Identification

Summary

Sirolimus is an mTOR inhibitor immunosuppressant used to prevent organ transplant rejections, treat lymphangioleiomyomatosis, and treat adults with perivascular epithelioid cell tumors.

Brand Names
Fyarro, Rapamune
Generic Name
Sirolimus
DrugBank Accession Number
DB00877
Background

Sirolimus, also known as rapamycin, is a macrocyclic lactone antibiotic produced by bacteria Streptomyces hygroscopicus, which was isolated from the soil of the Vai Atari region of Rapa Nui (Easter Island).5 It was first isolated and identified as an antifungal agent with potent anticandida activity; however, after its potent antitumor and immunosuppressive activities were later discovered, it was extensively investigated as an immunosuppressive and antitumour agent.3 Its primary mechanism of action is the inhibition of the mammalian target of rapamycin (mTOR), which is a serine/threonine-specific protein kinase that regulates cell growth, proliferation, and survival. mTOR is an important therapeutic target for various diseases, as it was shown to regulate longevity and maintain normal glucose homeostasis.6 Targeting mTOR received more attention especially in cancer, as mTOR signalling pathways are constitutively activated in many types of human cancer.1

Sirolimus was first approved by the FDA in 1999 for the prophylaxis of organ rejection in patients aged 13 years and older receiving renal transplants.4 In November 2000, the drug was recognized by the European Agency as an alternative to calcineurin antagonists for maintenance therapy with corticosteroids.5 In May 2015, the FDA approved sirolimus for the treatment of patients with lymphangioleiomyomatosis.10 In November 2021, albumin-bound sirolimus for intravenous injection was approved by the FDA for the treatment of adults with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumour (PEComa).9 Sirolimus was also investigated in other cancers such as skin cancer, Kaposi’s Sarcoma, cutaneous T-cell lymphomas, and tuberous sclerosis.4

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 914.187
Monoisotopic: 913.555141608
Chemical Formula
C51H79NO13
Synonyms
  • (-)-Rapamycin
  • Rapamycin
  • Sirolimús
  • Sirolimus
  • Sirolimusum
External IDs
  • AY-22989
  • WY-090217

Pharmacology

Indication

Sirolimus is indicated for the prophylaxis of organ rejection in patients aged 13 years or older receiving renal transplants. In patients at low-to moderate-immunologic risk, it is recommended that sirolimus be used initially in a regimen with cyclosporine and corticosteroids; cyclosporine should be withdrawn two to four months after transplantation. In patients at high-immunologic risk (defined as Black recipients and/or repeat renal transplant recipients who lost a previous allograft for immunologic reason and/or patients with high panel-reactive antibodies [PRA; peak PRA level > 80%]), it is recommended that sirolimus be used in combination with cyclosporine and corticosteroids for the first year following transplantation.8

It is also used to treat lymphangioleiomyomatosis.8

In the US, albumin-bound sirolimus for intravenous injection is indicated for the treatment of adult patients with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumour (PEComa).9

In Europe, it is recommended that sirolimus for the prophylaxis of organ rejection in renal transplants is used in combination with cyclosporin microemulsion and corticosteroids for two to three months. Sirolimus may be continued as maintenance therapy with corticosteroids only if cyclosporin microemulsion can be progressively discontinued.13

Pharmacology
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Associated Conditions
Associated Therapies
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Sirolimus is an immunosuppressant drug with antifungal and antitumour effects.2 In animal models, sirolimus prolonged allograft survival following various organ transplants and reversed an acute rejection of heart and kidney allografts in rats. Upon oral administration of 2 mg/day and 5 mg/day, sirolimus significantly reduced the incidence of organ rejection in low- to moderate-immunologic risk renal transplant patients at six months following transplantation compared with either azathioprine or placebo. In some studies, the immunosuppressive effect of sirolimus lasted up to six months after discontinuation of therapy: this tolerization effect is alloantigen-specific.8 Sirolimus potently inhibits antigen-induced proliferation of T cells, B cells, and antibody production.3

In rodent models of autoimmune disease, sirolimus suppressed immune-mediated events associated with systemic lupus erythematosus, collagen-induced arthritis, autoimmune type I diabetes, autoimmune myocarditis, experimental allergic encephalomyelitis, graft-versus-host disease, and autoimmune uveoretinitis.8

Mechanism of action

Sirolimus works by inhibiting T-lymphocyte activation and proliferation stimulated by antigens and cytokines such as interleukin (IL)-2, IL-4, and IL-15. In target cells, sirolimus binds to the cytoplasmic receptor FK506-binding protein-12 (FKBP12), an immunophilin, to form an immunosuppressive complex. FKBP12-sirolimus complex binds to and inhibits the activation of the mammalian target of rapamycin (mTOR),2,8 which is a serine/threonine-specific protein kinase that regulates cell growth, proliferation, survival, mobility, and angiogenesis.1,2 mTOR regulates the downstream signalling pathways involved in cell survival, such as the phosphatidylinositol-3 kinase (PI3K)/Akt signalling pathway.1 Inhibition of mTOR leads to the suppression of cytokine-driven T-cell proliferation, thus the progression from the G1 to the S phase of the cell cycle is inhibited. Sirolimus also inhibits antibody production. In vitro, sirolimus and other mTOR inhibitors inhibit the production of certain growth factors that may affect angiogenesis, fibroblast proliferation, and vascular permeability.8

Lymphangioleiomyomatosis is a disorder that primarily affects the lungs. It is characterized by lung tissue infiltration, unregulated alveolar smooth muscle proliferation, and cystic destruction of parenchyma. Although infrequent, it occurs as a symptomatic pulmonary complication in tuberous sclerosis complex (TSC), which is an inherited disorder caused by mutations in TSC genes.7 Loss of functional TSC gene leads to the aberrant activation of the mTOR signalling pathway, resulting in cellular proliferation and release of lymphangiogenic growth factors. Sirolimus inhibits the activated mTOR pathway and proliferation of alveolar smooth muscle cell proliferation.8

TargetActionsOrganism
ASerine/threonine-protein kinase mTOR
inhibitor
Humans
Absorption

In adult renal transplant patients with low- to moderate-immunologic risk, oral administration of 2 mg sirolimus led to a Cmax of 14.4 ± 5.3 ng/mL for oral solution and 15.0 ± 4.9 ng/mL for oral tablets. The tmax was 2.1 ± 0.8 hours for oral solution and 3.5 ± 2.4 hours for oral tablets. In healthy subjects, the tmax is one hour. In a multi-dose study, steady-state was reached six days following repeated twice-daily administration without an initial loading dose, with the average trough concentration of sirolimus increased approximately 2- to 3-fold. It is suspected that a loading dose of three times the maintenance dose will provide near steady-state concentrations within one day in most patients.8

The systemic availability of sirolimus is approximately 14%. In healthy subjects, the mean bioavailability of sirolimus after administration of the tablet is approximately 27% higher relative to the solution. Sirolimus tablets are not bioequivalent to the solution; however, clinical equivalence has been demonstrated at the 2 mg dose level. Sirolimus concentrations, following the administration of Rapamune Oral Solution to stable renal transplant patients, are dose-proportional between 3 and 12 mg/m2.8

Volume of distribution

The mean (± SD) blood-to-plasma ratio of sirolimus was 36 ± 18 L in stable renal allograft patients, indicating that sirolimus is extensively partitioned into formed blood elements. The mean volume of distribution (Vss/F) of sirolimus is 12 ± 8 L/kg.8

Protein binding

Sirolimus is 92% bound to human plasma proteins, mainly serum albumin (97%), α1-acid glycoprotein, and lipoproteins.8

Metabolism

Sirolimus undergoes extensive metabolism in the intestinal wall and liver. Sirolimus is primarily metabolized by O-demethylation and/or hydroxylation via CYP3A4 to form seven major metabolites, including hydroxy, demethyl, and hydroxydemethyl metabolites, which are pharmacologically inactive. Sirolimus also undergoes counter-transport from enterocytes of the small intestine into the gut lumen.8

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Route of elimination

Following oral administration of [14C] sirolimus in healthy subjects, about 91% of the radioactivity was recovered from feces and only 2.2% of the radioactivity was detected in urine. Some of the metabolites of sirolimus are also detectable in feces and urine.8

Half-life

The mean ± SD terminal elimination half-life (t½) of sirolimus after multiple dosing in stable renal transplant patients was estimated to be about 62 ± 16 hours.8

Clearance

In adult renal transplant patients with low- to moderate-immunologic risk, oral administration of 2 mg sirolimus led to oral clearance of 173 ± 50 mL/h/kg for oral solution and 139 ± 63 mL/h/kg for oral tablets.8

Adverse Effects
Adverseeffects
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Toxicity

Oral LD50 of sirolimus is 800 mg/kg in rats and 2500 mg/kg in mouse.12

Sirolimus is a narrow therapeutic index drug.5 Although there are reports of overdose with sirolimus, there is limited information on overdose in the clinical setting. Symptoms of overdose are consistent with the adverse effects of sirolimus. General supportive measures are recommended in the event of an overdose. Because sirolimus has low aqueous solubility and high erythrocyte and plasma protein binding, it is not expected to be dialyzable to any significant extent.8

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AbametapirThe serum concentration of Sirolimus can be increased when it is combined with Abametapir.
AbataceptThe metabolism of Sirolimus can be increased when combined with Abatacept.
AbciximabThe risk or severity of bleeding can be increased when Abciximab is combined with Sirolimus.
AbemaciclibThe serum concentration of Abemaciclib can be increased when it is combined with Sirolimus.
AbirateroneThe metabolism of Sirolimus can be decreased when combined with Abiraterone.
AcalabrutinibThe metabolism of Sirolimus can be decreased when combined with Acalabrutinib.
AcarboseThe therapeutic efficacy of Acarbose can be decreased when used in combination with Sirolimus.
AcenocoumarolThe therapeutic efficacy of Acenocoumarol can be increased when used in combination with Sirolimus.
AcetaminophenThe metabolism of Sirolimus can be increased when combined with Acetaminophen.
AcetazolamideThe metabolism of Sirolimus can be decreased when combined with Acetazolamide.
Interactions
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Food Interactions
  • Avoid grapefruit products. Grapefruit inhibits the CYP3A4 metabolism of sirolimus and increases its serum concentration.
  • Exercise caution with St. John's Wort. This herb induces CYP3A4 and P-gp; thus it may reduce sirolimus serum concentrations.
  • Take with or without food. Take consistently with regard to food.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
FyarroInjection, powder, lyophilized, for suspension5 mg/1mLIntravenousAadi Bioscience2021-11-22Not applicableUS flag
RapamuneTablet, sugar coated1 mg/1OralWyeth Pharmaceuticals Llc, a Subsidiary of Pfizer Inc.2001-07-01Not applicableUS flag
RapamuneTablet5 mgOralPfizer Canada UlcNot applicableNot applicableCanada flag
RapamuneTablet, coated2 mgOralPfizer Europe Ma Eeig2016-09-07Not applicableEU flag
RapamuneTablet, sugar coated2 mg/1OralWyeth Pharmaceuticals Inc.2006-10-10Not applicableUS flag
RapamuneSolution1.0 mg / mLOralPfizer Canada Ulc2001-05-15Not applicableCanada flag
RapamuneSolution1 mg/mlOralPfizer Europe Ma Eeig2016-09-07Not applicableEU flag
RapamuneTablet, coated0.5 mgOralPfizer Europe Ma Eeig2016-09-07Not applicableEU flag
RapamuneTablet, sugar coated0.5 mg/1OralWyeth Pharmaceuticals Llc, a Subsidiary of Pfizer Inc.2010-03-01Not applicableUS flag
RapamuneTablet2 mgOralPfizer Canada UlcNot applicableNot applicableCanada flag
Generic Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Gd-sirolimusTablet1.0 mgOralGenmed A Division Of Pfizer Canada UlcNot applicableNot applicableCanada flag
Gd-sirolimusTablet5 mgOralGenmed A Division Of Pfizer Canada UlcNot applicableNot applicableCanada flag
Gd-sirolimusSolution1.0 mg / mLOralGenmed A Division Of Pfizer Canada UlcNot applicableNot applicableCanada flag
Gd-sirolimusTablet2 mgOralGenmed A Division Of Pfizer Canada UlcNot applicableNot applicableCanada flag
SirolimusTablet, film coated0.5 mg/1OralAmerican Health Packaging2015-03-312020-04-30US flag
SirolimusTablet, sugar coated0.5 mg/1OralGreenstone LLC2014-01-07Not applicableUS flag
SirolimusTablet, film coated1 mg/1OralMajor Pharmaceuticals2020-10-16Not applicableUS flag
SirolimusTablet1 mg/1OralDr. Reddy's Laboratories Limited2014-10-27Not applicableUS flag
SirolimusTablet, film coated1 mg/1OralCadila Healthcare Limited2014-01-072014-01-03US flag
SirolimusTablet, film coated1 mg/1OralGlenmark Pharmaceuticals Inc., USA2020-10-16Not applicableUS flag

Categories

ATC Codes
S01XA23 — SirolimusL04AA10 — Sirolimus
Drug Categories
Chemical TaxonomyProvided by Classyfire
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
show 10 more
Substituents
Alcohol / Aliphatic heteropolycyclic compound / Alpha-amino acid ester / Alpha-amino acid or derivatives / Azacycle / Carbonyl group / Carboxamide group / Carboxylic acid derivative / Carboxylic acid ester / Cyclic alcohol
show 24 more
Molecular Framework
Aliphatic heteropolycyclic compounds
External Descriptors
cyclic ketone, antibiotic antifungal drug, organic heterotricyclic compound, secondary alcohol, ether, lactam, macrolide, cyclic acetal (CHEBI:9168) / Plyenes (C07909)
Affected organisms
  • Humans and other mammals

Chemical Identifiers

UNII
W36ZG6FT64
CAS number
53123-88-9
InChI Key
QFJCIRLUMZQUOT-HPLJOQBZSA-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,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-[(2R)-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

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 References
  1. 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. [Article]
  2. 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. [Article]
  3. Sehgal SN: Sirolimus: its discovery, biological properties, and mechanism of action. Transplant Proc. 2003 May;35(3 Suppl):7S-14S. [Article]
  4. Peters T, Traboulsi D, Tibbles LA, Mydlarski PR: Sirolimus: a therapeutic advance for dermatologic disease. Skin Therapy Lett. 2014 Jul-Aug;19(4):1-4. [Article]
  5. Yakupoglu YK, Kahan BD: Sirolimus: a current perspective. Exp Clin Transplant. 2003 Jun;1(1):8-18. [Article]
  6. Li J, Kim SG, Blenis J: Rapamycin: one drug, many effects. Cell Metab. 2014 Mar 4;19(3):373-9. doi: 10.1016/j.cmet.2014.01.001. Epub 2014 Feb 6. [Article]
  7. Hancock E, Tomkins S, Sampson J, Osborne J: Lymphangioleiomyomatosis and tuberous sclerosis. Respir Med. 2002 Jan;96(1):7-13. doi: 10.1053/rmed.2001.1206. [Article]
  8. FDA Approved Drug Products: RAPAMUNE (sirolimus) for oral use [Link]
  9. FDA Approved Drug Products: FYARRO (sirolimus protein-bound particles for injectable suspension) (albumin-bound), for intravenous use [Link]
  10. Pfizer News: PFIZER’S RAPAMUNE® (SIROLIMUS) BECOMES FIRST FDA-APPROVED TREATMENT FOR LYMPHANGIOLEIOMYOMATOSIS (LAM), A RARE PROGRESSIVE LUNG DISEASE [Link]
  11. ThermoFischer Scientific: Rapamycin MSDS [Link]
  12. Pfizer: RAPAMUNE MSDS [Link]
  13. EMA Summary of Product Characteristics: Rapamune (sirolimus) Oral Solution [Link]
Human Metabolome Database
HMDB15015
KEGG Drug
D00753
KEGG Compound
C07909
PubChem Compound
5284616
PubChem Substance
46505675
ChemSpider
10482078
BindingDB
36609
RxNav
35302
ChEBI
9168
ChEMBL
CHEMBL413
ZINC
ZINC000169289388
Therapeutic Targets Database
DNC001197
PharmGKB
PA451365
PDBe Ligand
RAP
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
Wikipedia
Sirolimus
PDB Entries
1c9h / 1fap / 1fkb / 1fkl / 1pbk / 1z58 / 2dg3 / 2dg4 / 2dg9 / 2vcd
show 12 more
FDA label
Download (480 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4Active Not RecruitingTreatmentConnective Tissue Diseases / Thrombocytopenia1
4Active Not RecruitingTreatmentLiver Diseases1
4CompletedNot AvailableGraft Versus Host Disease (cGvHD) / Kidney Transplantation / Renal Failure, Chronic Renal Failure1
4CompletedHealth Services ResearchCoronary Artery Restenosis / Coronary Heart Disease (CHD)1
4CompletedPreventionAcute Graft Rejection / Graft Function, Delayed1
4CompletedPreventionHepatitis C Virus (HCV) Infection1
4CompletedPreventionKidney Failure / Rejection, Transplant1
4CompletedPreventionKidney Transplant Infection1
4CompletedPreventionKidney Transplantation2
4CompletedPreventionKidney Transplantation / Rejection, Transplant / Renal Allograft Recipients1

Pharmacoeconomics

Manufacturers
  • Wyeth pharmaceuticals inc
Packagers
  • Cardinal Health
  • Hangzhou Zhongmei Huadong Pharmaceutical Co. Ltd.
  • Lake Erie Medical and Surgical Supply
  • Patheon Inc.
  • Poli Industria Chimica SPA
  • Wyeth Pharmaceuticals
Dosage Forms
FormRouteStrength
Injection, powder, lyophilized, for suspensionIntravenous5 mg/1mL
SolutionOral1.0 mg / mL
SolutionOral2 MG/2ML
SolutionOral5 MG/5ML
TabletOral1.0 mg
TabletOral2 mg
TabletOral5 mg
Tablet, coatedOral0.5 MG
Tablet, coatedOral2 MG
Tablet, sugar coatedOral1 mg/1
Tablet, sugar coatedOral2 mg/1
TabletOral
SolutionOral
SolutionOral1 mg/mL
SolutionOral100 mg
Tablet, sugar coatedOral0.5 mg
Tablet, sugar coatedOral1 mg
Tablet, coatedOral
Tablet, sugar coatedOral2 mg
Tablet, coatedOral1 mg
SolutionOral1 mg/1mL
TabletOral0.5 mg/1
TabletOral1 mg/1
TabletOral2 mg/1
Tablet, film coatedOral0.5 mg/1
Tablet, film coatedOral1 mg/1
Tablet, film coatedOral2 mg/1
Tablet, sugar coatedOral0.5 mg/1
Prices
Unit descriptionCostUnit
Rapamune 2 mg tablet20.59USD tablet
Rapamune 1 mg/ml Solution12.19USD ml
Rapamune 1 mg tablet11.95USD tablet
Rapamune 0.5 mg tablet5.86USD tablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US5212155No1993-05-182010-05-18US flag
CA2293793No2006-07-112018-06-11Canada flag
CA2103571No2003-04-292012-02-21Canada flag
US5989591Yes1999-11-232018-09-11US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
boiling point (°C)183-185https://www.fishersci.com/store/msds?partNumber=BP29631&productDescription=RAPAMYCIN&vendorId=VN00033897&countryCode=US&language=en
logP4.63https://pfe-pfizercom-prod.s3.amazonaws.com/products/material_safety_data/sirolimus_tablets_21-march-2018.pdf
Predicted Properties
PropertyValueSource
Water Solubility0.00173 mg/mLALOGPS
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 Area195.43 Å2ChemAxon
Rotatable Bond Count6ChemAxon
Refractivity250.66 m3·mol-1ChemAxon
Polarizability101.74 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET Features
PropertyValueProbability
Human Intestinal Absorption-0.7841
Blood Brain Barrier-0.9599
Caco-2 permeable-0.6341
P-glycoprotein substrateSubstrate0.8052
P-glycoprotein inhibitor IInhibitor0.8564
P-glycoprotein inhibitor IIInhibitor0.8021
Renal organic cation transporterNon-inhibitor0.8116
CYP450 2C9 substrateNon-substrate0.878
CYP450 2D6 substrateNon-substrate0.9138
CYP450 3A4 substrateSubstrate0.7776
CYP450 1A2 substrateNon-inhibitor0.9007
CYP450 2C9 inhibitorNon-inhibitor0.9125
CYP450 2D6 inhibitorNon-inhibitor0.9414
CYP450 2C19 inhibitorNon-inhibitor0.9158
CYP450 3A4 inhibitorNon-inhibitor0.9333
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.9742
Ames testNon AMES toxic0.6617
CarcinogenicityNon-carcinogens0.9546
BiodegradationNot ready biodegradable0.9593
Rat acute toxicity2.8689 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9831
hERG inhibition (predictor II)Non-inhibitor0.8443
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

Drugtargets2
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Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Inhibitor
General Function
Tfiiic-class transcription factor binding
Specific Function
Serine/threonine protein kinase which is a central regulator of cellular metabolism, growth and survival in response to hormones, growth factors, nutrients, energy and stress signals. MTOR directly...
Gene Name
MTOR
Uniprot ID
P42345
Uniprot Name
Serine/threonine-protein kinase mTOR
Molecular Weight
288889.05 Da
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. doi: 10.1016/j.bbapap.2009.12.001. Epub 2009 Dec 11. [Article]
  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. [Article]
  3. Sehgal SN: Sirolimus: its discovery, biological properties, and mechanism of action. Transplant Proc. 2003 May;35(3 Suppl):7S-14S. [Article]
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
  5. 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. [Article]
  6. Ozates NP, Sogutlu F, Lerminoglu F, Demir B, Gunduz C, Shademan B, Avci CB: Effects of rapamycin and AZD3463 combination on apoptosis, autophagy, and cell cycle for resistance control in breast cancer. Life Sci. 2021 Jan 1;264:118643. doi: 10.1016/j.lfs.2020.118643. Epub 2020 Oct 24. [Article]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Vitamin d3 25-hydroxylase 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 react...
Gene Name
CYP3A4
Uniprot ID
P08684
Uniprot Name
Cytochrome P450 3A4
Molecular Weight
57342.67 Da
References
  1. 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. [Article]
  2. Sadaba B, Campanero MA, Quetglas EG, Azanza JR: Clinical relevance of sirolimus drug interactions in transplant patients. Transplant Proc. 2004 Dec;36(10):3226-8. doi: 10.1016/j.transproceed.2004.10.056. [Article]
  3. Flockhart Table of Drug Interactions [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Oxygen binding
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 un...
Gene Name
CYP3A5
Uniprot ID
P20815
Uniprot Name
Cytochrome P450 3A5
Molecular Weight
57108.065 Da
References
  1. Flockhart Table of Drug Interactions [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
General Function
Oxygen binding
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 un...
Gene Name
CYP3A7
Uniprot ID
P24462
Uniprot Name
Cytochrome P450 3A7
Molecular Weight
57525.03 Da
References
  1. Flockhart Table of Drug Interactions [Link]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Binder
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. FDA Approved Drug Products: RAPAMUNE (sirolimus) for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Binder
General Function
Not Available
Specific Function
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...
Gene Name
ORM1
Uniprot ID
P02763
Uniprot Name
Alpha-1-acid glycoprotein 1
Molecular Weight
23511.38 Da
References
  1. FDA Approved Drug Products: RAPAMUNE (sirolimus) for oral use [Link]
Kind
Protein group
Organism
Humans
Pharmacological action
No
Actions
Binder
General Function
Phospholipid transporter activity
Specific Function
Participates in the reverse transport of cholesterol from tissues to the liver for excretion by promoting cholesterol efflux from tissues and by acting as a cofactor for the lecithin cholesterol ac...

Components:
References
  1. FDA Approved Drug Products: RAPAMUNE (sirolimus) for oral use [Link]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Substrate
Inhibitor
Inducer
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
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. [Article]
  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. [Article]
  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. [Article]
  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. [Article]
  5. FDA Approved Drug Products: RAPAMUNE (sirolimus) for oral use [Link]
Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Inhibitor
General Function
Sodium-independent organic anion transmembrane transporter activity
Specific Function
Mediates the Na(+)-independent uptake of organic anions such as pravastatin, taurocholate, methotrexate, dehydroepiandrosterone sulfate, 17-beta-glucuronosyl estradiol, estrone sulfate, prostagland...
Gene Name
SLCO1B1
Uniprot ID
Q9Y6L6
Uniprot Name
Solute carrier organic anion transporter family member 1B1
Molecular Weight
76447.99 Da
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. [Article]
Kind
Protein
Organism
Humans
Pharmacological action
No
General Function
Monovalent cation:proton antiporter activity
Specific Function
Solute transporter for tetraethylammonium (TEA), 1-methyl-4-phenylpyridinium (MPP), cimetidine, N-methylnicotinamide (NMN), metformin, creatinine, guanidine, procainamide, topotecan, estrone sulfat...
Gene Name
SLC47A1
Uniprot ID
Q96FL8
Uniprot Name
Multidrug and toxin extrusion protein 1
Molecular Weight
61921.585 Da
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. doi: 10.1152/ajprenal.00431.2009. Epub 2010 Jan 6. [Article]

Drug created at June 13, 2005 13:24 / Updated at January 20, 2022 04:55