Sirolimus

Synonyms :
(-)-Rapamycin, Rapamycin

Status : approved

Category

Immunosuppressive Agents

Therapeutic Classification

IMMUNOSUPPRESSANTS

ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS
IMMUNOSUPPRESSANTS
IMMUNOSUPPRESSANTS
Antifungal Agents

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]

Used

For the prophylaxis of organ rejection in patients receiving renal transplants.

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.

Dosage

Form Route Strength
Solution oral 1 mg/mL
Tablet oral 1.0 mg
Tablet oral 5 mg
Tablet, sugar coated oral .5 mg
Tablet, sugar coated oral 1 mg
Tablet, sugar coated oral 2 mg
Solution oral 1.0 mg
Tablet oral 1 mg
Tablet oral 2 mg
Tablet, film coated oral .5 mg

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.

Half Life

57-63 hours

Protein Binding

92%

Chemical Classification

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.

Macrolide lactams

Organic compounds

Phenylpropanoids and polyketides

Macrolide lactams

Chemical Name

(-)-Rapamycin

Brands

name Dosage form Country
Gd-sirolimus solution Canada
Gd-sirolimus tablet Canada
Gd-sirolimus tablet Canada
Gd-sirolimus tablet Canada
Rapamune solution US
Rapamune tablet, sugar coated US
Rapamune tablet, sugar coated US
Rapamune tablet, sugar coated US
Rapamune tablet Canada
Rapamune tablet Canada
Rapamune tablet, sugar coated US
Rapamune tablet Canada
Rapamune Oral Solution solution Canada
Sirolimus tablet, film coated US
Sirolimus tablet, film coated US
Sirolimus tablet US
Sirolimus tablet US
Sirolimus tablet, sugar coated US
Sirolimus tablet, sugar coated US
Sirolimus tablet, sugar coated US
Sirolimus tablet, film coated US

Drug Drug Interactions

  •  Acetohexamide  : Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents.
  •  Alogliptin  : Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents.
  •  Aprepitant  : May increase the serum concentration of Sirolimus.
  •  Benazepril  : May enhance the adverse/toxic effect of ACE Inhibitors.
  •  Boceprevir  : May increase the serum concentration of Sirolimus.
  •  Bosentan  : May decrease the serum concentration of CYP3A4 Substrates.
  •  Canagliflozin  : Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents.
  •  Captopril  : May enhance the adverse/toxic effect of ACE Inhibitors.
  •  Chlorpropamide  : Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents.
  •  Cilazapril  : May enhance the adverse/toxic effect of ACE Inhibitors.
  •  Clarithromycin  : Macrolide Antibiotics may decrease the metabolism of Sirolimus.
  •  Clozapine  : Myelosuppressive Agents may enhance the adverse/toxic effect of Clozapine. Specifically, the risk for agranulocytosis may be increased.
  •  Conivaptan  : May increase the serum concentration of CYP3A4 Substrates.
  •  Crizotinib  : May increase the serum concentration of Sirolimus.
  •  Cyclosporine  : May enhance the adverse/toxic effect of Cyclosporine (Systemic). An increased risk of calcineurin inhibitor-induced hemolytic uremic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA) has been described. Cyclosporine (Systemic) may increase the serum concentration of Sirolimus. This is of specific concern with Cyclosporine [MODIFIED].
  •  Dabrafenib  : May decrease the serum concentration of CYP3A4 Substrates.
  •  Dasatinib  : May increase the serum concentration of CYP3A4 Substrates.
  •  Deferasirox  : May decrease the serum concentration of CYP3A4 Substrates.
  •  Denosumab  : May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased.
  •  Efavirenz  : May decrease the serum concentration of Sirolimus.
  •  Enalapril  : May enhance the adverse/toxic effect of ACE Inhibitors.
  •  Enzalutamide  : May decrease the serum concentration of Sirolimus.
  •  Erythromycin  : Macrolide Antibiotics may decrease the metabolism of Sirolimus.
  •  Fluconazole  : May increase the serum concentration of Sirolimus.
  •  Fosaprepitant  : May increase the serum concentration of Sirolimus.
  •  Fosinopril  : May enhance the adverse/toxic effect of ACE Inhibitors.
  •  Fosphenytoin  : May decrease the serum concentration of Sirolimus.
  •  Gliclazide  : Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents.
  •  Glimepiride  : Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents.
  •  Gliquidone  : Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents.
  •  Glyburide  : Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents.
  •  Idelalisib  : May increase the serum concentration of CYP3A4 Substrates.
  •  Insulin Aspart  : Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents.
  •  Insulin Detemir  : Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents.
  •  Insulin Glargine  : Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents.
  •  Insulin Glulisine  : Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents.
  •  Insulin Lispro  : Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents.
  •  Insulin Regular  : Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents.
  •  Insulin, isophane  : Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents.
  •  Itraconazole  : May increase the serum concentration of Sirolimus.
  •  Ivacaftor  : May increase the serum concentration of CYP3A4 Substrates.
  •  Ketoconazole  : Ketoconazole (Systemic) may increase the serum concentration of Sirolimus.
  •  Leflunomide  : Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased.
  •  Linagliptin  : Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents.
  •  Lisinopril  : May enhance the adverse/toxic effect of ACE Inhibitors.
  •  Luliconazole  : May increase the serum concentration of CYP3A4 Substrates.
  •  Metamizole  : May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased
  •  Metformin  : Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents.
  •  Mifepristone  : May increase the serum concentration of Sirolimus.
  •  Mitotane  : May decrease the serum concentration of CYP3A4 Substrates.
  •  Moexipril  : May enhance the adverse/toxic effect of ACE Inhibitors.
  •  Natalizumab  : Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased.
  •  Nelfinavir  : May increase the serum concentration of Sirolimus.
  •  Netupitant  : May increase the serum concentration of CYP3A4 Substrates.
  •  Palbociclib  : May increase the serum concentration of CYP3A4 Substrates.
  •  Perindopril  : May enhance the adverse/toxic effect of ACE Inhibitors.
  •  Phenytoin  : May decrease the serum concentration of Sirolimus.
  •  Pimecrolimus  : May enhance the adverse/toxic effect of Immunosuppressants.
  •  Posaconazole  : May increase the serum concentration of Sirolimus.
  •  Quinapril  : May enhance the adverse/toxic effect of ACE Inhibitors.
  •  Ramipril  : May enhance the adverse/toxic effect of ACE Inhibitors.
  •  Ranolazine  : May increase the serum concentration of P-glycoprotein/ABCB1 Substrates.
  •  Repaglinide  : Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents.
  •  Rifampicin  : May increase the metabolism of Sirolimus.
  •  Roflumilast  : May enhance the immunosuppressive effect of Immunosuppressants.
  •  Saxagliptin  : Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents.
  •  Siltuximab  : May decrease the serum concentration of CYP3A4 Substrates.
  •  Sipuleucel-T  : Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T.
  •  Stiripentol  : May increase the serum concentration of CYP3A4 Substrates.
  •  Sulfisoxazole  : Macrolide Antibiotics may decrease the metabolism of Sirolimus.
  •  Tacrolimus  : Tacrolimus (Systemic) may enhance the adverse/toxic effect of Sirolimus. Sirolimus may enhance the adverse/toxic effect of Tacrolimus (Systemic). Sirolimus may decrease the serum concentration of Tacrolimus (Systemic).
  •  Telaprevir  : May increase the serum concentration of Sirolimus.
  •  Telithromycin  : Macrolide Antibiotics may decrease the metabolism of Sirolimus.
  •  Tocilizumab  : May decrease the serum concentration of CYP3A4 Substrates.
  •  Tofacitinib  : Immunosuppressants may enhance the immunosuppressive effect of Tofacitinib.
  •  Tolbutamide  : Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents.
  •  Trandolapril  : May enhance the adverse/toxic effect of ACE Inhibitors.
  •  Trastuzumab  : May enhance the neutropenic effect of Immunosuppressants.
  •  Vildagliptin  : Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents.
  •  Voriconazole  : May increase the serum concentration of Sirolimus.

Calculated Property

kind Value Source
logP 4.85 ALOGPS
logS -5.7 ALOGPS
Water Solubility 1.73e-03 g/l ALOGPS
logP 7.45 ChemAxon
IUPAC Name (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,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[30.3.1.0⁴,⁹]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone ChemAxon
Traditional IUPAC Name sirolimus ChemAxon
Molecular Weight 914.1719 ChemAxon
Monoisotopic Weight 913.555141619 ChemAxon
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=CC=CC=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 ChemAxon
Molecular Formula C51H79NO13 ChemAxon
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 ChemAxon
InChIKey InChIKey=QFJCIRLUMZQUOT-KLHQEZAJSA-N ChemAxon
Polar Surface Area (PSA) 195.43 ChemAxon
Refractivity 250.66 ChemAxon
Polarizability 100.46 ChemAxon
Rotatable Bond Count 6 ChemAxon
H Bond Acceptor Count 12 ChemAxon
H Bond Donor Count 3 ChemAxon
pKa (strongest acidic) 9.96 ChemAxon
pKa (strongest basic) -3 ChemAxon
Physiological Charge 0 ChemAxon
Number of Rings 4 ChemAxon
Bioavailability 0 ChemAxon
Rule of Five 0 ChemAxon
Ghose Filter 0 ChemAxon
MDDR-Like Rule 1 ChemAxon

Affected organism

Humans and other mammals

Target within organism

  • Serine/threonine-protein kinase mTOR : in Human
  • Peptidyl-prolyl cis-trans isomerase FKBP1A : in Human
  • Fibroblast growth factor 2 : in Human