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Identification
Name Tacrolimus
Accession Number DB00864 (APRD00276, EXPT01437)
Type small molecule
Groups approved
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
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
FK-506
FK5
K506
Tacarolimus
tacrolimus hydrate
Salts Not Available
Brand names
Name Company
Prograf
Protopic
Brand mixtures Not Available
Categories
  • Immunosuppressive Agents
CAS number 104987-11-3
Weight Average: 804.0182
Monoisotopic: 803.481976677
Chemical Formula C44H69NO12
InChI Key InChIKey=QJJXYPPXXYFBGM-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
Plain Text
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
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Not Available
Classes Not Available
Substructures Not Available
Pharmacology
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.
Pharmacodynamics Tacrolimus 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 action 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.
Absorption 20% bioavailability; less after eating food rich in fat
Volume of distribution
  • 2.6±2.1 L/kg [pediatric patients]
Protein binding 75-99%
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.
Route of elimination In man, less than 1% of the dose administered is excreted unchanged in urine. Fecal elimination accounted for 92.6±30.7%, urinary elimination accounted for 2.3±1.1%.
Half life 11.3 hours (range from 3.5 to 40.6 hours)
Clearance
  • 0.029 +/- 0.009 L/hr/kg [healthy subjects IV administered]
  • 0.172 +/- 0.088 L/hr/kg [Healthy subjects administered PO]
  • 0.138 +/- 0.071 L/hr/kg [liver transplantation pediatric patients]
  • 0.038 +/-0.014 L/hr/kg [patients with renal impairment 0.02 mg/kg/4 hr, IV]
  • 0.042 +/- 0.02 L/hr/kg [Mild Hepatic Impairment 0.02 mg/kg/4 hr, IV]
  • 0.034 +/- 0.019 L/hr/kg [Mild Hepatic Impairment 7.7 mg PO]
  • 0.017 +/- 0.013 L/hr/kg [Severe hepatic impairement 0.02 mg/kg/4 hr, IV]
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. LD50=134-194 mg/kg (rat).
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Astellas pharma us inc
  • Dr reddys laboratories ltd
  • Sandoz inc
  • Watson laboratories inc
  • Astellas Pharma US
Packagers
Dosage forms
Form Route Strength
Capsule Oral
Ointment Topical
Solution Intravenous
Prices
Unit description Cost Unit
Tacrolimus micronized powder 2800.0 USD g
Protopic 0.1% Ointment 60 gm Tube 255.34 USD tube
Protopic 0.03% Ointment 60 gm Tube 251.17 USD tube
Prograf 5 mg/ml ampule 163.94 USD ml
Protopic 0.03% Ointment 30 gm Tube 132.99 USD tube
Protopic 0.1% Ointment 30 gm Tube 124.42 USD tube
Prograf 5 mg capsule 24.26 USD capsule
Tacrolimus anhydrous 5 mg cap 22.3 USD each
Prograf 1 mg capsule 4.85 USD capsule
Tacrolimus 1 mg capsule 4.64 USD capsule
Tacrolimus anhydrous 1 mg cap 4.46 USD each
Protopic 0.1% ointment 4.17 USD g
Protopic 0.03% ointment 4.09 USD g
Prograf 0.5 mg capsule 2.43 USD capsule
Tacrolimus anhydrous 0.5 mg cap 2.23 USD each
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Patents
Country Patent Number Approved Expires (estimated)
United States 5665727 1994-09-09 2014-09-09
United States 5260301 1994-02-28 2011-02-28
Canada 2037408 2002-12-17 2011-03-01
Canada 1338491 1996-07-30 2013-07-30
Properties
State solid
Experimental Properties
Property Value Source
melting point 126 °C Not Available
water solubility Insoluble Not Available
logP 3.3 Not Available
Predicted Properties
Property Value Source
water solubility 4.02e-03 g/l ALOGPS
logP 3.19 ALOGPS
logP 5.59 ChemAxon
logS -5.3 ALOGPS
pKa (strongest acidic) 9.96 ChemAxon
pKa (strongest basic) -2.9 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 11 ChemAxon
hydrogen donor count 3 ChemAxon
polar surface area 178.36 ChemAxon
rotatable bond count 7 ChemAxon
refractivity 215.62 ChemAxon
polarizability 87.41 ChemAxon
References
Synthesis Reference Not Available
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
External Links
Resource Link
KEGG Compound C01375 Link_out
PubChem Compound 445647 Link_out
PubChem Substance 46506004 Link_out
ChEBI 61049 Link_out
ChEMBL 61049 Link_out
Therapeutic Targets Database DAP000162 Link_out
PharmGKB PA451578 Link_out
HET FK5 Link_out
Drug Product Database 2243144 Link_out
RxList http://www.rxlist.com/cgi/generic2/tacrolimus.htm Link_out
Drugs.com http://www.drugs.com/cdi/tacrolimus.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Tacrolimus Link_out
ATC Codes
  • D11AX14
  • L04AA05
AHFS Codes
  • 84:92.00
  • 92:00.00
PDB Entries
FDA label show (144 KB)
MSDS show (54.9 KB)
Interactions
Drug Interactions
Drug Interaction
Abarelix Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Amikacin Additive renal impairment may occur during concomitant therapy with aminoglycosides such as Amikacin. Use caution during concomitant therapy.
Amiodarone Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Amitriptyline Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Amoxapine Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Amphotericin B Additive renal impairment may occur during concomitant therapy with Amphotericin B. Use caution during concomitant therapy.
Amprenavir The 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.
Apomorphine Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Apramycin Additive renal impairment may occur during concomitant therapy with aminoglycosides such as Apramycin. Use caution during concomitant therapy.
Arsenic trioxide Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Artemether Additive QTc-prolongation may occur. Concomitant therapy should be avoided.
Atazanavir The 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.
Bleomycin Tacrolimus (Topical) may enhance the adverse/toxic effect of Immunosuppressants. Avoid use of tacrolimus ointment in patients receiving immunosuppressants.
BRENTUXIMAB VEDOTIN Avoid combination due to the potential enhancement of toxic effects of immunosuppressants.
Bromocriptine Bromocriptine 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.
Carbamazepine Carbamazepine 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.
Carboplatin Tacrolimus (Topical) may enhance the adverse/toxic effect of immunosuppressants such as carboplatin. Avoid use of tacrolimus ointment in patients receiving immunosuppressants.
Carmustine Tacrolimus (Topical) may enhance the adverse/toxic effect of immunosuppressants such as carmustine. Avoid use of tacrolimus ointment in patients receiving immunosuppressants.
Caspofungin Caspofungin 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.
Chlorambucil Tacrolimus (Topical) may enhance the adverse/toxic effect of immunosuppressants sucb as chlorambucil. Avoid use of tacrolimus ointment in patients receiving immunosuppressants.
Chloramphenicol Chloramphenicol 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.
Chlorpromazine Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Cimetidine Cimetidine 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.
Cisapride Additive 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.
Cisplatin Additive renal impairment may occur during concomitant therapy with aminoglycosides such as Cisplatin. Use caution during concomitant therapy.
Cladribine Tacrolimus (Topical) may enhance the adverse/toxic effect of immunosuppressants such as tacrolimus. Avoid use of tacrolimus ointment in patients receiving immunosuppressants.
Clarithromycin Additive 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.
Clofarabine Tacrolimus (topical) may enhance the adverse/toxic effect of immunosuppressants such as clofarabine. Avoid use of tacrolimus ointment in patients receiving immunosuppressants.
Clomipramine Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Clotrimazole The 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.
Conivaptan The 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.
Cyclosporine Additive renal impairment may occur during concomitant therapy with cyclosporine. Combination therapy should be avoided.
Danazol Danazol 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.
Darunavir The 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.
Dasatinib Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Delavirdine The 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.
Desipramine Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Diltiazem Diltiazem 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.
Disopyramide Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Dofetilide Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Dolasetron Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Domperidone Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Doxepin Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Dronedarone Tacrolimus 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.
Droperidol Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Erythromycin Additive 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 Estradiol Ethinyl 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.
Felodipine Felodipine increases tacrolimus levels
Flecainide Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Fluconazole Additive 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.
Fluoxetine Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Flupenthixol Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Fosamprenavir The 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.
Foscarnet Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Fosphenytoin The hydantoin decreases the effect of tacrolimus
Gatifloxacin Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Gentamicin Additive renal impairment may occur during concomitant therapy with aminoglycosides such as Gentamicin. Use caution during concomitant therapy.
Halofantrine Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Haloperidol Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Ibutilide Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Imatinib The 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.
Imipramine Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Indapamide Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Indinavir The 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.
Isoniazid The 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.
Isradipine Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Itraconazole The 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.
Ketoconazole The 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.
Lapatinib Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Levofloxacin Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Lopinavir The 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.
Loxapine Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Lumefantrine Additive QTc-prolongation may occur. Concomitant therapy should be avoided.
Maprotiline Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Mefloquine Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Mesoridazine Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Methadone Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Methylprednisolone Methylprednisone 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.
Metoclopramide Metoclopramide 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.
Metronidazole Metronidazole increases the levels/toxicity of tacrolimus
Mibefradil The 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.
Miconazole The 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.
Moxifloxacin Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Mycophenolate mofetil Tacrolimus may increase the plasma concentration of Mycophenolic acid. Monitor and adjust the dose of Mycophenolate mofetil to the therapeutic range.
Natalizumab Tacrolimus may increase the toxic/adverse effects of Natalizumab. Concurrent administration should be avoided due to increased risk of infection.
Nefazodone Nefazodone 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.
Nelfinavir The 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.
Neomycin Additive renal impairment may occur during concomitant therapy with aminoglycosides such as Neomycin. Use caution during concomitant therapy.
Netilmicin Additive renal impairment may occur during concomitant therapy with aminoglycosides such as Netilmicin. Use caution during concomitant therapy.
Nicardipine The 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.
Nifedipine The 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.
Nilotinib May cause additive QTc-prolonging effects. Concomitant therapy is contraindicated.
Norfloxacin Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Nortriptyline Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Octreotide Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Omeprazole Omeprazole 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.
Pentamidine Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Perflutren Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Phenobarbital Phenobarbital 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.
Phenytoin Phenytoin 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.
Pimozide Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Posaconazole The 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.
Probucol Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Procainamide Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Propafenone Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Protriptyline Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Quetiapine Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Quinidine Additive 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.
Quinupristin This combination presents an increased risk of toxicity
Ranolazine Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Rifabutin Carbamazepine 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.
Rifampin Rifampin 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.
Rilonacept results in increased immunosuppressive effects; increases the risk of infection.
Risperidone Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Ritonavir The 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.
Saquinavir The 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.
Silodosin The p-glycoprotein inhibitor, Tacrolimus, may increase the bioavailability of Silodosin. Increased Silodosin exposure may result in Silodosin toxicity. Concurrent use if not recommended.
Sirolimus Sirolimus 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.
Sotalol Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Sparfloxacin Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
St. John's Wort St. 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.
Streptomycin Additive renal impairment may occur during concomitant therapy with aminoglycosides such as Streptomycin. Use caution during concomitant therapy.
Sunitinib Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Telithromycin Additive 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.
Temsirolimus Temsirolimus may decrease the blood concentration of Tacrolimus. Concomitant therapy may increase the adverse/toxic effects of both agents. Concomitant therapy should be avoided.
Tetrabenazine May cause additive QTc-prolonging effects. Concomitant therapy should be avoided.
Thioridazine May cause additive QTc-prolonging effects. Concomitant therapy is contraindicated.
Thiothixene Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Tipranavir Tipranavir may decrease the metabolism and clearance of Tacrolimus. Dose adjustments may be required. Monitor for Tacrolimus efficacy and toxicity during concomitant therapy.
Tobramycin Additive renal impairment may occur during concomitant therapy with aminoglycosides such as Tobramycin. Use caution during concomitant therapy.
Topotecan The 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.
Toremifene Additive 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.
Trastuzumab Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
Trimipramine Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.
Troleandomycin The 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.
Verapamil The 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.
Voriconazole Voriconazole, 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.
Vorinostat Additive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).
Ziprasidone Additive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy should be avoided.
Zuclopenthixol Additive 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 Not Available
Targets

1. FK506-binding protein 1A

Pharmacological action: yes
Actions: inhibitor

May play a role in modulation of ryanodine receptor isoform-1 (RYR-1), a component of the calcium release channel of skeletal muscle sarcoplasmic reticulum. There are four molecules of FKBP12 per skeletal muscle RYR. PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides

Organism class: human
UniProt ID: P62942 Link_out
Gene: FKBP1A Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P24462 Link_out
Gene: CYP3A7 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics

UniProt ID: P20815 Link_out
Gene: CYP3A5 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate, inhibitor

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation reactions (e.g. caffeine 8-oxidation, omeprazole sulphoxidation, midazolam 1'-hydroxylation and midazolam 4- hydroxylation) of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. The enzyme also hydroxylates etoposide

UniProt ID: P08684 Link_out
Gene: CYP3A4
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Transporters

1. Multidrug resistance protein 1

Actions: substrate, inhibitor, inducer

Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells

UniProt ID: P08183 Link_out
Gene: ABCB1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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

Actions: substrate

May play a role in the processing of autolysosomes (By similarity)

UniProt ID: Q8WWZ7 Link_out
Gene: ABCA5 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

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
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19