Sirolimus

{{Short description|Pharmaceutical drug}} {{Use dmy dates|date=March 2025}} {{cs1 config |name-list-style=vanc|display-authors=6}} {{Infobox drug | Watchedfields = changed | verifiedrevid = 732542693 | image = Sirolimus structure.svg | image_class = skin-invert-image | width = 250 | alt = | image2 = Sirolimus-from-1C9H-3D-sticks.png | image_class2 = bg-transparent | width2 = 250 | alt2 = | caption =

| pronounce = | tradename = Rapamune, others | Drugs.com = | MedlinePlus = | DailyMedID = Sirolimus | pregnancy_AU = C | pregnancy_AU_comment = | pregnancy_category = | routes_of_administration = By mouth, intravenous, topical | class = | ATC_prefix = L04 | ATC_suffix = AH01 | ATC_supplemental = {{ATC|L01|EG04}}, {{ATC|S01|XA23}}, {{ATCvet|C01|EB90}}

| legal_AU =  | legal_AU_comment = | legal_BR =  | legal_BR_comment = | legal_CA =  | legal_CA_comment = | legal_DE =  | legal_DE_comment = | legal_NZ =  | legal_NZ_comment = | legal_UK =  | legal_UK_comment = | legal_US = Rx-only | legal_US_comment = <ref name="Rapamune FDA label">{{cite web | title = Rapamune- sirolimus solution Rapamune- sirolimus tablet, sugar coated | website = DailyMed | url = https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3275b824-3f82-4151-2ab2-0036a9ba0acc | access-date = 26 November 2021 | archive-date = 27 November 2021 | archive-url = https://web.archive.org/web/20211127050941/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3275b824-3f82-4151-2ab2-0036a9ba0acc | url-status = live }}</ref><ref name="Fyarro FDA label">{{cite web | title = Fyarro- sirolimus injection, powder, lyophilized, for suspension | website = DailyMed | url = https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0f9bb784-53e2-46f9-a65d-1c6c2a230eaf | access-date = 19 December 2021 | archive-date = 19 December 2021 | archive-url = https://web.archive.org/web/20211219212942/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0f9bb784-53e2-46f9-a65d-1c6c2a230eaf | url-status = live }}</ref><ref name="Hyftor FDA label">{{cite web | date = 28 January 2021 | title = Hyftor- sirolimus gel | website = DailyMed | url = https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=edb3ea90-5adc-48ec-99f5-ab963e302f18 | access-date = 23 March 2022 | archive-date = 24 March 2022 | archive-url = https://web.archive.org/web/20220324021200/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=edb3ea90-5adc-48ec-99f5-ab963e302f18 | url-status = live }}</ref> | legal_EU = Rx-only | legal_EU_comment = <ref name="Rapamune EPAR">{{cite web | date = 17 September 2018 | title = Rapamune EPAR | website = European Medicines Agency | url = https://www.ema.europa.eu/en/medicines/human/EPAR/rapamune | access-date = 26 November 2021 | archive-date = 13 August 2021 | archive-url = https://web.archive.org/web/20210813083523/https://www.ema.europa.eu/en/medicines/human/EPAR/rapamune | url-status = live }}</ref><ref name="Rapamune PI" /><ref name="Hyftor EPAR" /><ref name="Hyftor PI" /> | legal_UN =  | legal_UN_comment = | legal_status =

| bioavailability = 14% (oral solution), lower with high-fat meals; 18% (tablet), higher with high-fat meals<ref>{{cite journal | vauthors = Buck ML | date = 2006 | title = Immunosuppression With Sirolimus After Solid Organ Transplantation in Children | journal = Pediatric Pharmacotherapy | volume = 12 | issue = 2 | url = https://www.medscape.com/viewarticle/524753_4 | access-date = 4 April 2022 | archive-date = 18 April 2020 | archive-url = https://web.archive.org/web/20200418102941/https://www.medscape.com/viewarticle/524753_4 | url-status = live }}</ref> | protein_bound = 92% | metabolism = Liver | metabolites = | onset = | elimination_half-life = 57–63 hours<ref name="Pubchem Rapamycin" /> | duration_of_action = | excretion = Mostly fecal

| CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 53123–88–9 | CAS_supplemental = | PubChem = 5284616 | IUPHAR_ligand = | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB00877 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 10482078 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = W36ZG6FT64 | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D00753 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 9168 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 413 | NIAID_ChemDB = | PDB_ligand = RAP | synonyms = Rapamycin, ABI-009

| IUPAC_name = (1''R'',9''S'',12''S'',15''R'',16''E'',18''R'',19''R'',21''R'',23''S'',24''E'',26''E'',28''E'',30''S'',32''S'',35''R'')-1,18-dihydroxy-12-[(2''R'')-1-((1''S'',3''R'',4''R'')-4-hydroxy-3-methoxycyclohexyl)-2-propanyl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.0<sup>4,9</sup>]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone | C=51 |H=79 |N=1 |O=13 | SMILES = O[C@@H]1CC[C@H](C[C@H]1OC)C[C@@H](C)[C@@H]4CC(=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](OC)C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N3CCCC[C@H]3C(=O)O4 | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 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 | StdInChI_comment = | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = QFJCIRLUMZQUOT-HPLJOQBZSA-N | density = | density_notes = | melting_point = | melting_high = | melting_notes = | boiling_point = | boiling_notes = | solubility = 0.0026 <ref>{{cite journal | vauthors = Simamora P, Alvarez JM, Yalkowsky SH | date = February 2001 | title = Solubilization of rapamycin | journal = International Journal of Pharmaceutics | volume = 213 | issue = 1–2 | pages = 25–29 | doi = 10.1016/s0378-5173(00)00617-7 | pmid = 11165091 }}</ref> | sol_units = | specific_rotation = }}

'''Sirolimus''', also known as '''rapamycin''' and sold under the brand name '''Rapamune''' among others, is a macrolide compound that is used to coat coronary stents, prevent organ transplant rejection, treat a rare lung disease called lymphangioleiomyomatosis, and treat perivascular epithelioid cell tumour (PEComa).<ref name="Rapamune FDA label" /><ref name="Fyarro FDA label" /><ref name="Vezi">{{cite journal | vauthors = Vézina C, Kudelski A, Sehgal SN | date = October 1975 | title = Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle | journal = The Journal of Antibiotics | volume = 28 | issue = 10 | pages = 721–726 | doi = 10.7164/antibiotics.28.721 | pmid = 1102508 | title-link = doi | doi-access = free }}</ref> It has immunosuppressant functions in humans and is especially useful in preventing the rejection of kidney transplants. It is a mammalian target of rapamycin (mTOR) kinase inhibitor<ref name="Fyarro FDA label" /> that reduces the sensitivity of T cells and B cells to interleukin-2 (IL-2), inhibiting their activity.<ref name="Mukherjee_2009" />

This compound also has a use in cardiovascular drug-eluting stent technologies to inhibit restenosis.

[[File:Rapamycin plaque on Easter Island.JPG|300px|thumb|A plaque, written in Portuguese, commemorating the discovery of sirolimus on Easter Island, near Rano Kau]]

It is produced by the bacterium ''Streptomyces hygroscopicus'' and was isolated for the first time in 1972, from samples of ''S. hygroscopicus'' found on Easter Island.<ref>{{cite web | vauthors = Qari S, Walters P, Lechtenberg S | date = 21 May 2021 | title = The Dirty Drug and the Ice Cream Tub | website = Radiolab | url = https://www.wnycstudios.org/podcasts/radiolab/articles/dirty-drug-and-ice-cream-tub | access-date = 25 July 2021 | archive-date = 25 July 2021 | archive-url = https://web.archive.org/web/20210725033538/https://www.wnycstudios.org/podcasts/radiolab/articles/dirty-drug-and-ice-cream-tub | url-status = live }}</ref><ref>{{cite journal | vauthors = Seto B | date = November 2012 | title = Rapamycin and mTOR: a serendipitous discovery and implications for breast cancer | journal = Clinical and Translational Medicine | volume = 1 | issue = 1 | article-number = e29 | doi = 10.1186/2001-1326-1-29 | pmc = 3561035 | pmid = 23369283 | doi-access = free }}</ref><ref name="RapamycinOrigin">{{cite journal | vauthors = Pritchard DI | date = May 2005 | title = Sourcing a chemical succession for cyclosporin from parasites and human pathogens | journal = Drug Discovery Today | volume = 10 | issue = 10 | pages = 688–691 | doi = 10.1016/S1359-6446(05)03395-7 | pmid = 15896681 }}</ref> The compound was originally named rapamycin after the native name of the island, Rapa Nui.<ref name="Vezi" /> Sirolimus was initially developed as an antifungal agent. However, this use was abandoned when it was discovered to have potent immunosuppressive and antiproliferative properties due to its ability to inhibit mTOR. It was approved by the US Food and Drug Administration (FDA) in 1999.<ref name="Drug Approval Package: Rapamune">{{cite web | date = 30 March 2001 | title = Drug Approval Package: Rapamune (Sirolimus) | publisher = U.S. Food and Drug Administration (FDA) | url = https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/21083A.cfm | archive-date = 1 February 2022 | archive-url = https://web.archive.org/web/20220201061710/https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/21083A.cfm | id = NDA 021083 | url-status = live }}</ref> Hyftor (sirolimus gel) was authorized for topical treatment of facial angiofibroma in the European Union in May 2023.<ref name="Hyftor EPAR">{{cite web | date = 9 June 2023 | title = Hyftor EPAR | website = European Medicines Agency (EMA) | url = https://www.ema.europa.eu/en/medicines/human/EPAR/hyftor | access-date = 12 June 2023 }} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref>

== Medical uses == In the US, sirolimus, as Rapamune, is indicated for the prevention of organ transplant rejection<ref name="Rapamune FDA label" /> and for the treatment of lymphangioleiomyomatosis;<ref name="Rapamune FDA label" /> and, as Fyarro, in the form of protein-bound particles, for the treatment of adults with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumour (PEComa).<ref name="Fyarro FDA label" />

In the EU, sirolimus, as Rapamune, is indicated for the prophylaxis of organ rejection in adults at low to moderate immunological risk receiving a renal transplant<ref name="Rapamune EPAR" /><ref name="Rapamune PI">{{cite web | date = 15 March 2001 | title = Rapamune Product information | website = Union Register of medicinal products | url = https://ec.europa.eu/health/documents/community-register/html/h171.htm | access-date = 23 March 2025 }}</ref> and for the treatment of people with sporadic lymphangioleiomyomatosis with moderate lung disease or declining lung function;<ref name="Rapamune EPAR" /><ref name="Rapamune PI" /> and, as Hyftor, for the treatment of facial angiofibroma associated with tuberous sclerosis complex.<ref name="Hyftor EPAR" /><ref name="Hyftor PI" />

=== Prevention of transplant rejection === {{See also|Organ rejection|Immunosuppression#Deliberately induced}}

The chief advantage sirolimus has over calcineurin inhibitors is its low toxicity toward kidneys. Transplant patients maintained on calcineurin inhibitors long-term tend to develop impaired kidney function or even kidney failure; this can be avoided by using sirolimus instead. It is particularly advantageous in patients with kidney transplants for hemolytic–uremic syndrome, as this disease is likely to recur in the transplanted kidney if a calcineurin-inhibitor is used. However, on 7 October 2008, the FDA approved safety labeling revisions for sirolimus to warn of the risk for decreased renal function associated with its use.<ref>{{cite book | vauthors = Li JJ, Corey EJ | date = 3 April 2013 | title = Drug Discovery: Practices, Processes, and Perspectives | publisher = John Wiley & Sons | isbn = 978-1-118-35446-9 | url = https://books.google.com/books?id=mIyxO5cLEAcC | access-date = 1 August 2016 | archive-date = 19 August 2020 | archive-url = https://web.archive.org/web/20200819144751/https://books.google.com/books?id=mIyxO5cLEAcC | url-status = live }}</ref><ref>{{cite book | vauthors = Koprowski G | date = 7 February 2012 | title = Nanotechnology in Medicine: Emerging Applications | publisher = Momentum Press | isbn = 978-1-60650-250-1 | url = https://books.google.com/books?id=CVloCgAAQBAJ | access-date = 1 August 2016 | archive-date = 30 September 2020 | archive-url = https://web.archive.org/web/20200930051705/https://books.google.com/books?id=CVloCgAAQBAJ | url-status = live }}</ref> In 2009, the FDA notified healthcare professionals that a clinical trial conducted by Wyeth showed an increased mortality in stable liver transplant patients after switching from a calcineurin inhibitor-based immunosuppressive regimen to sirolimus.<ref>{{cite web | date = 11 June 2009 | title = Sirolimus (marketed as Rapamune) Safety | publisher = U.S. Food and Drug Administration (FDA) | url = https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm165731.htm | access-date = 1 August 2016 | archive-date = 16 September 2016 | archive-url = https://web.archive.org/web/20160916202213/https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm165731.htm }}</ref> A 2019 cohort study of nearly 10,000 lung transplant recipients in the US demonstrated significantly improved long-term survival using sirolimus + tacrolimus instead of mycophenolate mofetil + tacrolimus for immunosuppressive therapy starting at one year after transplant.<ref>{{cite journal | vauthors = Wijesinha M, Hirshon JM, Terrin M, Magder L, Brown C, Stafford K, Iacono A | date = August 2019 | title = Survival Associated With Sirolimus Plus Tacrolimus Maintenance Without Induction Therapy Compared With Standard Immunosuppression After Lung Transplant | journal = JAMA Network Open | volume = 2 | issue = 8 | article-number = e1910297 | doi = 10.1001/jamanetworkopen.2019.10297 | pmc = 6716294 | pmid = 31461151 | title-link = doi | doi-access = free }}</ref>

Sirolimus can also be used either alone or in conjunction with a calcineurin inhibitor (such as tacrolimus) or mycophenolate mofetil, or both, to provide steroid-free immunosuppression regimens. Impaired wound healing and thrombocytopenia are possible side effects of sirolimus; therefore, some transplant centers prefer not to use it immediately after the transplant operation, but instead administer it only after a period of weeks or months. Its optimal role in immunosuppression has not yet been determined, and it remains the subject of a number of ongoing clinical trials.<ref name="Mukherjee_2009">{{cite journal | vauthors = Mukherjee S, Mukherjee U | date = 1 January 2009 | title = A comprehensive review of immunosuppression used for liver transplantation | journal = Journal of Transplantation | volume = 2009 | article-number = 701464 | doi = 10.1155/2009/701464 | pmc = 2809333 | pmid = 20130772 | title-link = doi | doi-access = free }}</ref>

=== Lymphangioleiomyomatosis === In May 2015, the FDA approved sirolimus to treat lymphangioleiomyomatosis (LAM), a rare, progressive lung disease that primarily affects women of childbearing age. This made sirolimus the first drug approved to treat this disease.<ref name="FDA_2015" /> LAM involves lung tissue infiltration with smooth muscle-like cells with mutations of the tuberous sclerosis complex gene (TSC2). Loss of TSC2 gene function activates the mTOR signaling pathway, resulting in the release of lymphangiogenic growth factors. Sirolimus blocks this pathway.<ref name="Rapamune FDA label" />

The safety and efficacy of sirolimus treatment of LAM were investigated in clinical trials that compared sirolimus treatment with a placebo group in 89 patients for 12 months. The patients were observed for 12 months after the treatment had ended. The most commonly reported side effects of sirolimus treatment of LAM were mouth and lip ulcers, diarrhea, abdominal pain, nausea, sore throat, acne, chest pain, leg swelling, upper respiratory tract infection, headache, dizziness, muscle pain and elevated cholesterol. Serious side effects including hypersensitivity and swelling (edema) have been observed in renal transplant patients.<ref name="FDA_2015">{{cite press release |url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm448523.htm|title=FDA approves Rapamune to treat LAM, a very rare lung disease|vauthors=Pahon E|date=28 May 2015|publisher=U.S. Food and Drug Administration (FDA)|access-date=1 August 2016|archive-date=14 August 2016|archive-url=https://web.archive.org/web/20160814072556/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm448523.htm}}</ref>

While sirolimus was considered for treatment of LAM, it received orphan drug designation status because LAM is a rare condition.<ref name="FDA_2015" />

The safety of LAM treatment by sirolimus in people younger than 18 years old has not been tested.<ref name="Rapamune FDA label" />

=== Coronary stent coating === {{further|Drug-eluting stent}}

The antiproliferative effect of sirolimus has also been used in conjunction with coronary stents to prevent restenosis in coronary arteries following balloon angioplasty. The sirolimus is formulated in a polymer coating that affords controlled release through the healing period following coronary intervention. Several large clinical studies have demonstrated lower restenosis rates in patients treated with sirolimus-eluting stents when compared to bare-metal stents, resulting in fewer repeat procedures. However, this kind of stent may also increase the risk of vascular thrombosis.<ref name="Shuchman">{{cite journal | vauthors = Shuchman M | date = November 2006 | title = Trading restenosis for thrombosis? New questions about drug-eluting stents | journal = The New England Journal of Medicine | volume = 355 | issue = 19 | pages = 1949–1952 | doi = 10.1056/NEJMp068234 | pmid = 17093244 }}</ref>

=== Vascular malformations === Sirolimus is used to treat vascular malformations. Treatment with sirolimus can decrease pain and the fullness of vascular malformations, improve coagulation levels, and slow the growth of abnormal lymphatic vessels.<ref>{{cite web | title = Venous Malformation | work = Boston Children's Hospital | url = https://www.childrenshospital.org/conditions/venous-malformation | access-date = 22 April 2020 | archive-date = 17 January 2021 | archive-url = https://web.archive.org/web/20210117101459/https://www.childrenshospital.org/conditions-and-treatments/conditions/v/venous-malformation/treatments | url-status = live }}</ref> Sirolimus is a relatively new medical therapy for the treatment of vascular malformations<ref name="pmid32200879">{{cite journal | vauthors = Dekeuleneer V, Seront E, Van Damme A, Boon LM, Vikkula M | date = April 2020 | title = Theranostic Advances in Vascular Malformations | journal = The Journal of Investigative Dermatology | volume = 140 | issue = 4 | pages = 756–763 | doi = 10.1016/j.jid.2019.10.001 | pmid = 32200879 | title-link = doi | doi-access = free | hdl = 2078.1/228316 | hdl-access = free }}</ref> in recent years, sirolimus has emerged as a new medical treatment option for both vascular tumors and vascular malformations, as a mammalian target of rapamycin (mTOR), capable of integrating signals from the PI3K/AKT pathway to coordinate proper cell growth and proliferation. Hence, sirolimus is ideal for "proliferative" vascular tumors through the control of tissue overgrowth disorders caused by inappropriate activation of the PI3K/AKT/mTOR pathway as an antiproliferative agent.<ref name="pmid31864650">{{cite journal | vauthors = Lee BB | date = January 2020 | title = Sirolimus in the treatment of vascular anomalies | journal = Journal of Vascular Surgery | volume = 71 | issue = 1 | page = 328 | doi = 10.1016/j.jvs.2019.08.246 | pmid = 31864650 | title-link = doi | doi-access = free }}</ref><ref name="pmid27723921">{{cite journal | vauthors = Triana P, Dore M, Cerezo VN, Cervantes M, Sánchez AV, Ferrero MM, González MD, Lopez-Gutierrez JC | date = February 2017 | title = Sirolimus in the Treatment of Vascular Anomalies | journal = European Journal of Pediatric Surgery | volume = 27 | issue = 1 | pages = 86–90 | doi = 10.1055/s-0036-1593383 | pmid = 27723921 | title-link = doi | doi-access = free }}</ref>

=== Angiofibromas === Sirolimus has been used as a topical treatment of angiofibromas with tuberous sclerosis complex (TSC). Facial angiofibromas occur in 80% of patients with TSC, and the condition is very disfiguring. A retrospective review of English-language medical publications reporting on topical sirolimus treatment of facial angiofibromas found sixteen separate studies with positive patient outcomes after using the drug. The reports involved a total of 84 patients, and improvement was observed in 94% of subjects, especially if treatment began during the early stages of the disease. Sirolimus treatment was applied in several different formulations (ointment, gel, solution, and cream), ranging from 0.003 to 1% concentrations. Reported adverse effects included one case of perioral dermatitis, one case of cephalea, and four cases of irritation.<ref>{{cite journal | vauthors = Balestri R, Neri I, Patrizi A, Angileri L, Ricci L, Magnano M | date = January 2015 | title = Analysis of current data on the use of topical rapamycin in the treatment of facial angiofibromas in tuberous sclerosis complex | journal = Journal of the European Academy of Dermatology and Venereology | volume = 29 | issue = 1 | pages = 14–20 | doi = 10.1111/jdv.12665 | pmid = 25174683 | s2cid = 9967001 }}</ref>

In April 2022, sirolimus was approved by the FDA for treating angiofibromas.<ref name="Drug Approval Package: Hyftor" /><ref name="FDAnews 2022">{{cite web | date = 7 April 2022 | title = FDA Approves Nobelpharma's Topical Treatment for Facial Angiofibroma | website = FDAnews | url = https://www.fdanews.com/articles/207319-fda-approves-nobelpharmas-topical-treatment-for-facial-angiofibroma | access-date = 24 May 2022 | archive-date = 1 June 2022 | archive-url = https://web.archive.org/web/20220601085706/https://www.fdanews.com/articles/207319-fda-approves-nobelpharmas-topical-treatment-for-facial-angiofibroma }}</ref>

== Adverse effects == The most common adverse reactions (≥30% occurrence, leading to a 5% treatment discontinuation rate) observed with sirolimus in clinical studies of organ rejection prophylaxis in individuals with kidney transplants include: peripheral edema, hypercholesterolemia, abdominal pain, headache, nausea, diarrhea, pain, constipation, hypertriglyceridemia, hypertension, increased creatinine, fever, urinary tract infection, anemia, arthralgia, and thrombocytopenia.<ref name="Rapamune FDA label" />

The most common adverse reactions (≥20% occurrence, leading to an 11% treatment discontinuation rate) observed with sirolimus in clinical studies for the treatment of lymphangioleiomyomatosis are: peripheral edema, hypercholesterolemia, abdominal pain, headache, nausea, diarrhea, chest pain, stomatitis, nasopharyngitis, acne, upper respiratory tract infection, dizziness, and myalgia.<ref name="Rapamune FDA label" />

The following adverse effects occurred in 3–20% of individuals taking sirolimus for organ rejection prophylaxis following a kidney transplant:<ref name="Rapamune FDA label" /> {| class="wikitable" ! System ! Adverse effects |- | Body as a whole || Sepsis, lymphocele, herpes zoster infection, herpes simplex infection |- |Cardiovascular || Venous thromboembolism (pulmonary embolism and deep venous thrombosis), rapid heart rate |- |Digestive || Stomatitis |- |Hematologic/lymphatic || Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), leukopenia |- |Metabolic || Abnormal healing, increased lactic dehydrogenase (LDH), hypokalemia, diabetes |- |Musculoskeletal || Bone necrosis |- |Respiratory || Pneumonia, epistaxis |- |Skin || Melanoma, squamous cell carcinoma, basal cell carcinoma |- |Urogenital || Pyelonephritis, ovarian cysts, menstrual disorders (amenorrhea and menorrhagia) |}

=== Diabetes-like symptoms === While sirolimus inhibition of mTORC1 appears to mediate the drug's benefits, it also inhibits mTORC2, which results in diabetes-like symptoms.<ref name="Rapamycin-induced insulin resistanc">{{cite journal | vauthors = Lamming DW, Ye L, Katajisto P, Goncalves MD, Saitoh M, Stevens DM, Davis JG, Salmon AB, Richardson A, Ahima RS, Guertin DA, Sabatini DM, Baur JA | date = March 2012 | title = Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity | journal = Science | volume = 335 | issue = 6076 | pages = 1638–1643 | doi = 10.1126/science.1215135 | pmc = 3324089 | pmid = 22461615 | bibcode = 2012Sci...335.1638L }}</ref> This includes decreased glucose tolerance and insensitivity to insulin.<ref name="Rapamycin-induced insulin resistanc"/> Sirolimus treatment may additionally increase the risk of type 2 diabetes.<ref>{{cite journal | vauthors = Johnston O, Rose CL, Webster AC, Gill JS | date = July 2008 | title = Sirolimus is associated with new-onset diabetes in kidney transplant recipients | journal = Journal of the American Society of Nephrology | volume = 19 | issue = 7 | pages = 1411–1418 | doi = 10.1681/ASN.2007111202 | pmc = 2440303 | pmid = 18385422 }}</ref> In mouse studies, these symptoms can be avoided through the use of alternate dosing regimens or analogs such as everolimus or temsirolimus.<ref>{{cite journal | vauthors = Arriola Apelo SI, Neuman JC, Baar EL, Syed FA, Cummings NE, Brar HK, Pumper CP, Kimple ME, Lamming DW | date = February 2016 | title = Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system | journal = Aging Cell | volume = 15 | issue = 1 | pages = 28–38 | doi = 10.1111/acel.12405 | pmc = 4717280 | pmid = 26463117 }}</ref>

=== Lung toxicity === Pulmonary toxicity, or toxicity to lungs, is a serious complication associated with sirolimus therapy,<ref name="ReferenceA">{{cite journal | vauthors = Chhajed PN, Dickenmann M, Bubendorf L, Mayr M, Steiger J, Tamm M | year = 2006 | title = Patterns of pulmonary complications associated with sirolimus | journal = Respiration; International Review of Thoracic Diseases | volume = 73 | issue = 3 | pages = 367–374 | doi = 10.1159/000087945 | pmid = 16127266 | s2cid = 24408680 }}</ref><ref>{{cite journal | vauthors = Morelon E, Stern M, Israël-Biet D, Correas JM, Danel C, Mamzer-Bruneel MF, Peraldi MN, Kreis H | date = September 2001 | title = Characteristics of sirolimus-associated interstitial pneumonitis in renal transplant patients | journal = Transplantation | volume = 72 | issue = 5 | pages = 787–790 | doi = 10.1097/00007890-200109150-00008 | pmid = 11571438 | s2cid = 12116798 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Filippone EJ, Carson JM, Beckford RA, Jaffe BC, Newman E, Awsare BK, Doria C, Farber JL | date = September 2011 | title = Sirolimus-induced pneumonitis complicated by pentamidine-induced phospholipidosis in a renal transplant recipient: a case report | journal = Transplantation Proceedings | volume = 43 | issue = 7 | pages = 2792–2797 | doi = 10.1016/j.transproceed.2011.06.060 | pmid = 21911165 | url = https://jdc.jefferson.edu/cgi/viewcontent.cgi?article=1087&context=medfp | access-date = 24 September 2019 | archive-date = 7 August 2020 | archive-url = https://web.archive.org/web/20200807064741/https://jdc.jefferson.edu/cgi/viewcontent.cgi?article=1087&context=medfp | format = PDF | url-status = live | url-access = subscription }}</ref><ref>{{cite journal | vauthors = Pham PT, Pham PC, Danovitch GM, Ross DJ, Gritsch HA, Kendrick EA, Singer J, Shah T, Wilkinson AH | date = April 2004 | title = Sirolimus-associated pulmonary toxicity | journal = Transplantation | volume = 77 | issue = 8 | pages = 1215–1220 | doi = 10.1097/01.TP.0000118413.92211.B6 | pmid = 15114088 | s2cid = 24496443 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Mingos MA, Kane GC | date = December 2005 | title = Sirolimus-induced interstitial pneumonitis in a renal transplant patient | journal = Respiratory Care | volume = 50 | issue = 12 | pages = 1659–1661 | doi = 10.4187/respcare.05501659 | pmid = 16318648 }}</ref><ref>{{cite journal | vauthors = Das BB, Shoemaker L, Subramanian S, Johnsrude C, Recto M, Austin EH | date = March 2007 | title = Acute sirolimus pulmonary toxicity in an infant heart transplant recipient: case report and literature review | journal = The Journal of Heart and Lung Transplantation | volume = 26 | issue = 3 | pages = 296–298 | doi = 10.1016/j.healun.2006.12.004 | pmid = 17346635 }}</ref><ref>{{cite journal | vauthors = Delgado JF, Torres J, José Ruiz-Cano M, Sánchez V, Escribano P, Borruel S, María Cortina J, de la Calzada CS | date = September 2006 | title = Sirolimus-associated interstitial pneumonitis in 3 heart transplant recipients | journal = The Journal of Heart and Lung Transplantation | volume = 25 | issue = 9 | pages = 1171–1174 | doi = 10.1016/j.healun.2006.05.013 | pmid = 16962483 }}</ref>{{Excessive citations inline|date=December 2022}} especially in the case of lung transplants.<ref>{{cite journal | vauthors = McWilliams TJ, Levvey BJ, Russell PA, Milne DG, Snell GI | date = February 2003 | title = Interstitial pneumonitis associated with sirolimus: a dilemma for lung transplantation | journal = The Journal of Heart and Lung Transplantation | volume = 22 | issue = 2 | pages = 210–213 | doi = 10.1016/S1053-2498(02)00564-8 | pmid = 12581772 }}</ref> The mechanism of the interstitial pneumonitis caused by sirolimus and other macrolide mTOR inhibitors is unclear, and may have nothing to do with the mTOR pathway.<ref>{{cite journal | vauthors = Aparicio G, Calvo MB, Medina V, Fernández O, Jiménez P, Lema M, Figueroa A, Antón Aparicio LM | date = August 2009 | title = Comprehensive lung injury pathology induced by mTOR inhibitors | journal = Clinical & Translational Oncology | volume = 11 | issue = 8 | pages = 499–510 | doi = 10.1007/s12094-009-0394-y | pmid = 19661024 | hdl-access = free | s2cid = 39914334 | hdl = 2183/19864 }}</ref><ref>{{cite journal | vauthors = Paris A, Goupil F, Kernaonet E, Foulet-Rogé A, Molinier O, Gagnadoux F, Lebas FX | date = January 2012 | title = [Drug-induced pneumonitis due to sirolimus: an interaction with atorvastatin?] | language = fr | journal = Revue des Maladies Respiratoires | volume = 29 | issue = 1 | pages = 64–69 | doi = 10.1016/j.rmr.2010.03.026 | pmid = 22240222 }}</ref><ref>{{cite journal | vauthors = Maroto JP, Hudes G, Dutcher JP, Logan TF, White CS, Krygowski M, Cincotta M, Shapiro M, Duran I, Berkenblit A | date = May 2011 | title = Drug-related pneumonitis in patients with advanced renal cell carcinoma treated with temsirolimus | journal = Journal of Clinical Oncology | volume = 29 | issue = 13 | pages = 1750–1756 | doi = 10.1200/JCO.2010.29.2235 | pmid = 21444868 | title-link = doi | doi-access = free }}</ref> The interstitial pneumonitis is not dose-dependent, but is more common in patients with underlying lung disease.<ref name="ReferenceA"/><ref>{{cite journal | vauthors = Errasti P, Izquierdo D, Martín P, Errasti M, Slon F, Romero A, Lavilla FJ | date = October 2010 | title = Pneumonitis associated with mammalian target of rapamycin inhibitors in renal transplant recipients: a single-center experience | journal = Transplantation Proceedings | volume = 42 | issue = 8 | pages = 3053–3054 | doi = 10.1016/j.transproceed.2010.07.066 | pmid = 20970608 }}</ref>

=== Lowered effectiveness of immune system === There have been warnings about the use of sirolimus in transplants, where it may increase mortality due to an increased risk of infections.<ref name="Rapamune FDA label" />

=== Cancer risk === Sirolimus may increase an individual's risk for contracting skin cancers from exposure to sunlight or UV radiation, and risk of developing lymphoma.<ref name="Rapamune FDA label" /> In studies, the skin cancer risk under sirolimus was lower than under other immunosuppressants such as azathioprine and calcineurin inhibitors, and lower than under placebo.<ref name="Rapamune FDA label" /><ref>{{cite journal | vauthors = Euvrard S, Morelon E, Rostaing L, Goffin E, Brocard A, Tromme I, Broeders N, del Marmol V, Chatelet V, Dompmartin A, Kessler M, Serra AL, Hofbauer GF, Pouteil-Noble C, Campistol JM, Kanitakis J, Roux AS, Decullier E, Dantal J | date = July 2012 | title = Sirolimus and secondary skin-cancer prevention in kidney transplantation | journal = The New England Journal of Medicine | volume = 367 | issue = 4 | pages = 329–339 | doi = 10.1056/NEJMoa1204166 | pmid = 22830463 | hdl-access = free | title-link = doi | doi-access = free | hdl = 2445/178597 }}</ref>

=== Impaired wound healing === Individuals taking sirolimus are at increased risk of experiencing impaired or delayed wound healing, particularly if they have a body mass index more than 30 kg/m<sup>2</sup> (classified as obese).<ref name="Rapamune FDA label" />

== Interactions == Sirolimus is metabolized by the CYP3A4 enzyme and is a substrate of the P-glycoprotein (P-gp) efflux pump; hence, inhibitors of either protein may increase sirolimus concentrations in blood plasma, whereas inducers of CYP3A4 and P-gp may decrease sirolimus concentrations in blood plasma.<ref name="Rapamune FDA label" />

== Pharmacology == === Pharmacodynamics === {{See also|mTOR inhibitors}} Unlike the similarly named tacrolimus, sirolimus is not a calcineurin inhibitor, but it has a similar suppressive effect on the immune system. Sirolimus inhibits IL-2 and other cytokine receptor-dependent signal transduction mechanisms, via action on mTOR (mammalian Target Of Rapamycin, rapamycin being another name for sirolimus), and thereby blocks activation of T and B cells. Ciclosporin and tacrolimus inhibit the secretion of IL-2, by inhibiting calcineurin.<ref name="Mukherjee_2009" />

The mode of action of sirolimus is to bind the cytosolic protein FK-binding protein 12 (FKBP12) like tacrolimus. Unlike the tacrolimus-FKBP12 complex, which inhibits calcineurin (PP2B), the sirolimus-FKBP12 complex inhibits the mTOR pathway by directly binding to mTOR Complex 1 (mTORC1).<ref name="Mukherjee_2009" />

mTOR has also been called FRAP (FKBP-rapamycin-associated protein), RAFT (rapamycin and FKBP target), RAPT1, or SEP. The earlier names FRAP and RAFT were coined to reflect the fact that sirolimus must bind FKBP12 first, and only the FKBP12-sirolimus complex can bind mTOR. However, mTOR is now the widely accepted name, since Tor was first discovered via genetic and molecular studies of sirolimus-resistant mutants of ''Saccharomyces cerevisiae'' that identified FKBP12, Tor1, and Tor2 as the targets of sirolimus and provided robust support that the FKBP12-sirolimus complex binds to and inhibits Tor1 and Tor2.<ref name="Heitman_1991">{{cite journal | vauthors = Heitman J, Movva NR, Hall MN | date = August 1991 | title = Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast | journal = Science | volume = 253 | issue = 5022 | pages = 905–909 | doi = 10.1126/science.1715094 | pmid = 1715094 | s2cid = 9937225 | bibcode = 1991Sci...253..905H }}</ref><ref name="Mukherjee_2009" />

=== Pharmacokinetics === Sirolimus is metabolized primarily by the CYP3A4 enzyme (about 90%), and to a lesser degree by CYP3A5 and CYP2C8.<ref>{{cite journal | vauthors = Emoto C, Fukuda T, Venkatasubramanian R, Vinks AA | date = December 2015 | title = The impact of CYP3A5*3 polymorphism on sirolimus pharmacokinetics: insights from predictions with a physiologically-based pharmacokinetic model | journal = British Journal of Clinical Pharmacology | volume = 80 | issue = 6 | pages = 1438–1446 | doi = 10.1111/bcp.12743 | pmc = 4693485 | pmid = 26256674 }}</ref><ref>{{cite journal | vauthors = Davari B, Shokati T, Ward AM, Nguyen V, Klawitter J, Klawitter J, Christians U | date = July 2025 | title = Human Metabolism of Sirolimus Revisited | journal = Metabolites | volume = 15 | issue = 7 | pages = 489 | doi = 10.3390/metabo15070489 | pmc = 12299981 | pmid = 40710588 | doi-access = free }}</ref> It is also a substrate of the P-glycoprotein (P-gp) efflux pump.<ref name="Rapamune FDA label" /> It has linear pharmacokinetics.<ref name="pharmacokinetics1">{{cite journal | vauthors = Ferron GM, Mishina EV, Zimmerman JJ, Jusko WJ | date = April 1997 | title = Population pharmacokinetics of sirolimus in kidney transplant patients | journal = Clinical Pharmacology and Therapeutics | volume = 61 | issue = 4 | pages = 416–428 | doi = 10.1016/S0009-9236(97)90192-2 | pmid = 9129559 }}</ref> In studies on N=6 and N=36 subjects, peak concentration was obtained in 1.3 hours +/r- 0.5 hours and the terminal elimination was slow, with a half life around 60 hours +/- 10 hours.<ref name="pmid16418694">{{cite journal | vauthors = Leung LY, Lim HK, Abell MW, Zimmerman JJ | date = February 2006 | title = Pharmacokinetics and metabolic disposition of sirolimus in healthy male volunteers after a single oral dose | journal = Therapeutic Drug Monitoring | volume = 28 | issue = 1 | pages = 51–61 | doi = 10.1097/01.ftd.0000179838.33020.34 | pmid = 16418694 }}</ref><ref name="pharmacokinetics1" /> Sirolimus was not found to effect the concentration of ciclosporin, which is also metabolized primarily by the CYP3A4 enzyme.<ref name="pharmacokinetics1"/>

The bioavailabiliy of sirolimus is low, and the absorption of sirolimus into the blood stream from the intestine varies widely between patients, with some patients having up to eight times more exposure than others for the same dose. Drug levels are, therefore, taken to make sure patients get the right dose for their condition.<ref name="Mukherjee_2009" />{{primary source inline|date=June 2024}} This is determined by taking a blood sample before the next dose, which gives the trough level. However, good correlation is noted between trough concentration levels and drug exposure, known as area under the concentration-time curve, for both sirolimus (SRL) and tacrolimus (TAC) (SRL: r2 = 0.83; TAC: r2 = 0.82), so only one level need be taken to know its pharmacokinetic (PK) profile. PK profiles of SRL and of TAC are unaltered by simultaneous administration. Dose-corrected drug exposure of TAC correlates with SRL (r2 = 0.8), so patients have similar bioavailability of both.<ref>{{cite journal | vauthors = McAlister VC, Mahalati K, Peltekian KM, Fraser A, MacDonald AS | date = June 2002 | title = A clinical pharmacokinetic study of tacrolimus and sirolimus combination immunosuppression comparing simultaneous to separated administration | journal = Therapeutic Drug Monitoring | volume = 24 | issue = 3 | pages = 346–350 | doi = 10.1097/00007691-200206000-00004 | pmid = 12021624 | s2cid = 34950948 }}</ref>{{primary source inline|date=August 2016}}

== Chemistry == {{expand section|content on this topic from <ref name="Pubchem Rapamycin" />|date=August 2016}} Sirolimus is a natural product and macrocyclic lactone.<ref name="Pubchem Rapamycin">{{cite web | title = Rapamycin | website = PubChem Compound | publisher = National Center for Biotechnology Information | url = https://pubchem.ncbi.nlm.nih.gov/compound/5284616 | access-date = 1 August 2016 | archive-date = 16 August 2016 | archive-url = https://web.archive.org/web/20160816153302/https://pubchem.ncbi.nlm.nih.gov/compound/5284616 | url-status = live }}</ref>

=== Biosynthesis === The biosynthesis of the rapamycin core is accomplished by a type I polyketide synthase (PKS) in conjunction with a nonribosomal peptide synthetase (NRPS). The domains responsible for the biosynthesis of the linear polyketide of rapamycin are organized into three multienzymes, RapA, RapB, and RapC, which contain a total of 14 modules (figure 1). The three multienzymes are organized such that the first four modules of polyketide chain elongation are in RapA, the following six modules for continued elongation are in RapB, and the final four modules to complete the biosynthesis of the linear polyketide are in RapC.<ref name=Rapamycin_domains_and_primary_genes>{{cite journal | vauthors = Schwecke T, Aparicio JF, Molnár I, König A, Khaw LE, Haydock SF, Oliynyk M, Caffrey P, Cortés J, Lester JB | date = August 1995 | title = The biosynthetic gene cluster for the polyketide immunosuppressant rapamycin | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 17 | pages = 7839–7843 | doi = 10.1073/pnas.92.17.7839 | pmc = 41241 | pmid = 7644502 | title-link = doi | doi-access = free | bibcode = 1995PNAS...92.7839S }}</ref> Then, the linear polyketide is modified by the NRPS, RapP, which attaches L-pipecolate to the terminal end of the polyketide, and then cyclizes the molecule, yielding the unbound product, prerapamycin.<ref name=prerapamycin>{{cite journal | vauthors = Gregory MA, Gaisser S, Lill RE, Hong H, Sheridan RM, Wilkinson B, Petkovic H, Weston AJ, Carletti I, Lee HL, Staunton J, Leadlay PF | date = May 2004 | title = Isolation and characterization of pre-rapamycin, the first macrocyclic intermediate in the biosynthesis of the immunosuppressant rapamycin by S. hygroscopicus | journal = Angewandte Chemie | volume = 43 | issue = 19 | pages = 2551–2553 | doi = 10.1002/anie.200453764 | pmid = 15127450 | bibcode = 2004ACIE...43.2551G }}</ref> <div class="skin-invert-image">{{Wide image|Domain organization of PKS of rapamycin and biosynthetic intermediates.svg|1320px|Figure 1: Domain organization of PKS of rapamycin and biosynthetic intermediates}} {{multiple image | align = right | image1 = Prerapamycin skeletal.svg | width1 = 250 | alt1 = | caption1 = Figure 2: Prerapamycin, unbound product of PKS and NRPS | image2 = Prerapamycin to rapamycin.svg | width2 = 350 | alt2 = | caption2 = Figure 3: Sequence of "tailoring" steps, which convert unbound prerapamycin into rapamycin | footer = }}</div> class=skin-invert-image|thumb|right|Figure 4: Proposed mechanism of lysine cyclodeaminase conversion of L-lysine to L-pipecolic acid The core macrocycle, prerapamycin (figure 2), is then modified (figure 3) by an additional five enzymes, which lead to the final product, rapamycin. First, the core macrocycle is modified by RapI, SAM-dependent O-methyltransferase (MTase), which O-methylates at C39. Next, a carbonyl is installed at C9 by RapJ, a cytochrome P-450 monooxygenases (P-450). Then, RapM, another MTase, O-methylates at C16. Finally, RapN, another P-450, installs a hydroxyl at C27 immediately followed by O-methylation by Rap Q, a distinct MTase, at C27 to yield rapamycin.<ref name=Rapamycin_genes>{{cite journal | vauthors = Gregory MA, Hong H, Lill RE, Gaisser S, Petkovic H, Low L, Sheehan LS, Carletti I, Ready SJ, Ward MJ, Kaja AL, Weston AJ, Challis IR, Leadlay PF, Martin CJ, Wilkinson B, Sheridan RM | date = October 2006 | title = Rapamycin biosynthesis: Elucidation of gene product function | journal = Organic & Biomolecular Chemistry | volume = 4 | issue = 19 | pages = 3565–3568 | doi = 10.1039/b608813a | pmid = 16990929 }}</ref>

The biosynthetic genes responsible for rapamycin synthesis have been identified. As expected, three extremely large open reading frames (ORF's) designated as ''rapA'', ''rapB'', and ''rapC'' encode for three extremely large and complex multienzymes, RapA, RapB, and RapC, respectively.<ref name=Rapamycin_domains_and_primary_genes /> The gene ''rapL'' has been established to code for a NAD+-dependent lysine cycloamidase, which converts L-lysine to L-pipecolic acid (figure 4) for incorporation at the end of the polyketide.<ref name="rapamycin_report">{{cite journal | vauthors = Graziani EI | date = May 2009 | title = Recent advances in the chemistry, biosynthesis and pharmacology of rapamycin analogs | journal = Natural Product Reports | volume = 26 | issue = 5 | pages = 602–609 | doi = 10.1039/b804602f | pmid = 19387497 }}</ref><ref>{{cite journal | vauthors = Gatto GJ, Boyne MT, Kelleher NL, Walsh CT | date = March 2006 | title = Biosynthesis of pipecolic acid by RapL, a lysine cyclodeaminase encoded in the rapamycin gene cluster | journal = Journal of the American Chemical Society | volume = 128 | issue = 11 | pages = 3838–3847 | doi = 10.1021/ja0587603 | pmid = 16536560 | bibcode = 2006JAChS.128.3838G }}</ref> The gene ''rapP'', which is embedded between the PKS genes and translationally coupled to ''rapC'', encodes for an additional enzyme, an NPRS responsible for incorporating L-pipecolic acid, chain termination and cyclization of prerapamycin. In addition, genes ''rapI'', ''rapJ'', ''rapM'', ''rapN'', ''rapO'', and ''rapQ'' have been identified as coding for tailoring enzymes that modify the macrocyclic core to give rapamycin (figure 3). Finally, ''rapG'' and ''rapH'' have been identified to code for enzymes that have a positive regulatory role in the preparation of rapamycin through the control of rapamycin PKS gene expression.<ref name=rapG_rapH>{{cite journal | vauthors = Aparicio JF, Molnár I, Schwecke T, König A, Haydock SF, Khaw LE, Staunton J, Leadlay PF | date = February 1996 | title = Organization of the biosynthetic gene cluster for rapamycin in Streptomyces hygroscopicus: analysis of the enzymatic domains in the modular polyketide synthase | journal = Gene | volume = 169 | issue = 1 | pages = 9–16 | doi = 10.1016/0378-1119(95)00800-4 | pmid = 8635756 }}</ref> Biosynthesis of this 31-membered macrocycle begins as the loading domain is primed with the starter unit, 4,5-dihydroxocyclohex-1-ene-carboxylic acid, which is derived from the shikimate pathway.<ref name=Rapamycin_domains_and_primary_genes /> Note that the cyclohexane ring of the starting unit is reduced during the transfer to module 1.{{citation needed|date=March 2025}} The starting unit is then modified by a series of Claisen condensations with malonyl or methylmalonyl substrates, which are attached to an acyl carrier protein (ACP) and extend the polyketide by two carbons each.{{citation needed|date=March 2025}} After each successive condensation, the growing polyketide is further modified according to enzymatic domains that are present to reduce and dehydrate it, thereby introducing the diversity of functionalities observed in rapamycin (figure 1).{{citation needed|date=March 2025}} Once the linear polyketide is complete, L-pipecolic acid, which is synthesized by a lysine cycloamidase from an L-lysine, is added to the terminal end of the polyketide by an NRPS.{{citation needed|date=March 2025}} Then, the NSPS cyclizes the polyketide, giving prerapamycin, the first enzyme-free product.{{citation needed|date=March 2025}} The macrocyclic core is then customized by a series of post-PKS enzymes through methylations by MTases and oxidations by P-450s to yield rapamycin.{{citation needed|date=March 2025}}

== Society and culture == === Legal status === In February 2023, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Hyftor, intended for the treatment of angiofibroma.<ref name="Hyftor: Pending EC decision" /> The applicant for this medicinal product is Plusultra pharma GmbH.<ref name="Hyftor: Pending EC decision">{{cite web | date = 24 February 2023 | title = Hyftor: Pending EC decision | website = European Medicines Agency | url = https://www.ema.europa.eu/en/medicines/human/summaries-opinion/hyftor | access-date = 24 February 2023 | archive-date = 24 February 2023 | archive-url = https://web.archive.org/web/20230224165552/https://www.ema.europa.eu/en/medicines/human/summaries-opinion/hyftor | url-status = live }} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref> Hyftor was authorized for medical use in the European Union in May 2023.<ref name="Hyftor PI">{{cite web | date = 26 May 2023 | title = Hyftor Product information | website = Union Register of medicinal products | url = https://ec.europa.eu/health/documents/community-register/html/h1723.htm | access-date = 23 March 2025 }}</ref>

Sirolimus, as Rapamune solution, was approved for medical use in the United States in 1999;<ref name="Drug Approval Package: Rapamune" /> and as Rapamune tablets in August 2000.<ref>{{cite web | date = 11 October 2001 | title = Drug Approval Package: Rapamune (Sirolimus) NDA #21-110 | website = U.S. Food and Drug Administration (FDA) | url = https://www.accessdata.fda.gov/drugsatfda_docs/nda/2000/21110_Rapamune.cfm | access-date = 23 March 2025 }}</ref>

Sirolimus, as Fyarro, was approved for medical use in the United States in November 2021.<ref>{{cite web | date = 30 August 2022 | title = Drug Approval Package: Fyarro | website = U.S. Food and Drug Administration (FDA) | url = https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/213312Orig1s000TOC.cfm | access-date = 23 March 2025 | archive-date = 22 March 2025 | archive-url = https://web.archive.org/web/20250322032551/https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/213312Orig1s000TOC.cfm }}</ref><ref>{{cite press release |title=Aadi Bioscience Announces FDA Approval of its First Product Fyarro for Patients with Locally Advanced Unresectable or Metastatic Malignant Perivascular Epithelioid Cell Tumor (PEComa) |website=Aadi Bioscience |date=23 November 2021 |url=https://www.aadibio.com/aadi-bioscience-announces-fda-approval-of-its-first-product-fyarro-for-patients-with-locally-advanced-unresectable-or-metastatic-malignant-perivascular-epithelioid-cell-tumor-pecoma/ |access-date=26 November 2021 |archive-date=27 November 2021 |archive-url=https://web.archive.org/web/20211127054332/https://ir.aadibio.com/news-releases/news-release-details/aadi-bioscience-announces-fda-approval-its-first-product |url-status=live }}</ref>

Sirolimus, as Hyftor, was approved for medical use in the United States in March 2022.<ref name="Drug Approval Package: Hyftor">{{cite web | date = 19 May 2021 | title = Drug Approval Package: Hyftor | website = U.S. Food and Drug Administration (FDA) | url = https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/213478Orig1s000TOC.cfm | access-date = 23 March 2025 }}</ref>

== Research ==

=== Cancer === The antiproliferative effects of sirolimus may have a role in treating cancer. When dosed appropriately, sirolimus can enhance the immune response to tumor targeting<ref>{{cite journal | vauthors = Li Q, Rao R, Vazzana J, Goedegebuure P, Odunsi K, Gillanders W, Shrikant PA | date = April 2012 | title = Regulating mammalian target of rapamycin to tune vaccination-induced CD8(+) T cell responses for tumor immunity | journal = Journal of Immunology | volume = 188 | issue = 7 | pages = 3080–3087 | doi = 10.4049/jimmunol.1103365 | pmc = 3311730 | pmid = 22379028 }}</ref> or otherwise promote tumor regression in clinical trials.<ref>{{cite journal | vauthors = Easton JB, Houghton PJ | date = October 2006 | title = mTOR and cancer therapy | journal = Oncogene | volume = 25 | issue = 48 | pages = 6436–6446 | doi = 10.1038/sj.onc.1209886 | pmid = 17041628 | title-link = doi | s2cid = 19250234 | doi-access = }}</ref> Sirolimus seems to lower the cancer risk in some transplant patients.<ref name=Law2005>{{cite journal | vauthors = Law BK | date = October 2005 | title = Rapamycin: an anti-cancer immunosuppressant? | journal = Critical Reviews in Oncology/Hematology | volume = 56 | issue = 1 | pages = 47–60 | doi = 10.1016/j.critrevonc.2004.09.009 | pmid = 16039868 }}</ref>

Sirolimus was shown to inhibit the progression of dermal Kaposi's sarcoma in patients with renal transplants.<ref>{{cite journal | vauthors =  | date = May 2005 | title = A new role for sirolimus: regression of Kaposi's sarcoma in kidney-transplant recipients | journal = Nature Clinical Practice Urology | volume = 2 | issue = 5 | page = 211 | doi = 10.1038/ncponc0156x | s2cid = 198175394 | issn = 1743-4289 | doi-access = free }}</ref> Other mTOR inhibitors, such as temsirolimus (CCI-779) or everolimus (RAD001), are being tested for use in cancers such as glioblastoma multiforme and mantle cell lymphoma. However, these drugs have a higher rate of fatal adverse events in cancer patients than control drugs.<ref>{{cite web | vauthors = Bankhead C | date = 17 February 2013 | title = Fatal AEs Higher with mTOR Drugs in Cancer | work = Med Page Today | url = https://www.medpagetoday.com/MeetingCoverage/MGUCS/37404 | access-date = 19 February 2013 | archive-date = 28 February 2021 | archive-url = https://web.archive.org/web/20210228220120/https://www.medpagetoday.com/meetingcoverage/mgucs/37404 | url-status = live }}</ref>

A combination therapy of doxorubicin and sirolimus has been shown to drive Akt-positive lymphomas into remission in mice.{{citation needed|date=March 2025}} Akt signalling promotes cell survival in Akt-positive lymphomas and acts to prevent the cytotoxic effects of chemotherapy drugs, such as doxorubicin or cyclophosphamide.{{citation needed|date=March 2025}} Sirolimus blocks Akt signalling and the cells lose their resistance to the chemotherapy.{{citation needed|date=March 2025}} Bcl-2-positive lymphomas were completely resistant to the therapy; eIF4E-expressing lymphomas are not sensitive to sirolimus.<ref>{{cite journal | vauthors = Sun SY, Rosenberg LM, Wang X, Zhou Z, Yue P, Fu H, Khuri FR | date = August 2005 | title = Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition | journal = Cancer Research | volume = 65 | issue = 16 | pages = 7052–7058 | doi = 10.1158/0008-5472.CAN-05-0917 | pmid = 16103051 | title-link = doi | doi-access = }}</ref><ref name="Chan">{{cite journal | vauthors = Chan S | date = October 2004 | title = Targeting the mammalian target of rapamycin (mTOR): a new approach to treating cancer | journal = British Journal of Cancer | volume = 91 | issue = 8 | pages = 1420–1424 | doi = 10.1038/sj.bjc.6602162 | pmc = 2409926 | pmid = 15365568 }}</ref><ref name="ScienceDaily">{{cite journal | vauthors = Wendel HG, De Stanchina E, Fridman JS, Malina A, Ray S, Kogan S, Cordon-Cardo C, Pelletier J, Lowe SW | date = March 2004 | title = Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy | journal = Nature | volume = 428 | issue = 6980 | pages = 332–337 | doi = 10.1038/nature02369 | pmid = 15029198 | s2cid = 4426215 | bibcode = 2004Natur.428..332W | author-link7 = Carlos Cordon-Cardo }}</ref><ref>{{cite web | date = 17 March 2004 | title = Combination therapy drives cancer into remission | website = Cold Spring Harbor Laboratory | url = https://www.cshl.edu/combination-therapy-drives-cancer-into-remission/ | access-date = 23 March 2022 | archive-date = 1 June 2022 | archive-url = https://web.archive.org/web/20220601214952/https://www.cshl.edu/combination-therapy-drives-cancer-into-remission/ | url-status = live }}</ref><ref name="SignalingGateway">{{cite journal | vauthors = Novak K | date = May 2004 | title = Therapeutics: Means to an end | journal = Nature Reviews Cancer | volume = 4 | issue = 5 | page = 332 | doi = 10.1038/nrc1349 | s2cid = 45906785 | doi-access = free }}</ref>

=== Tuberous sclerosis complex === Sirolimus also shows promise in treating tuberous sclerosis complex (TSC), a congenital disorder that predisposes those afflicted to benign tumor growth in the brain, heart, kidneys, skin, and other organs.{{citation needed|date=March 2025}} After several studies conclusively linked mTOR inhibitors to remission in TSC tumors, specifically subependymal giant-cell astrocytomas in children and angiomyolipomas in adults, many US doctors began prescribing sirolimus (Wyeth's Rapamune) and everolimus (Novartis's RAD001) to TSC patients off-label.{{citation needed|date=March 2025}} Numerous clinical trials using both rapamycin analogs, involving both children and adults with TSC, are underway in the United States.<ref>{{cite journal | vauthors = Li M, Zhou Y, Chen C, Yang T, Zhou S, Chen S, Wu Y, Cui Y | date = February 2019 | title = Efficacy and safety of mTOR inhibitors (rapamycin and its analogues) for tuberous sclerosis complex: a meta-analysis | journal = Orphanet Journal of Rare Diseases | volume = 14 | issue = 1 | article-number = 39 | doi = 10.1186/s13023-019-1012-x | pmc = 6373010 | pmid = 30760308 | doi-access = free }}</ref>

=== Effects on longevity === mTOR, specifically mTORC1, was first shown to be important in aging in 2003, in a study on worms; sirolimus was shown to inhibit and slow aging in worms, yeast, and flies, and then to improve the condition of mouse models of various diseases of aging.<ref>{{cite web | vauthors = Lawton G | title = What is rapamycin? | language = en-US | website = New Scientist | url = https://www.newscientist.com/definition/rapamycin/ | access-date = 25 July 2021 | archive-date = 25 July 2021 | archive-url = https://web.archive.org/web/20210725034527/https://www.newscientist.com/definition/rapamycin/ | url-status = live }}</ref><ref name=Apelo2016rev>{{cite journal | vauthors = Arriola Apelo SI, Lamming DW | date = July 2016 | title = Rapamycin: An InhibiTOR of Aging Emerges From the Soil of Easter Island | journal = The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences | volume = 71 | issue = 7 | pages = 841–849 | doi = 10.1093/gerona/glw090 | pmc = 4906330 | pmid = 27208895 | quote = A diverse and severe set of negative side effects likely preclude the wide-scale use of rapamycin and its analogs as a prolongevity agent. }}</ref> Sirolimus was first shown to extend lifespan in wild-type mice in a study published by NIH investigators in 2009; the studies have been replicated in mice of many different genetic backgrounds.<ref name=Apelo2016rev/> A study published in 2020 found late-life sirolimus dosing schedules enhanced mouse lifespan in a sex-specific manner: limited rapamycin exposure enhanced male but not female lifespan, providing evidence for sex differences in sirolimus response.<ref name="pmid33145977">{{cite journal | vauthors = Strong R, Miller RA, Bogue M, Fernandez E, Javors MA, Libert S, Marinez PA, Murphy MP, Musi N, Nelson JF, Petrascheck M, Reifsnyder P, Richardson A, Salmon AB, Macchiarini F, Harrison DE | date = November 2020 | title = Rapamycin-mediated mouse lifespan extension: Late-life dosage regimes with sex-specific effects | journal = Aging Cell | volume = 19 | issue = 11 | article-number = e13269 | doi = 10.1111/acel.13269 | pmc = 7681050 | pmid = 33145977 }}</ref><ref>{{cite web | date = 11 November 2020 | title = Late-Life Rapamycin Regimens Extend Mouse Lifespan in a Sex-Specific Manner | website = Nicotinamide Mononucleotide (NMN) | url = https://www.nmn.com/news/late-life-rapamycin-regimens-extend-mouse-lifespan-sex-specific-manner | access-date = 23 March 2022 | archive-date = 28 February 2021 | archive-url = https://web.archive.org/web/20210228013745/https://www.nmn.com/news/late-life-rapamycin-regimens-extend-mouse-lifespan-sex-specific-manner | url-status = live }}</ref> The results are further supported by the finding that genetically modified mice with impaired mTORC1 signalling live longer.<ref name=Apelo2016rev/>

Sirolimus has potential for widespread use as a longevity-promoting drug, with evidence pointing to its ability to prevent age-associated decline of cognitive and physical health. In 2014, researchers at Novartis showed that a related compound, everolimus, increased elderly patients' immune response on an intermittent dose.<ref>{{cite journal | vauthors = Mannick JB, Del Giudice G, Lattanzi M, Valiante NM, Praestgaard J, Huang B, Lonetto MA, Maecker HT, Kovarik J, Carson S, Glass DJ, Klickstein LB | date = December 2014 | title = mTOR inhibition improves immune function in the elderly | journal = Science Translational Medicine | volume = 6 | issue = 268 | article-number = 268ra179 | doi = 10.1126/scitranslmed.3009892 | pmid = 25540326 | s2cid = 206685475 }}</ref> This led to many in the anti-aging community self-experimenting with the compound.<ref>{{cite news | vauthors = Janin A | date = May 2023 | title = Can a Kidney Transplant Drug Keep You From Aging? | language = en-US | url = https://www.wsj.com/articles/rapamycin-anti-aging-drug-longevity-a27575f4 | access-date = 9 May 2023 | archive-date = 8 May 2023 | archive-url = https://web.archive.org/web/20230508203232/https://www.wsj.com/articles/rapamycin-anti-aging-drug-longevity-a27575f4 | newspaper = Wall Street Journal | url-status = live }}</ref> However, because of the different biochemical properties of sirolimus, the dosing is potentially very different from that of everolimus. Ultimately, due to known side-effects of sirolimus, as well as inadequate evidence for optimal dosing, it was concluded in 2016 that more research was required before sirolimus could be widely prescribed for this purpose.<ref name="Apelo2016rev" /><ref>{{cite journal | vauthors = Johnson SC, Rabinovitch PS, Kaeberlein M | date = January 2013 | title = mTOR is a key modulator of ageing and age-related disease | journal = Nature | volume = 493 | issue = 7432 | pages = 338–345 | doi = 10.1038/nature11861 | pmc = 3687363 | pmid = 23325216 | bibcode = 2013Natur.493..338J }}</ref> Two human studies on the effects of sirolimus (rapamycin) on longevity did not show statistically significant benefits. However, due to limitations in the studies, further research is needed to fully assess its potential in humans.<ref>{{cite web | vauthors = Smith DG | date = 24 September 2024 | title = Rapamycin and Anti-Aging: What to Know | website = The New York Times | url = https://www.nytimes.com/2024/09/24/well/live/rapamycin-aging-longevity-benefits-risks.html | access-date = 23 March 2025 }}</ref>

Sirolimus has complex effects on the immune system—while IL-12 goes up and IL-10 decreases, which suggests an immunostimulatory response, TNF and IL-6 are decreased, which suggests an immunosuppressive response. The duration of the inhibition and the exact extent to which mTORC1 and mTORC2 are inhibited play a role, but were not yet well understood according to a 2015 paper.<ref>{{cite journal | vauthors = Weichhart T, Hengstschläger M, Linke M | date = October 2015 | title = Regulation of innate immune cell function by mTOR | journal = Nature Reviews. Immunology | volume = 15 | issue = 10 | pages = 599–614 | doi = 10.1038/nri3901 | pmc = 6095456 | pmid = 26403194 }}</ref>

=== Topical administration === When applied as a topical preparation, researchers showed that rapamycin can regenerate collagen and reverse clinical signs of aging in elderly patients.<ref>{{cite journal | vauthors = Chung CL, Lawrence I, Hoffman M, Elgindi D, Nadhan K, Potnis M, Jin A, Sershon C, Binnebose R, Lorenzini A, Sell C | date = December 2019 | title = Topical rapamycin reduces markers of senescence and aging in human skin: an exploratory, prospective, randomized trial | journal = GeroScience | volume = 41 | issue = 6 | pages = 861–869 | doi = 10.1007/s11357-019-00113-y | pmc = 6925069 | pmid = 31761958 }}</ref> The concentrations are far lower than those used to treat angiofibromas.{{citation needed|date=November 2024}}

=== SARS-CoV-2=== Rapamycin has been proposed as a treatment for severe acute respiratory syndrome coronavirus 2 insofar as its immunosuppressive effects could prevent or reduce the cytokine storm seen in very serious cases of COVID-19.<ref name="pmid33031791">{{cite journal | vauthors = Husain A, Byrareddy SN | date = November 2020 | title = Rapamycin as a potential repurpose drug candidate for the treatment of COVID-19 | journal = Chemico-Biological Interactions | volume = 331 | article-number = 109282 | doi = 10.1016/j.cbi.2020.109282 | pmc = 7536130 | pmid = 33031791 | bibcode = 2020CBI...33109282H }}</ref> Moreover, inhibition of cell proliferation by rapamycin could reduce viral replication.<ref name="pmid33031791" />

=== Atherosclerosis === Rapamycin can accelerate degradation of oxidized LDL cholesterol in endothelial cells, thereby lowering the risk of atherosclerosis.<ref name="pmid30666207">{{cite journal | vauthors = Liu Y, Yang F, Zou S, Qu L | date = 2019 | title = Rapamycin: A Bacteria-Derived Immunosuppressant That Has Anti-atherosclerotic Effects and Its Clinical Application | journal = Frontiers in Pharmacology | volume = 9 | article-number = 1520 | doi = 10.3389/fphar.2018.01520 | pmc = 6330346 | pmid = 30666207 | title-link = doi | doi-access = free }}</ref> Oxidized LDL cholesterol is a major contributor to atherosclerosis.<ref name="pmid15383655">{{cite journal | vauthors = Stocker R, Keaney JF | date = October 2004 | title = Role of oxidative modifications in atherosclerosis | journal = Physiological Reviews | volume = 84 | issue = 4 | pages = 1381–1478 | doi = 10.1152/physrev.00047.2003 | pmid = 15383655 | title-link = doi | doi-access = }}</ref>

=== Lupus === As of 2016, studies in cells, animals, and humans have suggested that mTOR activation is a process underlying systemic lupus erythematosus and that inhibiting mTOR with rapamycin may be a disease-modifying treatment.<ref name=Oaks2016rev>{{cite journal | vauthors = Oaks Z, Winans T, Huang N, Banki K, Perl A | date = December 2016 | title = Activation of the Mechanistic Target of Rapamycin in SLE: Explosion of Evidence in the Last Five Years | journal = Current Rheumatology Reports | volume = 18 | issue = 12 | article-number = 73 | doi = 10.1007/s11926-016-0622-8 | pmc = 5314949 | pmid = 27812954 }}</ref> As of 2016 rapamycin had been tested in small clinical trials in people with lupus.<ref name=Oaks2016rev/>

=== Lymphatic malformation (LM)=== Lymphatic malformation, lymphangioma or cystic hygroma, is an abnormal growth of lymphatic vessels that usually affects children around the head and neck area and more rarely involving the tongue causing macroglossia. LM is caused by a PIK3CA mutation during lymphangiogenesis early in gestational cell formation causing the malformation of lymphatic tissue. Treatment often consists of removal of the affected tissue via excision, laser ablation or sclerotherapy, but the rate of recurrence can be high and surgery can have complications. Sirolimus has shown evidence of being an effective treatment in alleviating symptoms and reducing the size of the malformation by way of altering the mTOR pathway in lymphangiogenesis. Although an off label use of the drug, Sirolimus has been shown to be an effective treatment for both microcystic and macrocystic LM. More research is however needed to develop and create targeted, effective treatment therapies for LM.<ref>{{cite journal | vauthors = Wiegand S, Dietz A, Wichmann G | date = August 2022 | title = Efficacy of sirolimus in children with lymphatic malformations of the head and neck | journal = European Archives of Oto-Rhino-Laryngology | volume = 279 | issue = 8 | pages = 3801–3810 | doi = 10.1007/s00405-022-07378-8 | pmc = 9249683 | pmid = 35526176 }}</ref>

=== Graft-versus-host disease === Due to its immunosuppressant activity, rapamycin has been assessed as prophylaxis or treatment agent of graft-versus-host disease (GVHD), a complication of hematopoietic stem cell transplantation. While contrasted results were obtained in clinical trials,<ref>{{cite journal | vauthors = Lutz M, Mielke S | date = November 2016 | title = New perspectives on the use of mTOR inhibitors in allogeneic haematopoietic stem cell transplantation and graft-versus-host disease | journal = British Journal of Clinical Pharmacology | volume = 82 | issue = 5 | pages = 1171–1179 | doi = 10.1111/bcp.13022 | pmc = 5061796 | pmid = 27245261 | title-link = doi | doi-access = free }}</ref> pre-clinical studies have shown that rapamycin can mitigate GVHD by increasing the proliferation of regulatory T cells, inhibiting cytotoxic T cells and lowering the differentiation of effector T cells.<ref>{{cite journal | vauthors = Blazar BR, Taylor PA, Panoskaltsis-Mortari A, Vallera DA | date = June 1998 | title = Rapamycin inhibits the generation of graft-versus-host disease- and graft-versus-leukemia-causing T cells by interfering with the production of Th1 or Th1 cytotoxic cytokines | journal = Journal of Immunology | volume = 160 | issue = 11 | pages = 5355–5365 | doi = 10.4049/jimmunol.160.11.5355 | pmid = 9605135 | s2cid = 31313976 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Ehx G, Ritacco C, Hannon M, Dubois S, Delens L, Willems E, Servais S, Drion P, Beguin Y, Baron F | date = August 2021 | title = Comprehensive analysis of the immunomodulatory effects of rapamycin on human T cells in graft-versus-host disease prophylaxis | journal = American Journal of Transplantation | volume = 21 | issue = 8 | pages = 2662–2674 | doi = 10.1111/ajt.16505 | pmid = 33512760 | s2cid = 231766741 | doi-access = free | hdl = 2268/256132 | hdl-access = free }}</ref>

=== Applications in biology research === Rapamycin is used in biology research as an agent for chemically induced dimerization.<ref>{{cite journal | vauthors = Rivera VM, Clackson T, Natesan S, Pollock R, Amara JF, Keenan T, Magari SR, Phillips T, Courage NL, Cerasoli F, Holt DA, Gilman M | date = September 1996 | title = A humanized system for pharmacologic control of gene expression | journal = Nature Medicine | volume = 2 | issue = 9 | pages = 1028–1032 | doi = 10.1038/nm0996-1028 | pmid = 8782462 | s2cid = 30469863 }}</ref> In this application, rapamycin is added to cells expressing two fusion constructs, one of which contains the rapamycin-binding FRB domain from mTOR and the other of which contains an FKBP domain. Each fusion protein also contains additional domains that are brought into proximity when rapamycin induces binding of FRB and FKBP. In this way, rapamycin can be used to control and study protein localization and interactions.{{citation needed|date=November 2024}}

=== Neurodegenerative disorders === As suppression of autophagy has been indicated as a contributing factor in a variety of neurodegenerative disorders, including Alzheimer's disease, rapamycin has been proposed as a potential treatment for these conditions, although results suggest it may not be effective in all cases.<ref>{{cite journal | vauthors = Carosi JM, Sargeant TJ | date = August 2023 | title = Rapamycin and Alzheimer disease: a hypothesis for the effective use of rapamycin for treatment of neurodegenerative disease | journal = Autophagy | volume = 19 | issue = 8 | pages = 2386–2390 | doi = 10.1080/15548627.2023.2175569 | pmc = 10351443 | pmid = 36727410 }}</ref>

== Veterinary uses == A number of veterinary medicine teaching hospitals are participating in a long-term clinical study examining the effect of rapamycin on the longevity of dogs.<ref>{{multiref2|1={{cite web | date = 29 July 2022 | title = Study to assess healthy aging in dogs: the Dog Aging Project and Test of Rapamycin in Aging Dogs (TRIAD study) | website = University of Georgia College of Veterinary Medicine | url = https://vet.uga.edu/clinical-trial/study-to-assess-healthy-aging-in-dogs-the-dog-aging-project-and-test-of-rapamycin-in-aging-dogs-triad-study/ | access-date = 23 February 2023 | archive-date = 23 February 2023 | archive-url = https://web.archive.org/web/20230223234710/https://vet.uga.edu/clinical-trial/study-to-assess-healthy-aging-in-dogs-the-dog-aging-project-and-test-of-rapamycin-in-aging-dogs-triad-study/ | url-status = live }} |2={{cite web | date = 28 March 2022 | title = Dog Aging Project TRIAD Study | website = Washington State University Veterinary Teaching Hospital | url = https://hospital.vetmed.wsu.edu/2022/03/28/dog-aging-project-triad-study/ | access-date = 23 February 2023 | archive-date = 23 February 2023 | archive-url = https://web.archive.org/web/20230223234732/https://hospital.vetmed.wsu.edu/2022/03/28/dog-aging-project-triad-study/ | url-status = live }} |3={{cite web | title = Dog aging project - TRIAD (Test of Rapamycin in Aging Dogs) | website = Iowa State University College of Veterinary Medicine | url = https://vetmed.iastate.edu/vmc/clinical-trials/dog-aging-project-triad-test-rapamycin-aging-dogs | access-date = 23 February 2023 | archive-date = 23 February 2023 | archive-url = https://web.archive.org/web/20230223234717/https://vetmed.iastate.edu/vmc/clinical-trials/dog-aging-project-triad-test-rapamycin-aging-dogs | url-status = live }}}}</ref>

A clinical trial led by NC State College of Veterinary Medicine (HALT), run at a number of veterinary hospitals across the US, found that rapamycin reverses the effects of hypertrophic cardiomyopathy in cats.<ref>{{cite web | date = 7 February 2025 | title = Studies Led by NC State's Top Researcher Propelling First Drug to Treat Feline Heart Condition to Market | work = Veterinary Medicine News | url = https://news.cvm.ncsu.edu/studies-led-by-nc-states-top-researcher-propelling-first-drug-to-treat-feline-heart-condition-to-market/ }}</ref>

In March 2025, the US Food and Drug Administration announced conditional approval of sirolimus delayed-release tablets (Felycin-CA1) for the management of ventricular hypertrophy in cats with subclinical hypertrophic cardiomyopathy.<ref>{{cite web | date = 14 March 2025 | title = Freedom of Information Summary Conditional Approval Application Felycin-CA1 | url = https://animaldrugsatfda.fda.gov/adafda/app/search/public/document/downloadFoi/16672 | access-date = 22 March 2025 | format = PDF }}</ref><ref name="FDA PR 20250314">{{cite web | date = 14 March 2025 | title = FDA Conditionally Approves Drug for Heart Disease in Cats | website = U.S. Food and Drug Administration (FDA) | url = https://www.fda.gov/animal-veterinary/cvm-updates/fda-conditionally-approves-drug-management-ventricular-hypertrophy-cats | access-date = 22 March 2025 }} {{PD-notice}}</ref> This is the first product approved for use in cats with hypertrophic cardiomyopathy for any indication.<ref name="FDA PR 20250314" /> Cardiomyopathy is a disease of the heart muscle.<ref name="FDA PR 20250314" /> Hypertrophic cardiomyopathy in cats causes thickening of the heart's left ventricle.<ref name="FDA PR 20250314" /> It is the most common heart disease in cats and is one of the most common causes of death in cats.<ref name="FDA PR 20250314" /> While the cause is unknown in most cases, hypertrophic cardiomyopathy is associated with a genetic mutation in certain breeds, such as Maine Coons, Ragdolls, and Persians.<ref name="FDA PR 20250314" /> Hypertrophic cardiomyopathy is a progressive disease.<ref name="FDA PR 20250314" /> Cats in the subclinical phase have thickening of their heart wall but do not show clinical symptoms of the disease yet.<ref name="FDA PR 20250314" /> Cats may live for years in the subclinical phase, while others may progress to congestive heart failure, arterial thromboembolism, or sudden death.<ref name="FDA PR 20250314" />

== See also == * List of drugs affected by grapefruit

== References == {{reflist}}

== Further reading == {{refbegin}} * {{cite journal | vauthors = Benjamin D, Colombi M, Moroni C, Hall MN | date = October 2011 | title = Rapamycin passes the torch: a new generation of mTOR inhibitors | journal = Nature Reviews. Drug Discovery | volume = 10 | issue = 11 | pages = 868–880 | doi = 10.1038/nrd3531 | pmid = 22037041 | s2cid = 1227277 }} * {{cite journal | vauthors = Freixo C, Ferreira V, Martins J, Almeida R, Caldeira D, Rosa M, Costa J, Ferreira J | date = January 2020 | title = Efficacy and safety of sirolimus in the treatment of vascular anomalies: A systematic review | journal = Journal of Vascular Surgery | volume = 71 | issue = 1 | pages = 318–327 | doi = 10.1016/j.jvs.2019.06.217 | pmid = 31676179 | s2cid = 207831199 | doi-access = free }} * {{cite journal | vauthors = Geeurickx M, Labarque V | date = September 2021 | title = A narrative review of the role of sirolimus in the treatment of congenital vascular malformations | journal = Journal of Vascular Surgery. Venous and Lymphatic Disorders | volume = 9 | issue = 5 | pages = 1321–1333 | doi = 10.1016/j.jvsv.2021.03.001 | pmid = 33737259 | doi-access = free }} {{refend}}

== External links == {{Commons category}}

* [https://www.wnycstudios.org/podcasts/radiolab/articles/dirty-drug-and-ice-cream-tub ''The Dirty Drug and the Ice Cream Tub''] Radiolab episode on the discovery of rapamycin * {{ClinicalTrialsGov|NCT02494570|A Phase 2 Study of ABI-009 in Patients With Advanced Malignant PEComa (AMPECT)}}

{{Immunosuppressants}} {{Targeted cancer therapeutic agents}} {{Xenobiotic-sensing receptor modulators}} {{Portal bar | Medicine}} {{Authority control}}

Category:Anti-aging substances Category:Chemical biology Category:Drugs developed by Pfizer Category:Drugs developed by Wyeth Category:Immunosuppressants Category:Lactams Category:Macrolides Category:MTOR inhibitors Category:Ophthalmology drugs Category:Orphan drugs Category:Polyenes