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Identification
NameSirolimus
Accession NumberDB00877  (APRD00178, DB02439)
Typesmall molecule
Groupsapproved, investigational
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
Synonyms
SynonymLanguageCode
(-)-RapamycinNot AvailableNot Available
RapamycinNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
RapamuneWyeth Pharma
Brand mixturesNot Available
Categories
CAS number53123-88-9
WeightAverage: 914.1719
Monoisotopic: 913.555141619
Chemical FormulaC51H79NO13
InChI KeyQFJCIRLUMZQUOT-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
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
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 the prophylaxis of organ rejection in patients receiving renal transplants.
PharmacodynamicsSirolimus, 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 actionSirolimus 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.
AbsorptionNot Available
Volume of distributionNot Available
Protein binding92%
Metabolism
SubstrateEnzymesProduct
Sirolimus
41-O-demethylrapamycinDetails
Route of eliminationNot Available
Half life57-63 hours
ClearanceNot Available
ToxicityNot Available
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption - 0.7841
Blood Brain Barrier - 0.9599
Caco-2 permeable - 0.6341
P-glycoprotein substrate Substrate 0.8052
P-glycoprotein inhibitor I Inhibitor 0.8564
P-glycoprotein inhibitor II Inhibitor 0.8021
Renal organic cation transporter Non-inhibitor 0.8116
CYP450 2C9 substrate Non-substrate 0.878
CYP450 2D6 substrate Non-substrate 0.9138
CYP450 3A4 substrate Substrate 0.7776
CYP450 1A2 substrate Non-inhibitor 0.9007
CYP450 2C9 substrate Non-inhibitor 0.9125
CYP450 2D6 substrate Non-inhibitor 0.9414
CYP450 2C19 substrate Non-inhibitor 0.9158
CYP450 3A4 substrate Non-inhibitor 0.9333
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9742
Ames test Non AMES toxic 0.6617
Carcinogenicity Non-carcinogens 0.9546
Biodegradation Not ready biodegradable 0.9593
Rat acute toxicity 2.8689 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9831
hERG inhibition (predictor II) Non-inhibitor 0.8443
Pharmacoeconomics
Manufacturers
  • Wyeth pharmaceuticals inc
Packagers
Dosage forms
FormRouteStrength
SolutionOral
TabletOral
Prices
Unit descriptionCostUnit
Rapamune 2 mg tablet20.59USDtablet
Rapamune 1 mg/ml Solution12.19USDml
Rapamune 1 mg tablet11.95USDtablet
Rapamune 0.5 mg tablet5.86USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States59895911998-09-112018-09-11
United States52121551993-05-182010-05-18
Canada22937932006-07-112018-06-11
Canada21035712003-04-292012-02-21
Properties
Statesolid
Experimental Properties
PropertyValueSource
logP4.3Not Available
Predicted Properties
PropertyValueSource
water solubility1.73e-03 g/lALOGPS
logP4.85ALOGPS
logP7.45ChemAxon
logS-5.7ALOGPS
pKa (strongest acidic)9.96ChemAxon
pKa (strongest basic)-3ChemAxon
physiological charge0ChemAxon
hydrogen acceptor count12ChemAxon
hydrogen donor count3ChemAxon
polar surface area195.43ChemAxon
rotatable bond count6ChemAxon
refractivity250.66ChemAxon
polarizability100.46ChemAxon
number of rings4ChemAxon
bioavailability0ChemAxon
rule of fiveNoChemAxon
Ghose filterNoChemAxon
Veber's ruleNoChemAxon
MDDR-like ruleYesChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference

Madhup K. Dhaon, Chi-nung Hsiao, Subhash R. Patel, Peter J. Bonk, Sanjay R. Chemburkar, Yong Y. Chen, “One pot synthesis of tetrazole derivatives of sirolimus.” U.S. Patent US20080167335, issued July 10, 2008.

US20080167335
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
ResourceLink
KEGG DrugD00753
KEGG CompoundC07909
BindingDB50240955
ChEBI9168
ChEMBLCHEMBL413
Therapeutic Targets DatabaseDNC001197
PharmGKBPA451365
HETARD
Drug Product Database2243237
RxListhttp://www.rxlist.com/cgi/generic2/sirolimus.htm
Drugs.comhttp://www.drugs.com/cdi/sirolimus.html
WikipediaSirolimus
ATC CodesL04AA10
AHFS Codes
  • 92:00.00
PDB Entries
FDA labelshow(480 KB)
MSDSNot Available
Interactions
Drug Interactions
Drug
AtazanavirIncreases the effect and toxicity of immunosuppressant
BoceprevirBoceprevir increases levels of sirolimus by affecting CYP3A4 metabolism. Concomitant therapy requires close monitoring.
ClarithromycinThe macrolide, clarithromycin, may increase the serum concentration of sirolimus.
CyclosporineIncreases the effect and toxicity of sirolimus
DiltiazemIncreases the effect and toxicity of sirolimus
DronedaroneSirolimus 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.
ErythromycinThe macrolide, erythromycin, may increase the serum concentration of sirolimus.
FosphenytoinThe hydantoin decreases sirolimus levels
ItraconazoleItraconazole may increase the effect and toxicity of sirolimus.
KetoconazoleKetoconazole may increase the effect and toxicity of sirolimus.
PhenytoinThe hydantoin decreases sirolimus levels
RifabutinThe rifamycin decreases the effect of sirolimus
RifampicinThe rifamycin decreases the effect of sirolimus
Rilonaceptresults in increased immunosuppressive effects; increases the risk of infection.
TacrolimusSirolimus 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.
TelithromycinTelithromycin 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.
TipranavirTipranavir may affect the efficacy/toxicity of Sirolimus.
TrandolaprilIncreased risk of angioedema. Monitor for signs and symptoms of facial and systemic edema and/or erythema.
TrastuzumabTrastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
VoriconazoleVoriconazole 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 InteractionsNot Available

Targets

1. Serine/threonine-protein kinase mTOR

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Serine/threonine-protein kinase mTOR P42345 Details

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. Peptidyl-prolyl cis-trans isomerase FKBP1A

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: other

Components

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

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. Fibroblast growth factor 2

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: other/unknown

Components

Name UniProt ID Details
Fibroblast growth factor 2 P09038 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate inhibitor

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

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

2. Cytochrome P450 3A5

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A5 P20815 Details

References:

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

3. Cytochrome P450 3A7

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A7 P24462 Details

References:

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

Transporters

1. Multidrug resistance protein 1

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: 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. 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

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: inhibitor

Components

Name UniProt ID Details
Solute carrier organic anion transporter family member 1B1 Q9Y6L6 Details

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

Kind: protein

Organism: Human

Pharmacological action: unknown

Components

Name UniProt ID Details
Multidrug and toxin extrusion protein 1 Q96FL8 Details

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