163.94USD ml
Protopic 0.03% Ointment 30 gm Tube132.99USD tube
Protopic 0.1% Ointment 30 gm Tube124.42USD tube
Prograf 5 mg capsule24.26USD capsule
Tacrolimus anhydrous 5 mg cap22.3USD each
Prograf 1 mg capsule4.85USD capsule
Tacrolimus 1 mg capsule4.64USD capsule
Tacrolimus anhydrous 1 mg cap4.46USD each
Protopic 0.1% ointment4.17USD g
Protopic 0.03% ointment4.09USD g
Prograf 0.5 mg capsule2.43USD capsule
Tacrolimus anhydrous 0.5 mg cap2.23USD each
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Patents
CountryPatent NumberApprovedExpires (estimated)
Canada13384911996-07-302013-07-30
Canada20374082002-12-172011-03-01
United States52603011994-02-282011-02-28
United States56657271994-09-092014-09-09
Properties
StateSolid
Experimental Properties
PropertyValueSource
melting point126 °CNot Available
water solubilityInsolubleFDA label
logP3.3Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.00402 mg/mLALOGPS
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 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity215.62 m3·mol-1ChemAxon
Polarizability87.41 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Mass Spec (NIST)Not Available
SpectraNot Available
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.

US5922729
General Reference
  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. Pubmed
  2. Pritchard DI: Sourcing a chemical succession for cyclosporin from parasites and human pathogens. Drug Discov Today. 2005 May 15;10(10):688-91. Pubmed
  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. Pubmed
  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. Pubmed
  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. Pubmed
  6. FDA label
External Links
ATC CodesD11AH01L04AD02
AHFS Codes
  • 84:92.00
  • 92:00.00
PDB Entries
FDA labelDownload (144 KB)
MSDSDownload (54.9 KB)
Interactions
Drug InteractionsNot Available
Food InteractionsNot Available

Targets

1. Peptidyl-prolyl cis-trans isomerase FKBP1A

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Peptidyl-prolyl cis-trans isomerase FKBP1A P62942 Details

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. Pubmed
  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. Pubmed

Enzymes

1. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed
  3. Ekins S, Bravi G, Wikel JH, Wrighton SA: Three-dimensional-quantitative structure activity relationship analysis of cytochrome P-450 3A4 substrates. J Pharmacol Exp Ther. 1999 Oct;291(1):424-33. Pubmed

2. Cytochrome P450 3A5

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A5 P20815 Details

References:

  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
  2. Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed

3. Cytochrome P450 3A7

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A7 P24462 Details

References:

  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.

Carriers

1. Serum albumin

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Serum albumin P02768 Details

References:

  1. FDA label

2. Alpha-1-acid glycoprotein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Alpha-1-acid glycoprotein 1 P02763 Details

References:

  1. FDA label

Transporters

1. Multidrug resistance protein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor inducer

Components

Name UniProt ID Details
Multidrug resistance protein 1 P08183 Details

References:

  1. Schuetz EG, Beck WT, Schuetz JD: Modulators and substrates of P-glycoprotein and cytochrome P4503A coordinately up-regulate these proteins in human colon carcinoma cells. Mol Pharmacol. 1996 Feb;49(2):311-8. Pubmed
  2. Saeki T, Ueda K, Tanigawara Y, Hori R, Komano T: Human P-glycoprotein transports cyclosporin A and FK506. J Biol Chem. 1993 Mar 25;268(9):6077-80. Pubmed
  3. Wandel C, Kim RB, Kajiji S, Guengerich P, Wilkinson GR, Wood AJ: P-glycoprotein and cytochrome P-450 3A inhibition: dissociation of inhibitory potencies. Cancer Res. 1999 Aug 15;59(16):3944-8. Pubmed
  4. Hashida T, Masuda S, Uemoto S, Saito H, Tanaka K, Inui K: Pharmacokinetic and prognostic significance of intestinal MDR1 expression in recipients of living-donor liver transplantation. Clin Pharmacol Ther. 2001 May;69(5):308-16. Pubmed
  5. Collett A, Tanianis-Hughes J, Hallifax D, Warhurst G: Predicting P-glycoprotein effects on oral absorption: correlation of transport in Caco-2 with drug pharmacokinetics in wild-type and mdr1a(-/-) mice in vivo. Pharm Res. 2004 May;21(5):819-26. Pubmed
  6. Quezada CA, Garrido WX, Gonzalez-Oyarzun MA, Rauch MC, Salas MR, San Martin RE, Claude AA, Yanez AJ, Slebe JC, Carcamo JG: Effect of tacrolimus on activity and expression of P-glycoprotein and ATP-binding cassette transporter A5 (ABCA5) proteins in hematoencephalic barrier cells. Biol Pharm Bull. 2008 Oct;31(10):1911-6. Pubmed

2. ATP-binding cassette sub-family A member 5

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
ATP-binding cassette sub-family A member 5 Q8WWZ7 Details

References:

  1. Quezada CA, Garrido WX, Gonzalez-Oyarzun MA, Rauch MC, Salas MR, San Martin RE, Claude AA, Yanez AJ, Slebe JC, Carcamo JG: Effect of tacrolimus on activity and expression of P-glycoprotein and ATP-binding cassette transporter A5 (ABCA5) proteins in hematoencephalic barrier cells. Biol Pharm Bull. 2008 Oct;31(10):1911-6. Pubmed

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Drug created on June 13, 2005 07:24 / Updated on September 16, 2013 17:12