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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, Hyftor, 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 The topical formulation of sirolimus, marketed as HYFTOR, was approved by the FDA in April 2022: this marks the first topical treatment approved in the US for facial angiofibroma associated with tuberous sclerosis complex.15
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Sirolimus (DB00877)
- 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
Topical sirolimus is indicated for the treatment of facial angiofibroma associated with tuberous sclerosis in adults and pediatric patients six years of age and older.14
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Chordoma ••• ••••• Management of Facial angiofibromas •••••••••••• ••••••••••• •••••• ••••••••• ••• Prevention of Graft-versus-host disease ••• ••••• Treatment of Graft-versus-host disease ••• ••••• Prevention of Heart transplant rejection ••• ••••• - Contraindications & Blackbox Warnings
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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
Target Actions Organism ASerine/threonine-protein kinase mTOR inhibitorHumans - 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
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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.
Drug Interaction Integrate drug-drug
interactions in your softwareAbametapir The serum concentration of Sirolimus can be increased when it is combined with Abametapir. Abatacept The metabolism of Sirolimus can be increased when combined with Abatacept. Abciximab The risk or severity of bleeding can be increased when Abciximab is combined with Sirolimus. Abemaciclib The serum concentration of Abemaciclib can be increased when it is combined with Sirolimus. Abrocitinib The serum concentration of Sirolimus can be increased when it is combined with Abrocitinib. - 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
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Fyarro Injection, powder, lyophilized, for suspension 5 mg/1mL Intravenous Aadi Bioscience 2021-12-06 Not applicable US 
Hyftor Gel 2.0 mg/1g Topical NOBELPHARMA AMERICA, LLC 2022-03-23 Not applicable US Hyftor Gel 2 mg/g Topical Plusultra Pharma Gmb H 2023-06-20 Not applicable EU 
Rapamune Tablet 1.0 mg Oral Pfizer Canada Ulc 2003-03-25 Not applicable Canada 
Rapamune Tablet, sugar coated 1 mg/1 Oral Wyeth Pharmaceuticals Llc, a Subsidiary of Pfizer Inc. 2001-07-01 2025-12-31 US - Generic Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Gd-sirolimus Tablet 2 mg Oral Genmed A Division Of Pfizer Canada Ulc Not applicable Not applicable Canada Gd-sirolimus Tablet 1.0 mg Oral Genmed A Division Of Pfizer Canada Ulc Not applicable Not applicable Canada Gd-sirolimus Tablet 5 mg Oral Genmed A Division Of Pfizer Canada Ulc Not applicable Not applicable Canada Gd-sirolimus Solution 1.0 mg / mL Oral Genmed A Division Of Pfizer Canada Ulc Not applicable Not applicable Canada Sirolimus Tablet, film coated 0.5 mg/1 Oral Zydus Pharmaceuticals USA Inc. 2014-01-15 Not applicable US
Categories
- ATC Codes
- L01EG04 — Sirolimus
- L01EG — Mammalian target of rapamycin (mTOR) kinase inhibitors
- L01E — PROTEIN KINASE INHIBITORS
- L01 — ANTINEOPLASTIC AGENTS
- L — ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS
- S01XA — Other ophthalmologicals
- S01X — OTHER OPHTHALMOLOGICALS
- S01 — OPHTHALMOLOGICALS
- S — SENSORY ORGANS
- Drug Categories
- Agents causing angioedema
- Anti-Bacterial Agents
- Anti-Infective Agents
- Antibiotics, Antineoplastic
- Antifungal Agents
- Antineoplastic and Immunomodulating Agents
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 CYP3A4 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 CYP3A5 Substrates
- Cytochrome P-450 CYP3A5 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 CYP3A7 Substrates
- Cytochrome P-450 CYP3A7 Substrates with a Narrow Therapeutic Index
- Cytochrome P-450 Substrates
- Decreased Immunologic Activity
- Hyperglycemia-Associated Agents
- Immunologic Factors
- Immunosuppressive Agents
- Immunotherapy
- Kinase Inhibitor
- Lactones
- Macrolides
- Mammalian target of rapamycin (mTOR) kinase inhibitors
- mTOR Inhibitor Immunosuppressant
- mTOR Inhibitors
- Myelosuppressive Agents
- Narrow Therapeutic Index Drugs
- OATP1B1/SLCO1B1 Inhibitors
- Ophthalmologicals
- P-glycoprotein inducers
- P-glycoprotein inhibitors
- P-glycoprotein substrates
- P-glycoprotein substrates with a Narrow Therapeutic Index
- Polyketides
- Protein Kinase Inhibitors
- Selective Immunosuppressants
- Sensory Organs
- Sirolimus and Prodrugs
- 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
- 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]
- 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]
- Sehgal SN: Sirolimus: its discovery, biological properties, and mechanism of action. Transplant Proc. 2003 May;35(3 Suppl):7S-14S. [Article]
- 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]
- Yakupoglu YK, Kahan BD: Sirolimus: a current perspective. Exp Clin Transplant. 2003 Jun;1(1):8-18. [Article]
- 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]
- 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]
- FDA Approved Drug Products: RAPAMUNE (sirolimus) for oral use [Link]
- FDA Approved Drug Products: FYARRO (sirolimus protein-bound particles for injectable suspension) (albumin-bound), for intravenous use [Link]
- Pfizer News: PFIZER’S RAPAMUNE® (SIROLIMUS) BECOMES FIRST FDA-APPROVED TREATMENT FOR LYMPHANGIOLEIOMYOMATOSIS (LAM), A RARE PROGRESSIVE LUNG DISEASE [Link]
- ThermoFischer Scientific: Rapamycin MSDS [Link]
- Pfizer: RAPAMUNE MSDS [Link]
- EMA Summary of Product Characteristics: Rapamune (sirolimus) Oral Solution [Link]
- FDA Approved Drug Products: HYFTOR (sirolimus topical gel) [Link]
- BioSpace News: FDA approves Nobelpharma's HYFTOR™ (sirolimus topical gel) 0.2% [Link]
- External Links
- Human Metabolome Database
- HMDB0015015
- KEGG Drug
- D00753
- KEGG Compound
- C07909
- PubChem Compound
- 5284616
- PubChem Substance
- 46505675
- ChemSpider
- 10482078
- BindingDB
- 36609
- 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 14 more
- FDA label
- Download (480 KB)
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Active Not Recruiting Treatment Coronary Artery Disease (CAD) 1 somestatus stop reason just information to hide Not Available Active Not Recruiting Treatment Haemoglobinopathies congenital / Sickle Cell Disease (SCD) 1 somestatus stop reason just information to hide Not Available Approved for Marketing Not Available Malignant Perivascular Epithelioid Cell Neoplasms / MTOR Pathway Abberation / TSC1 / TSC2 1 somestatus stop reason just information to hide Not Available Completed Not Available Aging 1 somestatus stop reason just information to hide Not Available Completed Not Available Autosomal Dominant Polycystic Kidney Disease （ADPKD) 1 somestatus stop reason just information to hide
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
Form Route Strength Injection, powder, lyophilized, for suspension Intravenous 5 mg/1mL Gel Topical 2 mg/g Gel Topical 2.0 mg/1g Solution Oral 0.10 g Tablet Oral 1.00 mg Solution Oral 1 mg Solution Oral 1.0 mg / mL Solution Oral 2 MG/2ML Solution Oral 5 MG/5ML Tablet Oral 1.0 mg Tablet Oral 1.020 mg Tablet Oral 2 mg Tablet Oral 5 mg Tablet, coated Oral 0.5 MG Tablet, coated Oral 2 MG Tablet, sugar coated Oral 1 mg/1 Tablet, sugar coated Oral 2 mg/1 Tablet Oral Solution Oral 1 mg/mL Solution Oral 100 mg Tablet, sugar coated Oral 0.5 mg Tablet, sugar coated Oral 1 mg Tablet, coated Oral Tablet, sugar coated Oral 2 mg Tablet, coated Oral 1 mg Solution Oral 100.000 mg Solution Oral 1 mg/1mL Tablet Oral 0.5 mg/1 Tablet Oral 1 mg/1 Tablet Oral 2 mg/1 Tablet, film coated Oral 0.5 mg/1 Tablet, film coated Oral 1 mg/1 Tablet, film coated Oral 2 mg/1 Tablet, sugar coated Oral 0.5 mg/1 - Prices
Unit description Cost Unit Rapamune 2 mg tablet 20.59USD tablet Rapamune 1 mg/ml Solution 12.19USD ml Rapamune 1 mg tablet 11.95USD tablet Rapamune 0.5 mg tablet 5.86USD tablet DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US5212155 No 1993-05-18 2010-05-18 US CA2293793 No 2006-07-11 2018-06-11 Canada CA2103571 No 2003-04-29 2012-02-21 Canada US5989591 Yes 1999-11-23 2018-09-11 US US10973806 No 2021-04-13 2036-06-29 US US8911786 No 2014-12-16 2029-02-14 US US10206887 No 2019-02-19 2030-04-15 US US10705070 No 2020-07-07 2036-03-05 US US11497737 No 2020-10-28 2040-10-28 US
Properties
- State
- Solid
- Experimental Properties
Property Value Source boiling point (°C) 183-185 https://www.fishersci.com/store/msds?partNumber=BP29631&productDescription=RAPAMYCIN&vendorId=VN00033897&countryCode=US&language=en logP 4.63 https://pfe-pfizercom-prod.s3.amazonaws.com/products/material_safety_data/sirolimus_tablets_21-march-2018.pdf - Predicted Properties
Property Value Source Water Solubility 0.00173 mg/mL 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 Å2 Chemaxon Rotatable Bond Count 6 Chemaxon Refractivity 250.66 m3·mol-1 Chemaxon Polarizability 101.74 Å3 Chemaxon Number of Rings 4 Chemaxon Bioavailability 0 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - 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 inhibitor Non-inhibitor 0.9125 CYP450 2D6 inhibitor Non-inhibitor 0.9414 CYP450 2C19 inhibitor Non-inhibitor 0.9158 CYP450 3A4 inhibitor 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
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 315.4114584 predictedDarkChem Lite v0.1.0 [M-H]- 318.2036584 predictedDarkChem Lite v0.1.0 [M-H]- 298.64835 predictedDeepCCS 1.0 (2019) [M+H]+ 317.6675584 predictedDarkChem Lite v0.1.0 [M+H]+ 300.37207 predictedDeepCCS 1.0 (2019) [M+Na]+ 317.6341584 predictedDarkChem Lite v0.1.0 [M+Na]+ 306.70102 predictedDeepCCS 1.0 (2019)
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Yes
- Actions
- Inhibitor
- General 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 (PubMed:12087098, PubMed:12150925, PubMed:12150926, PubMed:12231510, PubMed:12718876, PubMed:14651849, PubMed:15268862, PubMed:15467718, PubMed:15545625, PubMed:15718470, PubMed:18497260, PubMed:18762023, PubMed:18925875, PubMed:20516213, PubMed:20537536, PubMed:21659604, PubMed:23429703, PubMed:23429704, PubMed:25799227, PubMed:26018084, PubMed:29150432, PubMed:29236692, PubMed:31112131, PubMed:31601708, PubMed:32561715, PubMed:34519269, PubMed:37751742). MTOR directly or indirectly regulates the phosphorylation of at least 800 proteins (PubMed:15268862, PubMed:15467718, PubMed:17517883, PubMed:18372248, PubMed:18497260, PubMed:18925875, PubMed:20516213, PubMed:21576368, PubMed:21659604, PubMed:23429704, PubMed:29236692, PubMed:37751742). Functions as part of 2 structurally and functionally distinct signaling complexes mTORC1 and mTORC2 (mTOR complex 1 and 2) (PubMed:15268862, PubMed:15467718, PubMed:18497260, PubMed:18925875, PubMed:20516213, PubMed:21576368, PubMed:21659604, PubMed:23429704). In response to nutrients, growth factors or amino acids, mTORC1 is recruited to the lysosome membrane and promotes protein, lipid and nucleotide synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis (PubMed:12087098, PubMed:12150925, PubMed:12150926, PubMed:12231510, PubMed:12718876, PubMed:14651849, PubMed:15268862, PubMed:15467718, PubMed:15545625, PubMed:15718470, PubMed:18497260, PubMed:18762023, PubMed:18925875, PubMed:20516213, PubMed:20537536, PubMed:21659604, PubMed:23429703, PubMed:23429704, PubMed:25799227, PubMed:26018084, PubMed:29150432, PubMed:29236692, PubMed:31112131, PubMed:34519269). This includes phosphorylation of EIF4EBP1 and release of its inhibition toward the elongation initiation factor 4E (eiF4E) (PubMed:24403073, PubMed:29236692). Moreover, phosphorylates and activates RPS6KB1 and RPS6KB2 that promote protein synthesis by modulating the activity of their downstream targets including ribosomal protein S6, eukaryotic translation initiation factor EIF4B, and the inhibitor of translation initiation PDCD4 (PubMed:12087098, PubMed:12150925, PubMed:18925875, PubMed:29150432, PubMed:29236692). Stimulates the pyrimidine biosynthesis pathway, both by acute regulation through RPS6KB1-mediated phosphorylation of the biosynthetic enzyme CAD, and delayed regulation, through transcriptional enhancement of the pentose phosphate pathway which produces 5-phosphoribosyl-1-pyrophosphate (PRPP), an allosteric activator of CAD at a later step in synthesis, this function is dependent on the mTORC1 complex (PubMed:23429703, PubMed:23429704). Regulates ribosome synthesis by activating RNA polymerase III-dependent transcription through phosphorylation and inhibition of MAF1 an RNA polymerase III-repressor (PubMed:20516213). Activates dormant ribosomes by mediating phosphorylation of SERBP1, leading to SERBP1 inactivation and reactivation of translation (PubMed:36691768). In parallel to protein synthesis, also regulates lipid synthesis through SREBF1/SREBP1 and LPIN1 (PubMed:23426360). To maintain energy homeostasis mTORC1 may also regulate mitochondrial biogenesis through regulation of PPARGC1A (By similarity). In the same time, mTORC1 inhibits catabolic pathways: negatively regulates autophagy through phosphorylation of ULK1 (PubMed:32561715). Under nutrient sufficiency, phosphorylates ULK1 at 'Ser-758', disrupting the interaction with AMPK and preventing activation of ULK1 (PubMed:32561715). Also prevents autophagy through phosphorylation of the autophagy inhibitor DAP (PubMed:20537536). Also prevents autophagy by phosphorylating RUBCNL/Pacer under nutrient-rich conditions (PubMed:30704899). Prevents autophagy by mediating phosphorylation of AMBRA1, thereby inhibiting AMBRA1 ability to mediate ubiquitination of ULK1 and interaction between AMBRA1 and PPP2CA (PubMed:23524951, PubMed:25438055). mTORC1 exerts a feedback control on upstream growth factor signaling that includes phosphorylation and activation of GRB10 a INSR-dependent signaling suppressor (PubMed:21659604). Among other potential targets mTORC1 may phosphorylate CLIP1 and regulate microtubules (PubMed:12231510). The mTORC1 complex is inhibited in response to starvation and amino acid depletion (PubMed:12150925, PubMed:12150926, PubMed:24403073, PubMed:31695197). The non-canonical mTORC1 complex, which acts independently of RHEB, specifically mediates phosphorylation of MiT/TFE factors MITF, TFEB and TFE3 in the presence of nutrients, promoting their cytosolic retention and inactivation (PubMed:22343943, PubMed:22576015, PubMed:22692423, PubMed:24448649, PubMed:32612235, PubMed:36608670, PubMed:36697823). Upon starvation or lysosomal stress, inhibition of mTORC1 induces dephosphorylation and nuclear translocation of TFEB and TFE3, promoting their transcription factor activity (PubMed:22343943, PubMed:22576015, PubMed:22692423, PubMed:24448649, PubMed:32612235, PubMed:36608670). The mTORC1 complex regulates pyroptosis in macrophages by promoting GSDMD oligomerization (PubMed:34289345). MTOR phosphorylates RPTOR which in turn inhibits mTORC1 (By similarity). As part of the mTORC2 complex MTOR may regulate other cellular processes including survival and organization of the cytoskeleton (PubMed:15268862, PubMed:15467718). mTORC2 plays a critical role in the phosphorylation at 'Ser-473' of AKT1, a pro-survival effector of phosphoinositide 3-kinase, facilitating its activation by PDK1 (PubMed:15718470). mTORC2 may regulate the actin cytoskeleton, through phosphorylation of PRKCA, PXN and activation of the Rho-type guanine nucleotide exchange factors RHOA and RAC1A or RAC1B (PubMed:15268862). mTORC2 also regulates the phosphorylation of SGK1 at 'Ser-422' (PubMed:18925875). Regulates osteoclastogenesis by adjusting the expression of CEBPB isoforms (By similarity). Plays an important regulatory role in the circadian clock function; regulates period length and rhythm amplitude of the suprachiasmatic nucleus (SCN) and liver clocks (By similarity)
- Specific Function
- Atp binding
- Gene Name
- MTOR
- Uniprot ID
- P42345
- Uniprot Name
- Serine/threonine-protein kinase mTOR
- Molecular Weight
- 288889.05 Da
References
- 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]
- 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]
- Sehgal SN: Sirolimus: its discovery, biological properties, and mechanism of action. Transplant Proc. 2003 May;35(3 Suppl):7S-14S. [Article]
- Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
- 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]
- 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]
- Zhou Y, Zhang Y, Zhao D, Yu X, Shen X, Zhou Y, Wang S, Qiu Y, Chen Y, Zhu F: TTD: Therapeutic Target Database describing target druggability information. Nucleic Acids Res. 2024 Jan 5;52(D1):D1465-D1477. doi: 10.1093/nar/gkad751. [Article]
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of sterols, steroid hormones, retinoids and fatty acids (PubMed:10681376, PubMed:11093772, PubMed:11555828, PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:19965576, PubMed:20702771, PubMed:21490593, PubMed:21576599). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:12865317, PubMed:14559847, PubMed:15373842, PubMed:15764715, PubMed:21490593, PubMed:21576599, PubMed:2732228). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1) and 17beta-estradiol (E2), namely 2-hydroxy E1 and E2, as well as D-ring hydroxylated E1 and E2 at the C-16 position (PubMed:11555828, PubMed:12865317, PubMed:14559847). Plays a role in the metabolism of androgens, particularly in oxidative deactivation of testosterone (PubMed:15373842, PubMed:15764715, PubMed:22773874, PubMed:2732228). Metabolizes testosterone to less biologically active 2beta- and 6beta-hydroxytestosterones (PubMed:15373842, PubMed:15764715, PubMed:2732228). Contributes to the formation of hydroxycholesterols (oxysterols), particularly A-ring hydroxylated cholesterol at the C-4beta position, and side chain hydroxylated cholesterol at the C-25 position, likely contributing to cholesterol degradation and bile acid biosynthesis (PubMed:21576599). Catalyzes bisallylic hydroxylation of polyunsaturated fatty acids (PUFA) (PubMed:9435160). Catalyzes the epoxidation of double bonds of PUFA with a preference for the last double bond (PubMed:19965576). Metabolizes endocannabinoid arachidonoylethanolamide (anandamide) to 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acid ethanolamides (EpETrE-EAs), potentially modulating endocannabinoid system signaling (PubMed:20702771). Plays a role in the metabolism of retinoids. Displays high catalytic activity for oxidation of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes atRA toward 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Responsible for oxidative metabolism of xenobiotics. Acts as a 2-exo-monooxygenase for plant lipid 1,8-cineole (eucalyptol) (PubMed:11159812). Metabolizes the majority of the administered drugs. Catalyzes sulfoxidation of the anthelmintics albendazole and fenbendazole (PubMed:10759686). Hydroxylates antimalarial drug quinine (PubMed:8968357). Acts as a 1,4-cineole 2-exo-monooxygenase (PubMed:11695850). Also involved in vitamin D catabolism and calcium homeostasis. Catalyzes the inactivation of the active hormone calcitriol (1-alpha,25-dihydroxyvitamin D(3)) (PubMed:29461981)
- Specific Function
- 1,8-cineole 2-exo-monooxygenase activity
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- 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]
- 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]
- Flockhart Table of Drug Interactions [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of steroid hormones and vitamins (PubMed:10681376, PubMed:11093772, PubMed:12865317, PubMed:2732228). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase). Catalyzes the hydroxylation of carbon-hydrogen bonds (PubMed:10681376, PubMed:11093772, PubMed:12865317, PubMed:2732228). Exhibits high catalytic activity for the formation of catechol estrogens from 17beta-estradiol (E2) and estrone (E1), namely 2-hydroxy E1 and E2 (PubMed:12865317). Catalyzes 6beta-hydroxylation of the steroid hormones testosterone, progesterone, and androstenedione (PubMed:2732228). Catalyzes the oxidative conversion of all-trans-retinol to all-trans-retinal, a rate-limiting step for the biosynthesis of all-trans-retinoic acid (atRA) (PubMed:10681376). Further metabolizes all trans-retinoic acid (atRA) to 4-hydroxyretinoate and may play a role in hepatic atRA clearance (PubMed:11093772). Also involved in the oxidative metabolism of xenobiotics, including calcium channel blocking drug nifedipine and immunosuppressive drug cyclosporine (PubMed:2732228)
- Specific Function
- Aromatase activity
- Gene Name
- CYP3A5
- Uniprot ID
- P20815
- Uniprot Name
- Cytochrome P450 3A5
- Molecular Weight
- 57108.065 Da
References
- Flockhart Table of Drug Interactions [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- A cytochrome P450 monooxygenase involved in the metabolism of steroid hormones and vitamins during embryogenesis (PubMed:11093772, PubMed:12865317, PubMed:14559847, PubMed:17178770, PubMed:9555064). Mechanistically, uses molecular oxygen inserting one oxygen atom into a substrate, and reducing the second into a water molecule, with two electrons provided by NADPH via cytochrome P450 reductase (NADPH--hemoprotein reductase) (PubMed:11093772, PubMed:12865317, PubMed:14559847, PubMed:17178770, PubMed:9555064). Catalyzes the hydroxylation of carbon-hydrogen bonds. Metabolizes 3beta-hydroxyandrost-5-en-17-one (dehydroepiandrosterone, DHEA), a precursor in the biosynthesis of androgen and estrogen steroid hormones (PubMed:17178770, PubMed:9555064). Exhibits high catalytic activity for the formation of hydroxyestrogens from estrone (E1), particularly D-ring hydroxylated estrone at the C16-alpha position (PubMed:12865317, PubMed:14559847). Mainly hydroxylates all trans-retinoic acid (atRA) to 4-hydroxyretinoate and may play a role in atRA clearance during fetal development (PubMed:11093772). Also involved in the oxidative metabolism of xenobiotics including anticonvulsants (PubMed:9555064)
- Specific Function
- All-trans retinoic acid 18-hydroxylase activity
- Gene Name
- CYP3A7
- Uniprot ID
- P24462
- Uniprot Name
- Cytochrome P450 3A7
- Molecular Weight
- 57469.95 Da
References
- Flockhart Table of Drug Interactions [Link]
Carriers
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Binder
- General Function
- Binds water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs (Probable). Its main function is the regulation of the colloidal osmotic pressure of blood (Probable). Major zinc transporter in plasma, typically binds about 80% of all plasma zinc (PubMed:19021548). Major calcium and magnesium transporter in plasma, binds approximately 45% of circulating calcium and magnesium in plasma (By similarity). Potentially has more than two calcium-binding sites and might additionally bind calcium in a non-specific manner (By similarity). The shared binding site between zinc and calcium at residue Asp-273 suggests a crosstalk between zinc and calcium transport in the blood (By similarity). The rank order of affinity is zinc > calcium > magnesium (By similarity). Binds to the bacterial siderophore enterobactin and inhibits enterobactin-mediated iron uptake of E.coli from ferric transferrin, and may thereby limit the utilization of iron and growth of enteric bacteria such as E.coli (PubMed:6234017). Does not prevent iron uptake by the bacterial siderophore aerobactin (PubMed:6234017)
- Specific Function
- Antioxidant activity
- Gene Name
- ALB
- Uniprot ID
- P02768
- Uniprot Name
- Albumin
- Molecular Weight
- 69365.94 Da
References
- FDA Approved Drug Products: RAPAMUNE (sirolimus) for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Binder
- General Function
- Functions as a 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 the body. Appears to function in modulating the activity of the immune system during the acute-phase reaction
- Specific Function
- Not Available
- Gene Name
- ORM1
- Uniprot ID
- P02763
- Uniprot Name
- Alpha-1-acid glycoprotein 1
- Molecular Weight
- 23539.43 Da
References
- FDA Approved Drug Products: RAPAMUNE (sirolimus) for oral use [Link]
- Kind
- Protein group
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Binder
- General 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 acyltransferase (LCAT). As part of the SPAP complex, activates spermatozoa motility
- Specific Function
- Amyloid-beta binding
Components:
References
- FDA Approved Drug Products: RAPAMUNE (sirolimus) for oral use [Link]
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- SubstrateInhibitorInducer
- General Function
- Translocates drugs and phospholipids across the membrane (PubMed:2897240, PubMed:35970996, PubMed:8898203, PubMed:9038218). Catalyzes the flop of phospholipids from the cytoplasmic to the exoplasmic leaflet of the apical membrane. Participates mainly to the flop of phosphatidylcholine, phosphatidylethanolamine, beta-D-glucosylceramides and sphingomyelins (PubMed:8898203). Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells (PubMed:2897240, PubMed:35970996, PubMed:9038218)
- Specific Function
- Abc-type xenobiotic transporter activity
- Gene Name
- ABCB1
- Uniprot ID
- P08183
- Uniprot Name
- ATP-dependent translocase ABCB1
- Molecular Weight
- 141477.255 Da
References
- 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]
- 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]
- 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]
- 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]
- FDA Approved Drug Products: RAPAMUNE (sirolimus) for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Mediates the Na(+)-independent uptake of organic anions (PubMed:10358072, PubMed:15159445, PubMed:17412826). Shows broad substrate specificity, can transport both organic anions such as bile acid taurocholate (cholyltaurine) and conjugated steroids (dehydroepiandrosterone 3-sulfate, 17-beta-glucuronosyl estradiol, and estrone 3-sulfate), as well as eicosanoids (prostaglandin E2, thromboxane B2, leukotriene C4, and leukotriene E4), and thyroid hormones (T4/L-thyroxine, and T3/3,3',5'-triiodo-L-thyronine) (PubMed:10358072, PubMed:10601278, PubMed:10873595, PubMed:11159893, PubMed:12196548, PubMed:12568656, PubMed:15159445, PubMed:15970799, PubMed:16627748, PubMed:17412826, PubMed:19129463, PubMed:26979622). Can take up bilirubin glucuronides from plasma into the liver, contributing to the detoxification-enhancing liver-blood shuttling loop (PubMed:22232210). Involved in the clearance of endogenous and exogenous substrates from the liver (PubMed:10358072, PubMed:10601278). Transports coproporphyrin I and III, by-products of heme synthesis, and may be involved in their hepatic disposition (PubMed:26383540). May contribute to regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Can transport HMG-CoA reductase inhibitors (also known as statins), such as pravastatin and pitavastatin, a clinically important class of hypolipidemic drugs (PubMed:10601278, PubMed:15159445, PubMed:15970799). May play an important role in plasma and tissue distribution of the structurally diverse chemotherapeutic drug methotrexate (PubMed:23243220). May also transport antihypertension agents, such as the angiotensin-converting enzyme (ACE) inhibitor prodrug enalapril, and the highly selective angiotensin II AT1-receptor antagonist valsartan, in the liver (PubMed:16624871, PubMed:16627748). Shows a pH-sensitive substrate specificity towards prostaglandin E2 and T4 which may be ascribed to the protonation state of the binding site and leads to a stimulation of substrate transport in an acidic microenvironment (PubMed:19129463). Hydrogencarbonate/HCO3(-) acts as the probable counteranion that exchanges for organic anions (PubMed:19129463)
- Specific Function
- Bile acid transmembrane transporter activity
- Gene Name
- SLCO1B1
- Uniprot ID
- Q9Y6L6
- Uniprot Name
- Solute carrier organic anion transporter family member 1B1
- Molecular Weight
- 76447.99 Da
References
- 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
- Multidrug efflux pump that functions as a H(+)/organic cation antiporter (PubMed:16330770, PubMed:17509534). Plays a physiological role in the excretion of cationic compounds including endogenous metabolites, drugs, toxins through the kidney and liver, into urine and bile respectively (PubMed:16330770, PubMed:17495125, PubMed:17509534, PubMed:17582384, PubMed:18305230, PubMed:19158817, PubMed:21128598, PubMed:24961373). Mediates the efflux of endogenous compounds such as creatinine, vitamin B1/thiamine, agmatine and estrone-3-sulfate (PubMed:16330770, PubMed:17495125, PubMed:17509534, PubMed:17582384, PubMed:18305230, PubMed:19158817, PubMed:21128598, PubMed:24961373). May also contribute to regulate the transport of cationic compounds in testis across the blood-testis-barrier (Probable)
- Specific Function
- Antiporter activity
- Gene Name
- SLC47A1
- Uniprot ID
- Q96FL8
- Uniprot Name
- Multidrug and toxin extrusion protein 1
- Molecular Weight
- 61921.585 Da
References
- 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 September 17, 2024 22:26