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Identification
Name Sirolimus
Accession Number DB00877 (APRD00178, DB02439)
Type small molecule
Groups approved
Description

A macrolide compound obtained from Streptomyces hygroscopicus that acts by selectively blocking the transcriptional activation of cytokines thereby inhibiting cytokine production. It is bioactive only when bound to immunophilins. Sirolimus is a potent immunosuppressant and possesses both antifungal and antineoplastic properties. [PubChem]
Structure Thumb
Download: MOL | SDF | SMILES | InChI
Display: 2D Structure | 3D Structure
Synonyms
(-)-Rapamycin
Rapamycin
Salts Not Available
Brand names
Name Company
Rapamune Wyeth Pharma
Brand mixtures Not Available
Categories
  • Anti-Bacterial Agents
  • Antifungals
  • Immunosuppressive Agents
  • Antifungal Agents
  • Antibiotics, Antineoplastic
  • Macrolides
CAS number 53123-88-9
Weight Average: 914.1719
Monoisotopic: 913.555141619
Chemical Formula C51H79NO13
InChI Key InChIKey=QFJCIRLUMZQUOT-KLHQEZAJSA-N
InChI
InChI=1S/C51H79NO13/c1-30-16-12-11-13-17-31(2)42(61-8)28-38-21-19-36(7)51(60,65-38)48(57)49(58)52-23-15-14-18-39(52)50(59)64-43(33(4)26-37-20-22-40(53)44(27-37)62-9)29-41(54)32(3)25-35(6)46(56)47(63-10)45(55)34(5)24-30/h11-13,16-17,25,30,32-34,36-40,42-44,46-47,53,56,60H,14-15,18-24,26-29H2,1-10H3/b13-11+,16-12+,31-17+,35-25+/t30-,32-,33+,34-,36-,37+,38+,39+,40-,42+,43+,44-,46-,47+,51-/m1/s1
Plain Text
IUPAC Name
(1R,9S,12S,15R,18R,19R,21R,23S,30S,32S,35R)-1,18-dihydroxy-12-[(2S)-1-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]propan-2-yl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.0^{4,9}]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone
SMILES
[H][C@@]1(C[C@H](C)[C@]2([H])CC(=O)[C@H](C)\C=C(C)\[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)\C=C\C=C\C=C(C)\[C@H](C[C@]3([H])CC[C@@H](C)[C@@](O)(O3)C(=O)C(=O)N3CCCC[C@@]3([H])C(=O)O2)OC)CC[C@@H](O)[C@@H](C1)OC
Plain Text
Mass Spec Not Available
Taxonomy
Kingdom Not Available
Classes Not Available
Substructures Not Available
Pharmacology
Indication For the prophylaxis of organ rejection in patients receiving renal transplants.
Pharmacodynamics Sirolimus, a macrocyclic lactone produced by Streptomyces hygroscopicus, is an immunosuppressive agent indicated for the prophylaxis of organ rejection in patients receiving renal transplants. It is recommended that sirolimus be used in a regimen with cyclosporine and corticosteroids.
Mechanism of action Sirolimus inhibits T lymphocyte activation and proliferation that occurs in response to antigenic and cytokine (Interleukin IL-2, IL-4, and IL-15) stimulation by a mechanism that is distinct from that of other immunosuppressants. Sirolimus also inhibits antibody production. In cells, sirolimus binds to the immunophilin, FK Binding Protein-12 (FKBP-12), to generate an immunosuppressive complex. The sirolimus:FKBP-12 complex has no effect on calcineurin activity. This complex binds to and inhibits the activation of the mammalian Target Of Rapamycin (mTOR), a key regulatory kinase. This inhibition suppresses cytokine-driven T-cell proliferation, inhibiting the progression from the G1 to the S phase of the cell cycle.
Absorption Not Available
Volume of distribution Not Available
Protein binding 92%
Metabolism Not Available
Route of elimination Not Available
Half life 57-63 hours
Clearance Not Available
Toxicity Not Available
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Wyeth pharmaceuticals inc
Packagers
Dosage forms
Form Route Strength
Solution Oral
Tablet Oral
Prices
Unit description Cost Unit
Rapamune 2 mg tablet 20.59 USD tablet
Rapamune 1 mg/ml Solution 12.19 USD ml
Rapamune 1 mg tablet 11.95 USD tablet
Rapamune 0.5 mg tablet 5.86 USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Country Patent Number Approved Expires (estimated)
United States 5989591 1998-09-11 2018-09-11
United States 5212155 1993-05-18 2010-05-18
Canada 2293793 2006-07-11 2018-06-11
Canada 2103571 2003-04-29 2012-02-21
Properties
State solid
Experimental Properties
Property Value Source
logP 4.3 Not Available
Predicted Properties
Property Value Source
water solubility 1.73e-03 g/l ALOGPS
logP 4.85 ALOGPS
logP 7.45 ChemAxon
logS -5.7 ALOGPS
pKa (strongest acidic) 9.96 ChemAxon
pKa (strongest basic) -3 ChemAxon
physiological charge 0 ChemAxon
hydrogen acceptor count 12 ChemAxon
hydrogen donor count 3 ChemAxon
polar surface area 195.43 ChemAxon
rotatable bond count 6 ChemAxon
refractivity 250.66 ChemAxon
polarizability 100.46 ChemAxon
References
Synthesis Reference Not Available
General Reference
  1. Pritchard DI: Sourcing a chemical succession for cyclosporin from parasites and human pathogens. Drug Discov Today. 2005 May 15;10(10):688-91. Pubmed
  2. Shuchman M: Trading restenosis for thrombosis? New questions about drug-eluting stents. N Engl J Med. 2006 Nov 9;355(19):1949-52. Pubmed
  3. Sun SY, Rosenberg LM, Wang X, Zhou Z, Yue P, Fu H, Khuri FR: Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition. Cancer Res. 2005 Aug 15;65(16):7052-8. Pubmed
  4. Chan S: Targeting the mammalian target of rapamycin (mTOR): a new approach to treating cancer. Br J Cancer. 2004 Oct 18;91(8):1420-4. Pubmed
  5. Graziani EI: Recent advances in the chemistry, biosynthesis and pharmacology of rapamycin analogs. Nat Prod Rep. 2009 May;26(5):602-9. Epub 2009 Mar 5. Pubmed
External Links
Resource Link
KEGG Drug D00753 Link_out
KEGG Compound C07909 Link_out
BindingDB 50240955 Link_out
ChEBI 9168 Link_out
ChEMBL 9168 Link_out
Therapeutic Targets Database DNC001197 Link_out
PharmGKB PA451365 Link_out
HET ARD Link_out
Drug Product Database 2243237 Link_out
RxList http://www.rxlist.com/cgi/generic2/sirolimus.htm Link_out
Drugs.com http://www.drugs.com/cdi/sirolimus.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Sirolimus Link_out
ATC Codes
  • L04AA10
AHFS Codes
  • 92:00.00
PDB Entries
FDA label show (480 KB)
MSDS Not Available
Interactions
Drug Interactions
Drug Interaction
Atazanavir Increases the effect and toxicity of immunosuppressant
Clarithromycin The macrolide, clarithromycin, may increase the serum concentration of sirolimus.
Cyclosporine Increases the effect and toxicity of sirolimus
Diltiazem Increases the effect and toxicity of sirolimus
Dronedarone Sirolimus is a CYP3A substrate with a narrow therapeutic index thus concomitant therapy with dronedarone will increase plasma levels of sirolimus. Monitor plasma concentrations and adjust dose accordingly.
Erythromycin The macrolide, erythromycin, may increase the serum concentration of sirolimus.
Fosphenytoin The hydantoin decreases sirolimus levels
Itraconazole Itraconazole may increase the effect and toxicity of sirolimus.
Ketoconazole Ketoconazole may increase the effect and toxicity of sirolimus.
Phenytoin The hydantoin decreases sirolimus levels
Rifabutin The rifamycin decreases the effect of sirolimus
Rifampin The rifamycin decreases the effect of sirolimus
Rilonacept results in increased immunosuppressive effects; increases the risk of infection.
Tacrolimus 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.
Telithromycin Telithromycin may reduce clearance of Sirolimus. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Sirolimus if Telithromycin is initiated, discontinued or dose changed.
Tipranavir Tipranavir may affect the efficacy/toxicity of Sirolimus.
Trandolapril Increased risk of angioedema. Monitor for signs and symptoms of facial and systemic edema and/or erythema.
Trastuzumab Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
Voriconazole Voriconazole may increase the serum concentration of sirolimus likely by inhibition of CYP3A4-mediated metabolism or p-glyprotein transport of sirolimus. Consider alternate therapy or reduce the dose of sirolimus and monitor serum levels during concomitant therapy.
Food Interactions Not Available
Targets

1. Serine/threonine-protein kinase mTOR

Pharmacological action: yes
Actions: inhibitor

Acts as the target for the cell-cycle arrest and immunosuppressive effects of the FKBP12-rapamycin complex

Organism class: human
UniProt ID: P42345 Link_out
Gene: FRAP1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Dowling RJ, Topisirovic I, Fonseca BD, Sonenberg N: Dissecting the role of mTOR: lessons from mTOR inhibitors. Biochim Biophys Acta. 2010 Mar;1804(3):433-9. Epub 2009 Dec 11. Pubmed
  2. Shuuin T, Karashima H: [Mammalian target of rapamycin, its mode of action and clinical response in metastatic clear cell carcinoma] Gan To Kagaku Ryoho. 2009 Jul;36(7):1076-9. Pubmed
  3. Sehgal SN: Sirolimus: its discovery, biological properties, and mechanism of action. Transplant Proc. 2003 May;35(3 Suppl):7S-14S. Pubmed
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

2. FK506-binding protein 1A

Pharmacological action: yes
Actions: other

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. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Sehgal SN: Sirolimus: its discovery, biological properties, and mechanism of action. Transplant Proc. 2003 May;35(3 Suppl):7S-14S. Pubmed

3. Heparin-binding growth factor 2

Pharmacological action: yes
Actions: other/unknown

The heparin-binding growth factors are angiogenic agents in vivo and are potent mitogens for a variety of cell types in vitro. There are differences in the tissue distribution and concentration of these 2 growth factors

Organism class: human
UniProt ID: P09038 Link_out
Gene: FGF2 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Sehgal SN: Sirolimus: its discovery, biological properties, and mechanism of action. Transplant Proc. 2003 May;35(3 Suppl):7S-14S. Pubmed
Enzymes

1. 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

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.

3. 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.
Transporters

1. Multidrug resistance protein 1

Actions: 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. Wacher VJ, Silverman JA, Wong S, Tran-Tau P, Chan AO, Chai A, Yu XQ, O’Mahony D, Ramtoola Z: Sirolimus oral absorption in rats is increased by ketoconazole but is not affected by D-alpha-tocopheryl poly(ethylene glycol 1000) succinate. J Pharmacol Exp Ther. 2002 Oct;303(1):308-13. Pubmed
  3. Arceci RJ, Stieglitz K, Bierer BE: Immunosuppressants FK506 and rapamycin function as reversal agents of the multidrug resistance phenotype. Blood. 1992 Sep 15;80(6):1528-36. Pubmed
  4. Nagy H, Goda K, Fenyvesi F, Bacso Z, Szilasi M, Kappelmayer J, Lustyik G, Cianfriglia M, Szabo G Jr: Distinct groups of multidrug resistance modulating agents are distinguished by competition of P-glycoprotein-specific antibodies. Biochem Biophys Res Commun. 2004 Mar 19;315(4):942-9. Pubmed

2. Solute carrier organic anion transporter family member 1B1

Actions: inhibitor

Mediates the Na(+)-independent transport of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostaglandin E2, thromboxane B2, leukotriene C3, leukotriene E4, thyroxine and triiodothyronine. May play an important role in the clearance of bile acids and organic anions from the liver

UniProt ID: Q9Y6L6 Link_out
Gene: SLCO1B1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Fehrenbach T, Cui Y, Faulstich H, Keppler D: Characterization of the transport of the bicyclic peptide phalloidin by human hepatic transport proteins. Naunyn Schmiedebergs Arch Pharmacol. 2003 Nov;368(5):415-20. Epub 2003 Oct 3. Pubmed

3. Multidrug and toxin extrusion protein 1

Solute transporter for tetraethylammonium (TEA), 1- methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide (NMN), metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfate, acyclovir, ganciclovir and also the zwitterionic cephalosporin, cephalexin and cephradin. Seems to also play a role in the uptake of oxaliplatin (a new platinum anticancer agent). Able to transport paraquat (PQ or N,N-dimethyl-4-4'-bipiridinium); a widely used herbicid. Responsible for the secretion of cationic drugs across the brush border membranes

UniProt ID: Q96FL8 Link_out
Gene: SLC47A1 Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Meyer zu Schwabedissen HE, Verstuyft C, Kroemer HK, Becquemont L, Kim RB: Human multidrug and toxin extrusion 1 (MATE1/SLC47A1) transporter: functional characterization, interaction with OCT2 (SLC22A2), and single nucleotide polymorphisms. Am J Physiol Renal Physiol. 2010 Apr;298(4):F997-F1005. Epub 2010 Jan 6. Pubmed
Comments
Drug created on June 13, 2005 07:24 / Updated on February 08, 2013 16:19