Tacrolimus

Common Name

Tacrolimus Description

Tacrolimus (also FK-506 or Fujimycin) is an immunosuppressive drug whose main use is after organ transplant to reduce the activity of the patients 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

Synonyms

Value Source (-)-FK 506ChEBI 8-DEETHYL-8-[but-3-enyl]-ascomycinChEBI FK 506ChEBI FK506ChEBI PrografChEBI Tacrolimus anhydrousChEBI FK-506HMDB FK5HMDB K506HMDB TacarolimusHMDB Tacrolimus hydrateHMDB Anhydrous tacrolimusMeSH Tacrolimus, anhydrousMeSH Anhydrous, tacrolimusMeSH Fujisawa brand OF tacrolimusMeSH PrograftMeSH Cilag brand OF tacrolimusMeSH Janssen brand OF tacrolimusMeSH

Chemical Formlia

C₄₄H₆₉NO₁₂ Average Molecliar Weight

804.0182 Monoisotopic Molecliar Weight

803.481976677 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 Traditional Name

tacrolimus CAS Registry Number

104987-11-3 SMILES

InChI Identifier

InChI Key

QJJXYPPXXYFBGM-LFZNUXCKSA-N Chemical Taxonomy Description

This 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. Kingdom

Organic compounds Super Class

Phenylpropanoids and polyketides Class

Macrolide lactams Sub Class

Not Available Direct Parent

Macrolide lactams Alternative Parents

Alpha amino acid esters

Macrolides and analogues

Cyclohexanols

Piperidines

Oxanes

Tertiary carboxylic acid amides

Carboxylic acid esters

Cyclic alcohols and derivatives

Cyclic ketones

Hemiacetals

Lactams

Lactones

Azacyclic compounds

Dialkyl ethers

Oxacyclic compounds

Monocarboxylic acids and derivatives

Hydrocarbon derivatives

Organopnictogen compounds

Organonitrogen compounds

Organic oxides

Substituents

Macrolide lactam

Alpha-amino acid ester

Macrolide

Alpha-amino acid or derivatives

Cyclohexanol

Oxane

Piperidine

Cyclic alcohol

Tertiary carboxylic acid amide

Cyclic ketone

Secondary alcohol

Carboxamide group

Carboxylic acid ester

Hemiacetal

Ketone

Lactam

Lactone

Organoheterocyclic compound

Azacycle

Carboxylic acid derivative

Oxacycle

Dialkyl ether

Ether

Monocarboxylic acid or derivatives

Organopnictogen compound

Alcohol

Organic oxygen compound

Carbonyl group

Organooxygen compound

Organonitrogen compound

Organic nitrogen compound

Hydrocarbon derivative

Organic oxide

Aliphatic heteropolycyclic compound

Molecliar Framework

Aliphatic heteropolycyclic compounds External Descriptors

macrolide (CHEBI:61049 )

Macrolides and lactone polyketides (C01375 )

Macrolides and lactone polyketides (LMPK04000003 )

Ontology Status

Expected but not Quantified Origin

Drug

Biofunction

Immunosuppressive Agents

Application

Pharmaceutical

Cellliar locations

Cytoplasm

Membrane

Physical Properties State

Solid Experimental Properties

Property Value Reference Melting Point126 °CNot Available Boiling PointNot AvailableNot Available Water Solubility4.02e-03 g/LNot Available LogP3.3Not Available

Predicted Properties

Property Value Source Water Solubility0.004 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 ŲChemAxon Rotatable Bond Count7ChemAxon Refractivity215.62 m³·mol^-1ChemAxon Polarizability87.41 ųChemAxon Number of Rings4ChemAxon Bioavailability0ChemAxon Rlie of FiveYesChemAxon Ghose FilterYesChemAxon Vebers RlieYesChemAxon MDDR-like RlieYesChemAxon

Spectra Spectra

Spectrum Type Description Splash Key Predicted LC-MS/MS

Predicted LC-MS/MS Spectrum – 10V, PositiveNot Available Predicted LC-MS/MS

Predicted LC-MS/MS Spectrum – 20V, PositiveNot Available Predicted LC-MS/MS

Predicted LC-MS/MS Spectrum – 40V, PositiveNot Available Predicted LC-MS/MS

Predicted LC-MS/MS Spectrum – 10V, NegativeNot Available Predicted LC-MS/MS

Predicted LC-MS/MS Spectrum – 20V, NegativeNot Available Predicted LC-MS/MS

Predicted LC-MS/MS Spectrum – 40V, NegativeNot Available

Biological Properties Cellliar Locations

Cytoplasm

Membrane

Biofluid Locations

Blood

Urine

Tissue Location

Not Available Pathways

Not Available Normal Concentrations

Biofluid Status Value Age Sex Condition Reference Details BloodExpected but not Quantified Not AvailableNot AvailableTaking drug identified by DrugBank entry DB00864

21059682

details UrineExpected but not Quantified Not AvailableNot AvailableTaking drug identified by DrugBank entry DB00864

21059682

details

Abnormal Concentrations

Not Available Predicted Concentrations

Biofluid Value Original age Original sex Original condition Comments Blood0-1 uMAdlit (>18 years old)BothNormalPredicted based on drug qualities Blood0-1 umol/mmol creatinineAdlit (>18 years old)BothNormalPredicted based on drug qualities

Associated Disorders and Diseases Disease References

None Associated OMIM IDs

None External Links DrugBank ID

DB00864 DrugBank Metabolite ID

Not Available Phenol Explorer Compound ID

Not Available Phenol Explorer Metabolite ID

Not Available FoodDB ID

Not Available KNApSAcK ID

Not Available Chemspider ID

393220 KEGG Compound ID

C01375 BioCyc ID

Not Available BiGG ID

Not Available Wikipedia Link

Tacrolimus NuGOwiki Link

HMDB15002 Metagene Link

HMDB15002 METLIN ID

Not Available PubChem Compound

445643 PDB ID

FK5 ChEBI ID

61049

Product: Penthiopyrad

References Synthesis Reference Not Available Material Safety Data Sheet (MSDS) Not Available General References

1. 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:1715244 ]
2. 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:2445721 ]
3. Pritchard DI: Sourcing a chemical succession for cyclosporin from parasites and human pathogens. Drug Discov Today. 2005 May 15;10(10):688-91. [PubMed:15896681 ]
4. 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:16021174 ]
5. 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:16702731 ]
6. (). FDA label . .

Enzymes

General function:

Involved in monooxygenase activity

Specific function:

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. Acts as a 1,8-cineole 2-exo-monooxygenase. The enzyme also hydroxylates etoposide.

Gene Name:

CYP3A4

Uniprot ID:

P08684

Molecular weight:

57255.585

References

1. 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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]
2. 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:10490933 ]

General function:

Involved in monooxygenase activity

Specific function:

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.

Gene Name:

CYP3A5

Uniprot ID:

P20815

Molecular weight:

57108.065

References

1. 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. doi: 10.1093/nar/gkp970. Epub 2009 Nov 24. [PubMed:19934256 ]

General function:

Involved in monooxygenase activity

Specific function:

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.

Gene Name:

CYP3A7

Uniprot ID:

P24462

Molecular weight:

57525.03

General function:

Involved in protein folding

Specific function:

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

Gene Name:

FKBP1A

Uniprot ID:

P62942

Molecular weight:

11950.7

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:16289353 ]
2. Masri M, Rizk S, Barbari A, Stephan A, Kamel G, Rost M: An assay for the determination of sirolimus levels in the lymphocyte of transplant patients. Transplant Proc. 2007 May;39(4):1204-6. [PubMed:17524933 ]

Transporters

General function:

Involved in ATP binding

Specific function:

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

Gene Name:

ABCB1

Uniprot ID:

P08183

Molecular weight:

141477.3

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:8632764 ]
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:7681059 ]
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:10463589 ]
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:11371998 ]
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:15180340 ]
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:18827354 ]

PMID: 21471379

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