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Revision as of 10:29, 21 November 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,081 edits Saving copy of the {{drugbox}} taken from revid 461556719 of page Tacrolimus for the Chem/Drugbox validation project (updated: 'UNII', 'ChEMBL').  Latest revision as of 16:37, 12 January 2025 edit Arthurfragoso (talk | contribs)Extended confirmed users, Template editors4,591 edits dark mode fix 
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{{Short description|Immunosuppressive drug}}
{{ambox | text = This page contains a copy of the infobox ({{tl|drugbox}}) taken from revid of page ] with values updated to verified values.}}
{{Use British English|date=April 2020}}
{{drugbox
{{Use dmy dates|date=January 2024}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{Infobox drug
| Verifiedfields = changed | Verifiedfields = changed
| UNII_Ref = {{fdacite|changed|FDA}} | Watchedfields = changed
| verifiedrevid = 461746192
| UNII = WM0HAQ4WNM
| image = Tacrolimus2DCSD.svg
| verifiedrevid = 401617043
| image_class = skin-invert-image
| IUPAC_name = 3S-<br>
| width = 250
,4S<sup>*</sup>,5R<sup>*</sup>,8S<sup>*</sup>,9E,12R<sup>*</sup>,14R<sup>*</sup>,15S<sup>*</sup>,16R<sup>*</sup>,18S<sup>*</sup>,19S<sup>*</sup>,26aR<sup>*</sup><br>
| alt =
-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a<br>
| image2 = Tacrolimus-1YAT-ball-and-stick-model.png
-hexadecahydro-5, 19-dihydroxy<br>
| width2 = 250
-3-[2-(4-hydroxy-3-methoxycyclohexyl)<br>
| alt2 =
-1-methylethenyl]-14,16-dimethoxy<br>
| caption =
-4,10,12,18-tetramethyl-8-(2-propenyl)<br>

-15,19-epoxy-3H-pyrido oxaazacyclotricosine-1,7,20,21(4H,23H)<br>
<!-- Clinical data -->
-tetrone, monohydrate
| pronounce =
| image = Tacrolimus-Armistead-2D-skeletal.png
| tradename = Prograf, Advagraf, Protopic, others
| width = 250px
| Drugs.com = {{drugs.com|monograph|tacrolimus}}
| image2 = Tacrolimus-3D-sticks.png
| MedlinePlus = a601117
| width2 = 250px
| DailyMedID = Tacrolimus
| InChI = 1/C44H69NO12/c1-10-13-31-19-25(2)18-26(3)20-37(54-8)40-38(55-9)22-28(5)44(52,57-40)41(49)42(50)45-17-12-11-14-32(45)43(51)56-39(29(6)34(47)24-35(31)48)27(4)21-30-15-16-33(46)36(23-30)53-7/h10,19,21,26,28-34,36-40,46-47,52H,1,11-18,20,22-24H2,2-9H3/b25-19-,27-21+/t26-,28+,29+,30-,31+,32-,33+,34-,36+,37-,38-,39+,40+,44+/m0/s1
| pregnancy_AU = C
| InChIKey = QJJXYPPXXYFBGM-LJIGMGMYBJ
| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Tacrolimus Use During Pregnancy | website=Drugs.com | date=3 October 2019 | url=https://www.drugs.com/pregnancy/tacrolimus.html | access-date=29 April 2020}}</ref>
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| pregnancy_category=
| StdInChI = 1S/C44H69NO12/c1-10-13-31-19-25(2)18-26(3)20-37(54-8)40-38(55-9)22-28(5)44(52,57-40)41(49)42(50)45-17-12-11-14-32(45)43(51)56-39(29(6)34(47)24-35(31)48)27(4)21-30-15-16-33(46)36(23-30)53-7/h10,19,21,26,28-34,36-40,46-47,52H,1,11-18,20,22-24H2,2-9H3/b25-19-,27-21+/t26-,28+,29+,30-,31+,32-,33+,34-,36+,37-,38-,39+,40+,44+/m0/s1
| routes_of_administration = ], ], ]
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| class =
| StdInChIKey = QJJXYPPXXYFBGM-LJIGMGMYSA-N
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 104987-11-3
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 4976056
| ATC_prefix = D11 | ATC_prefix = D11
| ATC_suffix = AH01 | ATC_suffix = AH01
| ATC_supplemental= {{ATC|L04|AD02}} | ATC_supplemental= <br />{{ATC|L04|AD02}}

| PubChem = 6473866
<!-- Legal status -->
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| ChEMBL = <!-- blanked - oldvalue: 1200738 --> | legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled -->
| legal_AU_comment =
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->
| legal_BR_comment =
| legal_CA = Rx-only
| legal_CA_comment =<ref>{{cite web | title=Drug and medical device highlights 2019: Helping you maintain and improve your health | website=] | date=18 November 2020 | url=https://www.canada.ca/en/health-canada/services/publications/drugs-health-products/drug-medical-device-highlights-2019.html | access-date=28 March 2024}}</ref>
| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment =
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment =
| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->
| legal_UK_comment =
| legal_US = Rx-only
| legal_US_comment = <ref name="Prograf FDA label">{{cite web | title=Prograf- tacrolimus capsule, gelatin coated Prograf- tacrolimus injection, solution Prograf- tacrolimus granule, for suspension | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7f667de1-9dfa-4bd6-8ba0-15ee2d78873b | access-date=16 July 2021}}</ref>
| legal_EU = Rx-only
| legal_EU_comment = <ref>{{cite web | title=Advagraf EPAR | website=European Medicines Agency | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/advagraf | access-date=16 July 2021}}</ref><ref>{{cite web | title=Protopic EPAR | website=European Medicines Agency | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/protopic | access-date=16 July 2021}}</ref>
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment =
| legal_status = Rx-only

<!-- Pharmacokinetic data -->
| bioavailability = 24% (5–67%), less after eating food rich in fat
| protein_bound = ≥98.8%
| metabolism = ] ], ]
| metabolites =
| onset =
| elimination_half-life = 11.3 h for transplant patients (range 3.5–40.6 h)
| duration_of_action =
| excretion = Mostly fecal

<!-- Identifiers -->
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 104987-11-3
| CAS_supplemental =
| PubChem = 445643
| IUPHAR_ligand =
| DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00864 | DrugBank = DB00864
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 393220
| UNII_Ref = {{fdacite|changed|FDA}}
| UNII = Y5L2157C4J
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D08556
| KEGG2_Ref = {{keggcite|correct|kegg}}
| KEGG2 = D00107
| ChEBI_Ref =
| ChEBI = 61049
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 269732
| NIAID_ChemDB =
| PDB_ligand = FK5
| synonyms = FK-506, fujimycin

<!-- Chemical and physical data -->
| IUPAC_name = (−)-(3''S'',4''R'',5''S'',8''R'',9''E'',12''S'',14''S'',15''R'',16''S'',18''R'',26a''S'')-8-allyl-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-<nowiki/>{(''E'')-2--1-methylvinyl}-14,16-dimethoxy-4,10,12,18-tetramethyl-15,19-epoxy-3''H''-pyrido oxaazacyclotricosane-1,7,20,21(4''H'',23''H'')-tetrone
| C=44 | H=69 | N=1 | O=12 | C=44 | H=69 | N=1 | O=12
| SMILES = O(C)12(O(O)((C)C1)C(=O)C(=O)N3(C(=O)O(\C(=C\4C(OC)(O)CC4)\C)(C)(O)CC(=O)(CC=C)/C=C(\C)/C(C)C2OC)(CCCC3))
| molecular_weight = 804.018 g/mol
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| smiles = O=C3C(=O)N1CCCC1C(=O)O(C(=C/2CC(O)(OC)C2)/C)(C)(O)CC(=O)(/C=C(/C(C(OC)4O3(O)(C)C4OC)C)C)C\C=C
| StdInChI = 1S/C44H69NO12/c1-10-13-31-19-25(2)18-26(3)20-37(54-8)40-38(55-9)22-28(5)44(52,57-40)41(49)42(50)45-17-12-11-14-32(45)43(51)56-39(29(6)34(47)24-35(31)48)27(4)21-30-15-16-33(46)36(23-30)53-7/h10,19,21,26,28-34,36-40,46-47,52H,1,11-18,20,22-24H2,2-9H3/b25-19+,27-21+/t26-,28+,29+,30-,31+,32-,33+,34-,36+,37-,38-,39+,40+,44+/m0/s1
| bioavailability = 20%, less after eating food rich in fat
| StdInChI_comment =
| protein_bound =75-99%
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| metabolism = Hepatic ]
| StdInChIKey = QJJXYPPXXYFBGM-LFZNUXCKSA-N
| elimination_half-life = 11.3 h (range 3.5-40.6 h)
| density =
| excretion = Mostly faecal
| density_notes =
| pregnancy_category = C
| melting_point =
| legal_status =
| melting_high =
| routes_of_administration = Topical, oral, ]
| melting_notes =
| boiling_point =
| boiling_notes =
| solubility =
| sol_units =
| specific_rotation =
}} }}

'''Tacrolimus''', sold under the brand name '''Prograf''' among others, is an ]. After ] ], the risk of organ ] is moderate. To lower the risk of organ rejection, tacrolimus is given. The drug can also be sold as a ] in the treatment of T cell-mediated diseases such as ] and ]. For example, it is prescribed for severe refractory ] after a ] transplant, exacerbations of ], ], and ]. It can be used to treat ] in cats and dogs.<ref>{{cite journal | vauthors = Berdoulay A, English RV, Nadelstein B | title = Effect of topical 0.02% tacrolimus aqueous suspension on tear production in dogs with keratoconjunctivitis sicca | journal = Veterinary Ophthalmology | volume = 8 | issue = 4 | pages = 225–232 | year = 2005 | pmid = 16008701 | doi = 10.1111/j.1463-5224.2005.00390.x | doi-access = free }}</ref><ref>{{cite web|title=Tacrolimus for Dogs and Cats|url=https://www.wedgewoodpetrx.com/learning-center/medication-information-for-pet-and-horse-owners/tacrolimus-for-dogs-and-cats.html}}</ref>

Tacrolimus inhibits ], which is involved in the production of ], a ] that promotes the development and ] of ]s, as part of the body's learned (or ]) immune response.

Chemically, it is a ] ]<ref>{{cite journal | vauthors = Baldo A, Cafiero M, Di Caterino P, Di Costanzo L | title = Tacrolimus ointment in the management of atopic dermatitis | journal = Clinical, Cosmetic and Investigational Dermatology | volume = 2 | pages = 1–7 | date = January 2009 | pmid = 21436963 | pmc = 3047924 | doi = 10.2147/ccid.s3378 | doi-access = free }}</ref> that was first discovered in 1987, from the fermentation broth of a ]ese ] sample that contained the ] '']''. It is on the ].<ref name="WHO23rd">{{cite book | vauthors = ((World Health Organization)) | title = The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) | year = 2023 | hdl = 10665/371090 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2023.02 | hdl-access=free }}</ref> In 2021, it was the 296th most commonly prescribed medication in the United States, with more than 500,000 prescriptions.<ref>{{cite web | title=The Top 300 of 2021 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=14 January 2024 | archive-date=15 January 2024 | archive-url=https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Tacrolimus - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Tacrolimus | access-date = 14 January 2024}}</ref>

{{TOC limit|3}}

==Medical uses==
===Organ transplantation===
It has similar immunosuppressive properties to ], but is much more potent. Immunosuppression with tacrolimus was associated with a significantly lower rate of acute rejection compared with ciclosporin-based immunosuppression (30.7% vs 46.4%) in one study.<ref name="Medscape2004-McCauley">{{cite web | vauthors = McCauley J |date=19 May 2004 | url = http://www.medscape.com/viewarticle/474429 | title=Long-Term Graft Survival In Kidney Transplant Recipients | work=Slide Set Series on Analyses of Immunosuppressive Therapies | publisher=] | access-date=6 June 2006}}</ref> Clinical outcome is better with tacrolimus than with ciclosporin during the first year of liver transplantation.<ref>{{cite journal | vauthors = Haddad EM, McAlister VC, Renouf E, Malthaner R, Kjaer MS, Gluud LL | title = Cyclosporin versus tacrolimus for liver transplanted patients | journal = The Cochrane Database of Systematic Reviews | volume = 2006 | issue = 4 | pages = CD005161 | date = October 2006 | pmid = 17054241 | pmc = 8865611 | doi = 10.1002/14651858.CD005161.pub2 | veditors = McAlister V }}</ref><ref>{{cite journal | vauthors = O'Grady JG, Burroughs A, Hardy P, Elbourne D, Truesdale A | title = Tacrolimus versus microemulsified ciclosporin in liver transplantation: the TMC randomised controlled trial | journal = Lancet | volume = 360 | issue = 9340 | pages = 1119–1125 | date = October 2002 | pmid = 12387959 | doi = 10.1016/S0140-6736(02)11196-2 | s2cid = 10417106 }}</ref> Long-term outcome has not been improved to the same extent. Tacrolimus is normally prescribed as part of a post-transplant cocktail including ], ], and ] inhibitors such as ]. Dosages are titrated to target blood levels at specific times after medication administration.<ref>{{cite journal | vauthors = Lee MN, Butani L | title = Improved pharmacokinetic monitoring of tacrolimus exposure after pediatric renal transplantation | journal = Pediatric Transplantation | volume = 11 | issue = 4 | pages = 388–393 | date = June 2007 | pmid = 17493218 | doi = 10.1111/j.1399-3046.2006.00618.x | s2cid = 23530214 | doi-access = free }}</ref>

===Skin===
{{See also|Eczema#Medications|l1=Medications used in treatment of eczema}}
]

As an ], tacrolimus is used in the treatment of ] (eczema), in particular ], if topical corticosteroids and moisturisers fail in helping.<ref>{{cite journal |vauthors = Cury Martins J, Martins C, Aoki V, Gois AF, Ishii HA, da Silva EM |title = Topical tacrolimus for atopic dermatitis |journal = The Cochrane Database of Systematic Reviews |volume = 2015 |issue = 7 |pages = CD009864 |date = July 2015 |pmid = 26132597 |pmc = 6461158 |doi = 10.1002/14651858.CD009864.pub2 }}</ref><ref name="Cancer risk with topical calcineuri">{{cite journal |vauthors = Devasenapathy N, Chu A, Wong M, Srivastava A, Ceccacci R, Lin C, MacDonald M, Wen A, Steen J, Levine M, Pyne L, Schneider L, Chu DK |title = Cancer risk with topical calcineurin inhibitors, pimecrolimus and tacrolimus, for atopic dermatitis: a systematic review and meta-analysis |journal = The Lancet. Child & Adolescent Health |volume = 7 |issue = 1 |pages = 13–25 |date = January 2023 |pmid = 36370744 |doi = 10.1016/S2352-4642(22)00283-8 |s2cid = 253470127 }}</ref> It suppresses inflammation in a similar way to ]s, and is equally as effective as a mid-potency steroid. An important advantage of tacrolimus is that, unlike steroids, it does not cause skin thinning (]), or other steroid related side effects.<ref name="AC-Protopic" /><ref name="Cancer risk with topical calcineuri"/>

It is applied on the active lesions until they heal off, but may also be used continuously in low doses (twice a week), and applied to the thinner skin over the face and eyelids.{{Citation needed|date=December 2008}} Clinical trials of up to one year have been conducted. Recently it has also been used to treat segmental ] in children, especially in areas on the face.<ref>{{cite journal |vauthors = Silverberg NB, Lin P, Travis L, Farley-Li J, Mancini AJ, Wagner AM, Chamlin SL, Paller AS |title = Tacrolimus ointment promotes repigmentation of vitiligo in children: a review of 57 cases |journal = Journal of the American Academy of Dermatology |volume = 51 |issue = 5 |pages = 760–766 |date = November 2004 |pmid = 15523355 |doi = 10.1016/j.jaad.2004.05.036 }}</ref>

===Eyes===
Tacrolimus solution, as drops, is sometimes prescribed by veterinarians for ], and other ] maladies, in the eyes of domestic ]s, ]s, and ]s.<ref>{{cite web| publisher=]| title=Tacrolimus, Ophthalmic| date=2017| url=https://www.mspca.org/wp-content/uploads/2017/04/Plumbs-Tacrolimus-Ophthalmic.pdf| access-date=5 August 2022| archive-date=18 December 2022| archive-url=https://web.archive.org/web/20221218152242/https://www.mspca.org/wp-content/uploads/2017/04/Plumbs-Tacrolimus-Ophthalmic.pdf| url-status=dead}}</ref> It has been studied for use in human eyes.<ref>{{cite web| publisher=U.S. National Library of Medicine| title=Treatment of Dry Eye Using 0.03% Tacrolimus Eye Drops| date=10 May 2013| url=https://clinicaltrials.gov/ct2/show/NCT01850979| access-date=5 August 2022| vauthors = Naves FE, Sakassegawa E }}</ref><ref>{{cite journal | vauthors = Yazu H, Fukagawa K, Shimizu E, Sato Y, Fujishima H | title = Long-term outcomes of 0.1% tacrolimus eye drops in eyes with severe allergic conjunctival diseases | journal = Allergy, Asthma, and Clinical Immunology | volume = 17 | issue = 1 | pages = 11 | date = February 2021 | pmid = 33522964 | pmc = 7852099 | doi = 10.1186/s13223-021-00513-w | doi-access = free }}</ref>

==Contraindications and precautions==
Contraindications and precautions include:<ref name="AC" />
* ] disease
* Immunosuppression
* ]s
* ]
* ] disease, such as:
** ]
** ]
* ]
* ]
* ] prolongation
* ] (]) exposure
* ] juice<ref name="DrugMetab-Fukatsu">{{cite journal | vauthors = Fukatsu S, Fukudo M, Masuda S, Yano I, Katsura T, Ogura Y, Oike F, Takada Y, Inui K | title = Delayed effect of grapefruit juice on pharmacokinetics and pharmacodynamics of tacrolimus in a living-donor liver transplant recipient | journal = Drug Metabolism and Pharmacokinetics | volume = 21 | issue = 2 | pages = 122–125 | date = April 2006 | pmid = 16702731 | doi = 10.2133/dmpk.21.122 }}</ref>

===Topical use===
* Occlusive dressing
* Known or suspected malignant lesions
* ] or similar skin diseases
* Certain skin infections<ref name="AC-Protopic">{{cite book|title=Austria-Codex|editor=Haberfeld, H|at=Protopic|publisher=Österreichischer Apothekerverlag|location=Vienna|year=2015|language=de}}</ref>

==Side effects==
===By mouth or intravenous use===
Side effects can be severe and include ], cardiac damage, ], ], liver and ] problems (tacrolimus ]),<ref name="pmid19218475">{{cite journal | vauthors = Naesens M, Kuypers DR, Sarwal M | title = Calcineurin inhibitor nephrotoxicity | journal = Clinical Journal of the American Society of Nephrology | volume = 4 | issue = 2 | pages = 481–508 | date = February 2009 | pmid = 19218475 | doi = 10.2215/CJN.04800908 | doi-access = free }}</ref> ], ], ], ], ]ing, lung damage (] also causes lung damage),<ref>{{cite journal | vauthors = Miwa Y, Isozaki T, Wakabayashi K, Odai T, Matsunawa M, Yajima N, Negishi M, Ide H, Kasama T, Adachi M, Hisayuki T, Takemura T | title = Tacrolimus-induced lung injury in a rheumatoid arthritis patient with interstitial pneumonitis | journal = Modern Rheumatology | volume = 18 | issue = 2 | pages = 208–211 | year = 2008 | pmid = 18306979 | doi = 10.1007/s10165-008-0034-3 | s2cid = 39537409 }}</ref> and various neuropsychiatric problems such as loss of appetite, ], ], confusion, weakness, ], vivid nightmares, ]s, ], ]s, ]s, and ].<ref>{{cite journal | vauthors = O'Donnell MM, Williams JP, Weinrieb R, Denysenko L | title = Catatonic mutism after liver transplant rapidly reversed with lorazepam | journal = General Hospital Psychiatry | volume = 29 | issue = 3 | pages = 280–281 | year = 2007 | pmid = 17484951 | doi = 10.1016/j.genhosppsych.2007.01.004 }}
</ref>

In addition, it may potentially increase the severity of existing fungal or infectious conditions such as ] or ] viral infections.<ref name="AC" />

====Carcinogenesis and mutagenesis====
In people receiving immunosuppressants to reduce transplant graft rejection, an increased risk of malignancy (cancer) is a recognised complication.<ref name="AC" /> The most common cancers are ]<ref>{{Cite web|url=https://www.cancer.org/cancer/non-hodgkin-lymphoma/about/key-statistics.html|title=Key Statistics for Non-Hodgkin Lymphoma|website=www.cancer.org|access-date=19 February 2020}}</ref> and ]s. The risk appears to be related to the intensity and duration of treatment.

===Topical use===
The most common adverse events associated with the use of topical tacrolimus ointments, especially if used over a wide area, include a burning or itching sensation on the initial applications, with increased sensitivity to sunlight and heat on the affected areas.{{Citation needed|date=January 2022}} Less common are ], headache, cough, and burning eyes.<ref name="JAcadDerm-Hanifin">{{cite journal | vauthors = Hanifin JM, Paller AS, Eichenfield L, Clark RA, Korman N, Weinstein G, Caro I, Jaracz E, Rico MJ | title = Efficacy and safety of tacrolimus ointment treatment for up to 4 years in patients with atopic dermatitis | journal = Journal of the American Academy of Dermatology | volume = 53 | issue = 2 Suppl 2 | pages = S186–S194 | date = August 2005 | pmid = 16021174 | doi = 10.1016/j.jaad.2005.04.062 }}</ref>

====Cancer risks====
{{Further|Eczema#Medications}}
Tacrolimus and a related drug for eczema (]) were suspected of carrying a cancer risk, though the matter is still a subject of controversy. The FDA issued a health warning in March 2005 for the drug, based on animal models and a small number of patients. Until further human studies yield more conclusive results, the FDA recommends that users be advised of the potential risks. However, current practice by ] dermatologists is not to consider this a significant real concern and they are increasingly recommending the use of these new drugs.<ref name="BAD2002">{{cite web | vauthors = Cox NH, Smith CH |date=December 2002 |url=http://www.bad.org.uk/Portals/_Bad/Guidelines/Position%20Statements%20&%20Other%20Documents/Advice%20re%20topical%20tacrolimus.pdf |title=Advice to dermatologists re topical tacrolimus |work=Therapy Guidelines Committee |publisher=British Association of Dermatologists |url-status=dead |archive-url=https://web.archive.org/web/20131213072822/http://www.bad.org.uk/Portals/_Bad/Guidelines/Position%20Statements%20%26%20Other%20Documents/Advice%20re%20topical%20tacrolimus.pdf |archive-date=13 December 2013 }}</ref> A 2023 systematic review and meta-analysis published in ] concluded with moderate-certainty evidence that the two drugs were not associated with any increased risk of cancer.<ref>{{cite journal | vauthors = Devasenapathy N, Chu A, Wong M, Srivastava A, Ceccacci R, Lin C, MacDonald M, Wen A, Steen J, Levine M, Pyne L, Schneider L, Chu DK | title = Cancer risk with topical calcineurin inhibitors, pimecrolimus and tacrolimus, for atopic dermatitis: a systematic review and meta-analysis | language = English | journal = The Lancet. Child & Adolescent Health | volume = 7 | issue = 1 | pages = 13–25 | date = January 2023 | pmid = 36370744 | doi = 10.1016/S2352-4642(22)00283-8 | s2cid = 253470127 }}</ref>

== Interactions ==

Also like cyclosporin, it has a wide range of interactions. Tacrolimus is primarily metabolised by the ] system of liver enzymes, and there are many substances that interact with this system and induce or inhibit the system's metabolic activity.<ref name="AC">{{cite book|title=Austria-Codex|editor=Haberfeld, H|at=Prograf|publisher=Österreichischer Apothekerverlag|location=Vienna|year=2015|language=de}}</ref>

Interactions include that with ] which increases tacrolimus plasma concentrations. As infections are a major cause of morbidity and mortality in the post-transplant patient, the most commonly{{citation needed|date=October 2016}} reported interactions include interactions with anti-microbial drugs. Macrolide antibiotics including ] and ], as well as several of the newer classes of antifungals, especially of the azole class (], ]), increase tacrolimus levels by competing for cytochrome enzymes.<ref name="AC" />

==Pharmacology==
===Mechanism of action===
], the target protein of tacrolimus]]
Tacrolimus is a ] ]. In ], activation of the T cell receptor normally increases intracellular calcium, which acts via ] to activate ]. Calcineurin then dephosphorylates the transcription factor ] (NF-AT), which moves to the nucleus of the T cell and increases the activity of genes coding for IL-2 and related cytokines. Tacrolimus prevents the dephosphorylation of NF-AT.<ref>{{cite book| vauthors = Ganong WF |title= Review of medical physiology|edition=22nd |publisher=Lange medical books|page=530|isbn=978-0-07-144040-0|date= 8 March 2005}}</ref>

In detail, tacrolimus reduces ] activity by binding to the immunophilin ] (FK506 binding protein), creating a new complex. This FKBP12–FK506 complex interacts with and inhibits calcineurin, thus inhibiting both T ] signal transduction and IL-2 transcription.<ref name="Cell1991-Liu">{{cite journal | vauthors = Liu J, Farmer JD, Lane WS, Friedman J, Weissman I, Schreiber SL | title = Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes | journal = Cell | volume = 66 | issue = 4 | pages = 807–815 | date = August 1991 | pmid = 1715244 | doi = 10.1016/0092-8674(91)90124-H | s2cid = 22094672 }}</ref> Although this activity is similar to that of cyclosporin, the incidence of acute rejection is reduced by tacrolimus use over cyclosporin use.<ref name="Medscape2004-McCauley" /> Although short-term immunosuppression concerning patient and graft survival is found to be similar between the two drugs, tacrolimus results in a more favorable lipid profile, and this may have important long-term implications given the prognostic influence of rejection on graft survival.<ref>{{cite journal | vauthors = Abou-Jaoude MM, Najm R, Shaheen J, Nawfal N, Abboud S, Alhabash M, Darwish M, Mulhem A, Ojjeh A, Almawi WY | title = Tacrolimus (FK506) versus cyclosporine microemulsion (neoral) as maintenance immunosuppression therapy in kidney transplant recipients | journal = Transplantation Proceedings | volume = 37 | issue = 7 | pages = 3025–3028 | date = September 2005 | pmid = 16213293 | doi = 10.1016/j.transproceed.2005.08.040 }}</ref>

===Pharmacokinetics===
Oral tacrolimus is slowly absorbed in the ], with a total ] of 20 to 25% (but with variations from 5 to 67%) and ] (C<sub>max</sub>) reached after one to three hours. Taking the drug together with a meal, especially one rich in fat, slows down resorption and reduces bioavailability. In the blood, tacrolimus is mainly bound to ]s; only 5% are found in the ], of which more than 98.8% are bound to ]s.<ref name="AC" /><ref name="Dinnendahl">{{cite book|title=Arzneistoff-Profile|editor1=Dinnendahl, V |editor2=Fricke, U |publisher=Govi Pharmazeutischer Verlag|location=Eschborn, Germany|date=2003|edition=18|volume=9|isbn=978-3-7741-9846-3|language=de}}</ref>

The substance is metabolized in the liver, mainly via ], and in the intestinal wall. All ]s found in the circulation are inactive. ] varies widely and seems to be higher for healthy persons (43 hours on average) than for patients with liver transplants (12 hours) or kidney transplants (16 hours), due to differences in ]. Tacrolimus is predominantly eliminated via the faeces in form of its metabolites.<ref name="AC" /><ref name="Dinnendahl" />

When applied locally on eczema, tacrolimus has little to no bioavailability.<ref name="AC" />

===Pharmacogenetics===
The predominant enzyme responsible for metabolism of tacrolimus is ]. ]s within ''CYP3A5'' that result in changes to the activity of the CYP3A5 protein can affect concentrations of tacrolimus within the body. In particular, individuals who are ] for the G ] at the ] (SNP) rs776746 (also known as CYP3A5 *3/*3) have a non-functional CYP3A5 protein. The frequency of the G allele varies worldwide, from 4% in some African populations to 80–90% in Caucasian populations.<ref name="Bains2012">{{cite web| vauthors = Bains RK |title=Molecular diversity and population structure at the CYP3A5 gene in Africa|url=http://discovery.ucl.ac.uk/1356293/7/1356293_R%20Bains%20ELECTRONIC%20VERSION%20thesis%20-%20post%20viva.pdf|publisher=University College London|access-date=13 June 2016}}</ref> Across a large number of studies, individuals homozygous for the G allele have been shown to have higher concentrations of tacrolimus and require lower doses of the drug, as compared to individuals who are not homozygous for the G allele. Achieving target concentrations of tacrolimus is important – if levels are too low, then there is a risk of ], if levels are too high, there is a risk of drug toxicities. There is evidence to suggest that dosing patients based on rs776746 ] can result in faster and more frequent achievement of target tacrolimus levels. However, there is a lack of consistent evidence as to whether dosing based on rs776746 genotype results in improved clinical outcomes (such as a decreased risk for transplant rejection or drug toxicities), likely because patients taking tacrolimus are subject to ].<ref>{{cite journal | vauthors = Staatz CE, Tett SE | title = Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation | journal = Clinical Pharmacokinetics | volume = 43 | issue = 10 | pages = 623–653 | date = 2004 | pmid = 15244495 | doi = 10.2165/00003088-200443100-00001 | s2cid = 33877550 }}</ref><ref>{{cite journal | vauthors = Staatz CE, Goodman LK, Tett SE | title = Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: Part I | journal = Clinical Pharmacokinetics | volume = 49 | issue = 3 | pages = 141–175 | date = March 2010 | pmid = 20170205 | doi = 10.2165/11317350-000000000-00000 | s2cid = 28346861 }}</ref><ref>{{cite journal | vauthors = Staatz CE, Goodman LK, Tett SE | title = Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: Part II | journal = Clinical Pharmacokinetics | volume = 49 | issue = 4 | pages = 207–221 | date = April 2010 | pmid = 20214406 | doi = 10.2165/11317550-000000000-00000 | s2cid = 27047235 }}</ref><ref>{{cite journal | vauthors = Barbarino JM, Staatz CE, Venkataramanan R, Klein TE, Altman RB | title = PharmGKB summary: cyclosporine and tacrolimus pathways | journal = Pharmacogenetics and Genomics | volume = 23 | issue = 10 | pages = 563–585 | date = October 2013 | pmid = 23922006 | pmc = 4119065 | doi = 10.1097/fpc.0b013e328364db84 }}</ref>

Studies have shown that genetic polymorphisms of genes other than CYP3A5, such as NR1I2<ref>{{cite journal | vauthors = Benkali K, Prémaud A, Picard N, Rérolle JP, Toupance O, Hoizey G, Turcant A, Villemain F, Le Meur Y, Marquet P, Rousseau A | title = Tacrolimus population pharmacokinetic-pharmacogenetic analysis and Bayesian estimation in renal transplant recipients | journal = Clinical Pharmacokinetics | volume = 48 | issue = 12 | pages = 805–816 | date = 1 January 2009 | pmid = 19902988 | doi = 10.2165/11318080-000000000-00000 | s2cid = 19900291 }}</ref><ref>{{cite journal | vauthors = Choi Y, Jiang F, An H, Park HJ, Choi JH, Lee H | title = A pharmacogenomic study on the pharmacokinetics of tacrolimus in healthy subjects using the DMETTM Plus platform | journal = The Pharmacogenomics Journal | volume = 17 | issue = 1 | pages = 105–106 | date = January 2017 | pmid = 27958377 | doi = 10.1038/tpj.2016.85 | doi-access = free }}</ref> (encoding ]), also significantly influence the pharmacokinetics of tacrolimus.

==History==
Tacrolimus was discovered in 1987; it was among the first macrolide immunosuppressants discovered, preceded by the discovery of ] (sirolimus) on ] (Easter Island) in 1975.<ref name="JAntibiot1987-Kino">{{cite journal | vauthors = Kino T, Hatanaka H, Hashimoto M, Nishiyama M, Goto T, Okuhara M, Kohsaka M, Aoki H, Imanaka H | title = FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics | journal = The Journal of Antibiotics | volume = 40 | issue = 9 | pages = 1249–1255 | date = September 1987 | pmid = 2445721 | doi = 10.7164/antibiotics.40.1249 | doi-access = free }}</ref> It is produced by a soil bacterium, ''Streptomyces tsukubensis''.<ref name="DrugDiscovToday2005-Pritchard">{{cite journal | vauthors = Pritchard DI | title = Sourcing a chemical succession for cyclosporin from parasites and human pathogens | journal = Drug Discovery Today | volume = 10 | issue = 10 | pages = 688–691 | date = May 2005 | pmid = 15896681 | doi = 10.1016/S1359-6446(05)03395-7 }} Supports source organism, but not team information</ref> The name tacrolimus is derived from "] macrolide immunosuppressant".<ref>Ponner, B, Cvach, B (Fujisawa Pharmaceutical Co.): Protopic Update 2005</ref>

The early development (investigational new drug phase) of tacrolimus, called at the time by the development code FK-506, happened in the next several years. A firsthand account of that process is given in ]'s 1992 memoir.<ref name="Starzl-1992-chap-25">{{cite book |last=Starzl |first=Thomas E. |date=1992 |chapter=Chapter 25: The drug with no name |pages=288–308 |title=The Puzzle People: Memoirs Of A Transplant Surgeon |publisher=University of Pittsburgh Press |doi=10.2307/j.ctt9qh63b |isbn=978-0-8229-3714-2 |url=https://doi.org/10.2307/j.ctt9qh63b}}</ref>

Tacrolimus was first ] by the US ] (FDA) in 1994,<ref>{{cite web | title=Prograf: FDA-Approved Drugs | website=U.S. ] (FDA) | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=050708 | access-date=29 April 2020}}</ref><ref>{{cite web | title=Prograf: FDA-Approved Drugs | website=U.S. ] (FDA) | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=050709 | access-date=29 April 2020}}</ref> for use in ]; the indications were extended to include kidney transplants.<ref>Tacrolimus (Systemic) {{drugs.com|monograph|tacrolimus}}. Accessed 16 December 2021.</ref> Generic versions of tacrolimus were approved in the US in 2017.<ref>{{cite web | title=Tacrolimus: FDA-Approved Drugs | website=U.S. ] (FDA) | url=https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=203900 | access-date=29 April 2020}}</ref>

Tacrolimus was approved for medical use in the European Union in 2002, for the treatment of moderate to severe atopic dermatitis.<ref>{{cite web | title=Protopic EPAR | website=] (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/protopic | access-date=29 April 2020}} {{PD-notice}}</ref> In 2007, the indications were expanded to include the prophylaxis of transplant rejection in adult kidney or liver allograft recipients and the treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal products in adults.<ref>{{cite web | title=Advagraf EPAR | website=] (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/advagraf | access-date=29 April 2020}} {{PD-notice}}</ref> In 2009, the indications were expanded to include the prophylaxis of transplant rejection in adult and paediatric, kidney, liver or heart allograft recipients and the treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal products in adults and children.<ref>{{cite web | title=Modigraf EPAR | website=] (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/modigraf | access-date=29 April 2020}}</ref>

==Available forms==
A branded version of the drug is owned by ], and is sold under the brand name Prograf, given twice daily. A number of other manufacturers hold marketing authorisation for alternative brands of the twice-daily formulation.<ref name="BNFonline">{{cite web|last1=Joint Formulary Committee|title=British National Formulary (online)|url=http://www.medicinescomplete.com/|publisher=London: BMJ Group and Pharmaceutical Press|access-date=24 September 2015}}</ref>

Once-daily formulations with marketing authorisation include Advagraf (Astellas Pharma) and Envarsus (marketed as Envarsus XR in US by ] and marketed in Europe by ]).<ref name="BNFonline" /> These formulations are intended to reduce pharmacokinetic variation in blood levels and facilitate compliance with dosing.{{citation needed|date=April 2020}}

The topical formulation is marketed by ] under the name '''Protopic'''.<ref name="BNFonline" />

==Biosynthesis==

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The biosynthesis of tacrolimus is hybrid synthesis of both type 1 ] (PKS 1) and ] syntheses (NRPS). The research shows the hybrid synthesis consists of ten modules of type 1 polyketide synthase and one module of nonribosomal peptide synthase. The synthetic enzymes for tacrolimus are found in 19 gene clusters named fkb. The 19 genes are fkbQ, fkbN, fkbM, fkbD, fkbA, fkbP, fkbO, fkbB, fkbC, fkbL, fkbK, fkbJ, fkbI, fkbH, fkbG, allD, allR, allK and allA.<ref name = "Ordóñez-Robles_2018">{{cite journal | vauthors = Ordóñez-Robles M, Santos-Beneit F, Martín JF | title = Unraveling Nutritional Regulation of Tacrolimus Biosynthesis in ''Streptomyces tsukubaensis'' through ''omic'' Approaches | journal = Antibiotics | volume = 7 | issue = 2 | pages = 39 | date = May 2018 | pmid = 29724001 | pmc = 6022917 | doi = 10.3390/antibiotics7020039 | doi-access = free }}</ref>

There are several possible ways of biosynthesis of tacrolimus. The fundamental units for biosynthesis are following: one molecule of 4,5-dihydroxycyclohex-1-enecarboxylic acid (DHCHC) as a starter unit, four molecules of malonyl-CoA, five molecules of methylmalonyl-CoA, one molecule of allylmalonyl-CoA as elongation units. However, two molecules of malonyl-CoA are able to be replaced by two molecules of methoxymalonyl CoA. Once two malonyl-CoA molecules are replaced, post-synthase tailoring steps are no longer required where two methoxymalonyl CoA molecules are substituted. The biosynthesis of methoxymalonyl CoA to Acyl Carrier protein is proceeded by five enzymes (fkbG, fkbH, fkbI, fkbJ, and fkbK). Allylmalonyl-CoA is also able to be replaced by propionylmalonyl-CoA.<ref name = "Ordóñez-Robles_2018" />

The starter unit, DHCHC from the ] is formed by fkbO enzyme and loaded onto CoA-ligase domain (CoL). Then, it proceeds to NADPH dependent reduction(ER). Three enzymes, fkbA,B,C enforce processes from the loading module to the module 10, the last step of PKS 1. fkbB enzyme is responsible of allylmalonyl-CoA synthesis or possibly propionylmalonyl-CoA at C21, which it is an unusual step of general PKS 1. As mentioned, if two methoxymalonyl CoA molecules are substituted for two malonyl-CoA molecules, they will take place in module 7 and 8 (C13 and C15), and fkbA enzyme will enforce this process. After the last step (module 10) of PKS 1, one molecule of <small>L</small>-] formed from <small>L</small>-] and catalyzed through fkbL enzyme synthesizes with the molecule from the module 10. The process of <small>L</small>-pipecolic acid synthesis is NRPS enforced by fkbP enzyme. After synthesizing the entire subunits, the molecule is cyclized. After the cyclization, the pre-tacrolimus molecule goes through the post-synthase tailoring steps such as oxidation and ]. Particularly fkbM enzyme is responsible of alcohol methylation targeting the alcohol of DHCHC starter unit (Carbon number 31 depicted in brown), and fkbD enzyme is responsible of C9 (depicted in green). After these tailoring steps, the tacrolimus molecule becomes biologically active.<ref name = "Ordóñez-Robles_2018" /><ref name="Chen_2013">{{cite journal | vauthors = Chen D, Zhang L, Pang B, Chen J, Xu Z, Abe I, Liu W | title = FK506 maturation involves a cytochrome p450 protein-catalyzed four-electron C-9 oxidation in parallel with a C-31 O-methylation | journal = Journal of Bacteriology | volume = 195 | issue = 9 | pages = 1931–1939 | date = May 2013 | pmid = 23435975 | pmc = 3624582 | doi = 10.1128/JB.00033-13 }}</ref><ref name="Mo_2009">{{cite journal | vauthors = Mo S, Ban YH, Park JW, Yoo YJ, Yoon YJ | title = Enhanced FK506 production in Streptomyces clavuligerus CKD1119 by engineering the supply of methylmalonyl-CoA precursor | journal = Journal of Industrial Microbiology & Biotechnology | volume = 36 | issue = 12 | pages = 1473–1482 | date = December 2009 | pmid = 19756799 | doi = 10.1007/s10295-009-0635-7 | s2cid = 32967249 | doi-access = free }}</ref>

== Research ==
===Lupus nephritis===
Tacrolimus has been shown to reduce the risk of serious infections while also increasing ] of kidney function in ].<ref>{{cite journal | vauthors = Singh JA, Hossain A, Kotb A, Wells G | title = Risk of serious infections with immunosuppressive drugs and glucocorticoids for lupus nephritis: a systematic review and network meta-analysis | journal = BMC Medicine | volume = 14 | issue = 1 | pages = 137 | date = September 2016 | pmid = 27623861 | pmc = 5022202 | doi = 10.1186/s12916-016-0673-8 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Singh JA, Hossain A, Kotb A, Wells GA | title = Comparative effectiveness of immunosuppressive drugs and corticosteroids for lupus nephritis: a systematic review and network meta-analysis | journal = Systematic Reviews | volume = 5 | issue = 1 | pages = 155 | date = September 2016 | pmid = 27619512 | pmc = 5020478 | doi = 10.1186/s13643-016-0328-z | doi-access = free }}</ref>

===Ulcerative colitis===
Tacrolimus has been used to suppress the inflammation associated with ] (UC), a form of ]. Although almost exclusively used in trial cases only, tacrolimus has shown to be significantly effective in the suppression of flares of UC.<ref>{{cite journal | vauthors = Baumgart DC, Pintoffl JP, Sturm A, Wiedenmann B, Dignass AU | title = Tacrolimus is safe and effective in patients with severe steroid-refractory or steroid-dependent inflammatory bowel disease--a long-term follow-up | journal = The American Journal of Gastroenterology | volume = 101 | issue = 5 | pages = 1048–1056 | date = May 2006 | pmid = 16573777 | doi = 10.1111/j.1572-0241.2006.00524.x | s2cid = 10233231 }}</ref> A 2022 updated Cochrane systematic review found that tacrolimus may be superior to placebo in achieving remission and improvement in UC.<ref>{{cite journal | vauthors = Gordon M, Sinopoulou V, Akobeng AK, Pana M, Gasiea R, Moran GW | title = Tacrolimus (FK506) for induction of remission in corticosteroid-refractory ulcerative colitis | journal = The Cochrane Database of Systematic Reviews | volume = 2022 | issue = 4 | pages = CD007216 | date = April 2022 | pmid = 35388476 | pmc = 8987360 | doi = 10.1002/14651858.CD007216.pub2 }}</ref>

== References ==
{{Reflist}}

== Further reading ==
{{refbegin}}
* {{cite journal | vauthors = Lv X, Qi J, Zhou M, Shi B, Cai C, Tang Y, Pan T, Han Y | title = Comparative efficacy of 20 graft-versus-host disease prophylaxis therapies for patients after hematopoietic stem-cell transplantation: A multiple-treatments network meta-analysis | journal = Critical Reviews in Oncology/Hematology | volume = 150 | pages = 102944 | date = June 2020 | pmid = 32247246 | doi = 10.1016/j.critrevonc.2020.102944 | s2cid = 214794350 }}
{{refend}}

== External links ==
* {{cite web | title=Tacrolimus Injection | website=MedlinePlus | url=https://medlineplus.gov/druginfo/meds/a608037.html }}
* {{cite web | title=Tacrolimus Topical | website=MedlinePlus | url=https://medlineplus.gov/druginfo/meds/a602020.html }}
* {{MeSH name|Tacrolimus}}
* {{cite web | title=FDA Approves New Use of Transplant Drug Based on Real-World Evidence | website=U.S. ] (FDA) | date=30 September 2021 | url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-approves-new-use-transplant-drug-based-real-world-evidence }}

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