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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
Salts
Name/CAS Structure Properties
Tacrolimus Hydrate
Thumb
  • InChI Key: NWJQLQGQZSIBAF-MLAUYUEBSA-N
  • Monoisotopic Mass: 821.492541363
  • Average Mass: 822.0334
DBSALT000167
Brand names
NameCompany
Advagraf Not Available
Hecoria Not Available
PrografNot Available
ProtopicNot Available
Brand mixturesNot Available
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,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
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
Mass SpecNot Available
Taxonomy
KingdomOrganic Compounds
SuperclassPhenylpropanoids and Polyketides
ClassMacrolide Lactams
SubclassNot Available
Direct parentMacrolide Lactams
Alternative parentsAlpha Amino Acid Esters; Macrolides and Analogues; Cyclohexanols; Piperidines; Oxanes; Tertiary Carboxylic Acid Amides; Ketones; Hemiacetals; Tertiary Amines; Carboxylic Acid Esters; Cyclic Alcohols and Derivatives; Carboxylic Acids; Polyamines
Substituentscyclohexanol; piperidine; oxane; tertiary carboxylic acid amide; cyclic alcohol; carboxamide group; hemiacetal; secondary alcohol; tertiary amine; ketone; carboxylic acid ester; carboxylic acid; carboxylic acid derivative; ether; polyamine; alcohol; organonitrogen compound; amine; carbonyl group
Classification descriptionThis compound belongs to the macrolide lactams. These are cyclic polyketides containing both a cyclic amide and a cyclic ester group.
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
Property Value Probability
Human Intestinal Absorption - 0.8264
Blood Brain Barrier - 0.9659
Caco-2 permeable - 0.5977
P-glycoprotein substrate Substrate 0.7862
P-glycoprotein inhibitor I Inhibitor 0.8687
P-glycoprotein inhibitor II Inhibitor 0.7974
Renal organic cation transporter Non-inhibitor 0.8135
CYP450 2C9 substrate Non-substrate 0.9116
CYP450 2D6 substrate Non-substrate 0.9116
CYP450 3A4 substrate Substrate 0.7435
CYP450 1A2 substrate Non-inhibitor 0.8874
CYP450 2C9 substrate Non-inhibitor 0.9053
CYP450 2D6 substrate Non-inhibitor 0.9402
CYP450 2C19 substrate Non-inhibitor 0.8969
CYP450 3A4 substrate Non-inhibitor 0.869
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9807
Ames test Non AMES toxic 0.6355
Carcinogenicity Non-carcinogens 0.9422
Biodegradation Not ready biodegradable 0.9698
Rat acute toxicity 2.7541 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9817
hERG inhibition (predictor II) Non-inhibitor 0.8733
Pharmacoeconomics
Manufacturers
  • Astellas pharma us inc
  • Dr reddys laboratories ltd
  • Sandoz inc
  • Watson laboratories inc
  • Astellas Pharma US
Packagers
Dosage forms
FormRouteStrength
CapsuleOral0.5 mg, 1 mg, 3 mg, 5 mg
Injection, solutionIntravenous5 mg/mL
OintmentTopical0.03%, 0.1%
Prices
Unit descriptionCostUnit
Tacrolimus micronized powder2800.0USDg
Protopic 0.1% Ointment 60 gm Tube255.34USDtube
Protopic 0.03% Ointment 60 gm Tube251.17USDtube
Prograf 5 mg/ml ampule163.94USDml
Protopic 0.03% Ointment 30 gm Tube132.99USDtube
Protopic 0.1% Ointment 30 gm Tube124.42USDtube
Prograf 5 mg capsule24.26USDcapsule
Tacrolimus anhydrous 5 mg cap22.3USDeach
Prograf 1 mg capsule4.85USDcapsule
Tacrolimus 1 mg capsule4.64USDcapsule
Tacrolimus anhydrous 1 mg cap4.46USDeach
Protopic 0.1% ointment4.17USDg
Protopic 0.03% ointment4.09USDg
Prograf 0.5 mg capsule2.43USDcapsule
Tacrolimus anhydrous 0.5 mg cap2.23USDeach
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States56657271994-09-092014-09-09
United States52603011994-02-282011-02-28
Canada20374082002-12-172011-03-01
Canada13384911996-07-302013-07-30
Properties
Statesolid
Experimental Properties
PropertyValueSource
melting point126 °CNot Available
water solubilityInsolubleFDA label
logP3.3Not Available
Predicted Properties
PropertyValueSource
water solubility4.02e-03 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 area178.36ChemAxon
rotatable bond count7ChemAxon
refractivity215.62ChemAxon
polarizability87.41ChemAxon
number of rings4ChemAxon
bioavailability0ChemAxon
rule of fiveNoChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleYesChemAxon
Spectra
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
ResourceLink
KEGG DrugD00107
KEGG CompoundC01375
PubChem Compound445647
PubChem Substance46506004
ChEBI61049
ChEMBLCHEMBL269732
Therapeutic Targets DatabaseDAP000162
PharmGKBPA451578
HETFK5
Drug Product Database2243144
RxListhttp://www.rxlist.com/cgi/generic2/tacrolimus.htm
Drugs.comhttp://www.drugs.com/cdi/tacrolimus.html
WikipediaTacrolimus
ATC CodesD11AH01L04AD02
AHFS Codes
  • 84:92.00
  • 92:00.00
PDB Entries
FDA labelshow(144 KB)
MSDSshow(54.9 KB)
Interactions
Drug Interactions
Drug
AbarelixAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
ado-trastuzumab emtansineAvoid combination due to the increase in immunosuppressant side effects.
AmikacinAdditive renal impairment may occur during concomitant therapy with aminoglycosides such as Amikacin. Use caution during concomitant therapy.
AmiodaroneAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
AmitriptylineAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
AmoxapineAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Amphotericin BAdditive renal impairment may occur during concomitant therapy with Amphotericin B. Use caution during concomitant therapy.
AmprenavirThe protease inhibitor, Amprenavir, may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Amprenavir therapy is initiated, discontinued or altered.
ApomorphineAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
ApramycinAdditive renal impairment may occur during concomitant therapy with aminoglycosides such as Apramycin. Use caution during concomitant therapy.
Arsenic trioxideAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
ArtemetherAdditive QTc-prolongation may occur. Concomitant therapy should be avoided.
AtazanavirThe protease inhibitor, Atazanavir, may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Atazanavir therapy is initiated, discontinued or altered.
BleomycinTacrolimus (Topical) may enhance the adverse/toxic effect of Immunosuppressants. Avoid use of tacrolimus ointment in patients receiving immunosuppressants.
BoceprevirBoceprevir increases levels of tacrolimus by affecting CYP3A4 metabolism. Concomitant therapy requires close monitoring.
Brentuximab vedotinAvoid combination due to the potential enhancement of toxic effects of immunosuppressants.
BromocriptineBromocriptine may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Bromocriptine therapy is initiated, discontinued or altered.
CarbamazepineCarbamazepine may decrease the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Carbamazepine therapy is initiated, discontinued or altered.
CarboplatinTacrolimus (Topical) may enhance the adverse/toxic effect of immunosuppressants such as carboplatin. Avoid use of tacrolimus ointment in patients receiving immunosuppressants.
CarmustineTacrolimus (Topical) may enhance the adverse/toxic effect of immunosuppressants such as carmustine. Avoid use of tacrolimus ointment in patients receiving immunosuppressants.
CaspofunginCaspofungin may decrease the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Caspofungin therapy is initiated, discontinued or altered.
ChlorambucilTacrolimus (Topical) may enhance the adverse/toxic effect of immunosuppressants sucb as chlorambucil. Avoid use of tacrolimus ointment in patients receiving immunosuppressants.
ChloramphenicolChloramphenicol may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Chloramphenicol therapy is initiated, discontinued or altered.
ChlorpromazineAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
CimetidineCimetidine may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Cimetidine therapy is initiated, discontinued or altered.
CisaprideAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution. Cisapride may also increase the concentration of Tacrolimus in the blood.
CisplatinAdditive renal impairment may occur during concomitant therapy with aminoglycosides such as Cisplatin. Use caution during concomitant therapy.
CladribineTacrolimus (Topical) may enhance the adverse/toxic effect of immunosuppressants such as tacrolimus. Avoid use of tacrolimus ointment in patients receiving immunosuppressants.
ClarithromycinAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution. The macrolide antibiotic, Clarithromycin, may also increase the blood concentration of Tacrolimus.
ClofarabineTacrolimus (topical) may enhance the adverse/toxic effect of immunosuppressants such as clofarabine. Avoid use of tacrolimus ointment in patients receiving immunosuppressants.
ClomipramineAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
ClotrimazoleThe antifungal, Clotrimazole, may increase serum concentrations of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Clotrimazole therapy is initiated, discontinued or altered.
ConivaptanThe strong CYP3A4 inhibitor, Conivaptan, may decrease the metabolism and clearance of Tacrolimus, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Tacrolimus if Conivaptan is initiated, discontinued or dose changed.
CrizotinibStrong CYP3A4 inhibitors may increase levels of crizotinib. Consider alternative therapy.
CyclosporineAdditive renal impairment may occur during concomitant therapy with cyclosporine. Combination therapy should be avoided.
DanazolDanazol may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Danazol therapy is initiated, discontinued or altered.
DarunavirThe protease inhibitor, Darunavir, may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Darunavir therapy is initiated, discontinued or altered.
DasatinibAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
DelavirdineThe strong CYP3A4 inhibitor, Delavirdine, may decrease the metabolism and clearance of Tacrolimus, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Tacrolimus if Delavirdine is initiated, discontinued or dose changed.
DesipramineAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
DiltiazemDiltiazem may increase the serum concentration of tacrolimus by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of tacrolimus if diltiazem therapy is initiated, discontinued or dose changed.
DisopyramideAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
DofetilideAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
DolasetronAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
DomperidoneAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
DoxepinAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
DronedaroneTacrolimus is a CYP3A substrate with a narrow therapeutic index thus concomitant therapy with dronedarone will increase plasma levels of tacrolimus. Monitor plasma concentrations and adjust dose accordingly.
DroperidolAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
ErythromycinAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution. The macrolide antibiotic, erythromycin, may also increase the blood concentration of tacrolimus.
Ethinyl EstradiolEthinyl estradiol may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Ethinyl estradiol therapy is initiated, discontinued or altered.
FelodipineFelodipine increases tacrolimus levels
FlecainideAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
FluconazoleAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution. The antifungal, fluconazole, may also increase serum concentrations of tacrolimus.
FluoxetineAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
FlupentixolAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
FosamprenavirThe protease inhibitor, Fosamprenavir, may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Fosamprenavir therapy is initiated, discontinued or altered.
FoscarnetAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
FosphenytoinThe hydantoin decreases the effect of tacrolimus
GatifloxacinAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
GentamicinAdditive renal impairment may occur during concomitant therapy with aminoglycosides such as Gentamicin. Use caution during concomitant therapy.
golimumabAvoid combination due to the enhancement of side effects from immunosuppressants.
HalofantrineAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
HaloperidolAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
HomoharringtonineAvoid combination as there is potential to increase immunosuppressant adverse effects.
IbutilideAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
ImatinibThe strong CYP3A4 inhibitor, Imatinib, may decrease the metabolism and clearance of Tacrolimus, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Tacrolimus if Imatinib is initiated, discontinued or dose changed.
ImipramineAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
IndapamideAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
IndinavirThe protease inhibitor, Indinavir, may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Indinavir therapy is initiated, discontinued or altered.
IsoniazidThe strong CYP3A4 inhibitor, Isoniazid, may decrease the metabolism and clearance of Tacrolimus, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Tacrolimus if Isoniazid is initiated, discontinued or dose changed.
IsradipineAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
ItraconazoleThe antifungal, Itraconazole, may increase serum concentrations of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Itraconazole therapy is initiated, discontinued or altered.
KetoconazoleThe antifungal, Ketoconazole, may increase serum concentrations of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Ketoconzole therapy is initiated, discontinued or altered.
LapatinibAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
LevofloxacinAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
LopinavirThe protease inhibitor, Lopinavir, may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Lopinavir therapy is initiated, discontinued or altered.
LoxapineAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
LumefantrineAdditive QTc-prolongation may occur. Concomitant therapy should be avoided.
MaprotilineAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
MefloquineAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
MesoridazineAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
MethadoneAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
MethylprednisoloneMethylprednisone may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Methylprednisone therapy is initiated, discontinued or altered.
MetoclopramideMetoclopramide may increase the concentration of Tacrolimus in the blood. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Metoclopramide therapy is initiated, discontinued or altered.
MetronidazoleMetronidazole increases the levels/toxicity of tacrolimus
MibefradilThe calcium channel blocker, Mibefradil, may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Mibefradil therapy is initiated, discontinued or altered.
MiconazoleThe strong CYP3A4 inhibitor, Miconazole, may decrease the metabolism and clearance of Tacrolimus, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Tacrolimus if Miconazole is initiated, discontinued or dose changed.
MoxifloxacinAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Mycophenolate mofetilTacrolimus may increase the plasma concentration of Mycophenolic acid. Monitor and adjust the dose of Mycophenolate mofetil to the therapeutic range.
NatalizumabTacrolimus may increase the toxic/adverse effects of Natalizumab. Concurrent administration should be avoided due to increased risk of infection.
NefazodoneNefazodone may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Nefazodone therapy is initiated, discontinued or altered.
NelfinavirThe protease inhibitor, Nelfinavir, may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Nelfinavir therapy is initiated, discontinued or altered.
NeomycinAdditive renal impairment may occur during concomitant therapy with aminoglycosides such as Neomycin. Use caution during concomitant therapy.
NetilmicinAdditive renal impairment may occur during concomitant therapy with aminoglycosides such as Netilmicin. Use caution during concomitant therapy.
NicardipineThe calcium channel blocker, Nicardipine, may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Nicardipine therapy is initiated, discontinued or altered.
NifedipineThe calcium channel blocker, Nifedipine, may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Nifedipine therapy is initiated, discontinued or altered.
NilotinibMay cause additive QTc-prolonging effects. Concomitant therapy is contraindicated.
NorfloxacinAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
NortriptylineAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
OctreotideAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
OmeprazoleOmeprazole may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Omeprazole therapy is initiated, discontinued or altered.
PaclitaxelAvoid combination of topical tacrolimus due to the potential enhancement of adverse effects of immunosuppressants.
PentamidineAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
PerflutrenAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
PhenobarbitalPhenobarbital may decrease the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Phenobarbital therapy is initiated, discontinued or altered.
PhenytoinPhenytoin may decrease the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Phenytoin therapy is initiated, discontinued or altered.
PimozideAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
PosaconazoleThe strong CYP3A4 inhibitor, Posaconazole, may decrease the metabolism and clearance of Tacrolimus, a CYP3A4 substrate. Consider alternate therapy or monitor for changes in therapeutic and adverse effects of Tacrolimus if Posaconazole is initiated, discontinued or dose changed.
ProbucolAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
ProcainamideAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
PropafenoneAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
ProtriptylineAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
QuetiapineAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
QuinidineAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution. Quinidine, a strong CYP3A4 inhibitor, may also increase the serum concentration of Tacrolimus by inhibiting its metabolism and clearance.
QuinupristinThis combination presents an increased risk of toxicity
RanolazineAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
RifabutinCarbamazepine may decrease the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Carbamazepine therapy is initiated, discontinued or altered.
RifampicinRifampin may decrease the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Rifampin therapy is initiated, discontinued or altered.
Rilonaceptresults in increased immunosuppressive effects; increases the risk of infection.
RisperidoneAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
RitonavirThe protease inhibitor, Ritonavir, may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Ritonavir therapy is initiated, discontinued or altered.
SaquinavirThe protease inhibitor, Saquinavir, may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Saquinavir therapy is initiated, discontinued or altered.
SilodosinThe p-glycoprotein inhibitor, Tacrolimus, may increase the bioavailability of Silodosin. Increased Silodosin exposure may result in Silodosin toxicity. Concurrent use if not recommended.
SirolimusSirolimus may decrease the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Sirolimus therapy is initiated, discontinued or altered.
SotalolAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
SparfloxacinAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
St. John's WortSt. John's Wort may decrease the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if St. John's Wort therapy is initiated, discontinued or altered.
StreptomycinAdditive renal impairment may occur during concomitant therapy with aminoglycosides such as Streptomycin. Use caution during concomitant therapy.
SunitinibAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
TelaprevirTelaprevir increases levels by affecting CYP3A4 metabolism. Must monitor levels closely with concomitant therapy.
TelithromycinAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution. Telithromycin, a strong CYP3A4 inhibitor, may also increase the serum concentration of Tacrolimus by inhibiting its metabolism and clearance.
TemsirolimusTemsirolimus may decrease the blood concentration of Tacrolimus. Concomitant therapy may increase the adverse/toxic effects of both agents. Concomitant therapy should be avoided.
TeriflunomideAvoid combination due to the increased toxic effects of immunosuppressants.
TetrabenazineMay cause additive QTc-prolonging effects. Concomitant therapy should be avoided.
ThioridazineMay cause additive QTc-prolonging effects. Concomitant therapy is contraindicated.
ThiothixeneAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
TipranavirTipranavir may decrease the metabolism and clearance of Tacrolimus. Dose adjustments may be required. Monitor for Tacrolimus efficacy and toxicity during concomitant therapy.
TobramycinAdditive renal impairment may occur during concomitant therapy with aminoglycosides such as Tobramycin. Use caution during concomitant therapy.
TofacitinibAvoid combination due to the potential increase in immunosuppressant associated adverse effects.
TopotecanThe p-glycoprotein inhibitor, Tacrolimus, may increase the bioavailability of oral Topotecan. A clinically significant effect is also expected with IV Topotecan. Concomitant therapy should be avoided.
ToremifeneAdditive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Consider alternate therapy. A thorough risk:benefit assessment is required prior to co-administration.
TrastuzumabTrastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
TrimipramineAdditive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
TroleandomycinThe macrolide antibiotic, Troleandomycin, may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Troleandomycin therapy is initiated, discontinued or altered.
VerapamilThe calcium channel blocker, Verapamil, may increase the blood concentration of Tacrolimus. Monitor for changes in the therapeutic/toxic effects of Tacrolimus if Verapamil therapy is initiated, discontinued or altered.
VoriconazoleVoriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of tacrolimus by decreasing its metabolism. Additive QTc prolongation may also occur. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of tacrolimus if voriconazole is initiated, discontinued or dose changed.
VorinostatAdditive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
ZiprasidoneAdditive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy should be avoided.
ZuclopenthixolAdditive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Zuclopenthixol acetateAdditive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Zuclopenthixol decanoateAdditive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Food Interactions
  • Food, especially food with a high-fat content, decreases the rate and extent of absorption.
  • The time of the meal affects tacrolimus bioavailability. Take tacrolimus capsules consistently everyday either with or without food.

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 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.

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 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

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