TacrolimusTacrolimus belongs to a group of drugs called macrolide lactones or calcineurin inhibitors. It has similar immunosuppressant activity to ciclosporin and is given orally or by injection to prevent organ transplantation rejection. Tacrolimus is available as capsules and concentrated injection. The trade name in New Zealand is Prograf. Clinical trials have shown tacrolimus (given orally or applied topically) is often an effective treatment for inflammatory skin diseases such as atopic dermatitis and psoriasis. The topical form of tacrolimus called Protopic is now available in many countries but not yet in New Zealand (January 2004). How does tacrolimus work?Tacrolimus works on the immune system and directly on skin cells. Its mechanism of action is similar to pimecrolimus (Elidel) cream. It binds to a receptor within the cell called the FK binding proteins. This resulting drug-protein complex inhibits calcineurin (a calcium-dependent phosphatase transmitting chemical) that in turn reduces the activity of T-lymphocytes in the immune system. As a consequence, T-cells fail to release their cytokines (these are the chemicals that cause inflammation, redness and itching). In addition, tacrolimus may also have direct effects on skin cells (keratinocytes). It appears to reduce the number of IL-8 cytokine receptors on the keratinocyte, hence reducing inflammation. What is tacrolimus used for?Tacrolimus ointment is mainly indicated for the treatment of moderate to severe atopic dermatitis in adults and children who are: responding poorly to conventional therapy (emollients, topical and oral steroids, antibiotics, phototherapy) and/or suffering side effects from conventional therapy. Children should only be treated with tacrolimus ointment 0.03%. A stronger ointment (0.1%) is also available for adults. Studies have shown that treatment with topical tacrolimus show benefits after about one week and maximum improvement at about 3 months. There is no cure for atopic dermatitis, but tacrolimus provides a steroid-free treatment for controlling the symptoms. It frequently relieves the itch and inflammation caused by atopic dermatitis. Topical tacrolimus may also be useful for lichen planus, discoid lupus and many other inflammatory skin diseases.

How to use tacrolimusTacrolimus ointment is a prescription medicine and should be used only as directed by your doctor. Initial treatment will be for a short period to assess the response. If it is effective it may be continued long-term (6-12 months) if required. A thin layer of ointment should be rubbed in gently and completely onto the affected area(s) twice daily. Once the inflamed skin has returned to normal, the ointment may be discontinued. To prevent frequent recurrences, it may be helpful to apply it to previously affected areas two or three times weekly. Side effectsMost patients tolerate tacrolimus ointment well. The most common side effect that can be experienced around the site of application is a feeling of warmth or a sensation of burning. This is usually mild to moderate in severity and goes away within a few days after starting treatment. However, if this reaction persists for more than one week you should see your doctor. Other less common side effects include headache, cough, fever, flu-like symptoms, muscle aches, infection of the hair follicle (folliculitis) and acne. Unlike topical corticosteroids, topical tacrolimus has not been shown to cause skin thinning, hence it is suitable for application to areas of skin that are thin such as the face, neck and flexures. There are concerns however that topical tacrolimus may aggravate herpes simplex and other viral infections. Long term use of oral tacrolimus, like other immune suppressive agents, is known to increase the risk of skin cancer. Related informationReferences: Bedford C. Tacrolimus Russell JJ. Topical Tacrolimus: A New Therapy for Atopic Dermatitis. Am Fam Physician 2002;66:1899-902 On DermNet NZ: Pimecrolimus Atopic dermatitis Other websites: Consumer medicine information Medsafe Medicine data sheets Medsafe Drugs, Herbs and Supplements MedlinePlus Books about skin diseases:See the DermNet NZ bookstore Author: Vanessa Ngan, staff writer DermNet does not provide an on-line consultation service. TacrolimusFrom Wikipedia, the free encyclopediaThis articleneeds additional citations for verification.Please helpimprove this articlebyadding citations to reliable sources. Unsourced material may bechallengedandremoved.(December 2009)

Tacrolimus

Systematic (IUPAC) name

3S-[3R*[E(1S*,3S*,4S*)],4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*,19S*,26aR*-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5, 19-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylethenyl]-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propenyl)-15,19-epoxy-3H-pyrido[2,1-c] [1,4] oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone, monohydrate

Clinical data

Pregnancy cat.C

Legal statusPrescription only

RoutesTopical, oral,iv

Pharmacokinetic data

Bioavailability20%, less after eating food rich in fat

Protein binding75-99%

MetabolismHepaticCYP3A4

Half-life11.3 h (range 3.5-40.6 h)

ExcretionMostly faecal

Identifiers

CAS number104987-11-3

ATC codeD11AH01L04AD02

PubChemCID 6473866

DrugBankDB00864

ChemSpider4976056

UNIIY5L2157C4J

ChEMBLCHEMBL269732

Chemical data

FormulaC44H69NO12

Mol. mass804.018 g/mol

SMILES[show]

InChI[show]

(what is this?)(verify)

Tacrolimus(alsoFK-506orfujimycin, trade namesPrograf,Advagraf,Protopic) is animmunosuppressivedrugthat is mainly used afterallogeneicorgan transplantto reduce the activity of the patient'simmune systemand so lower the risk of organrejection. It is also used in a topical preparation in the treatment ofatopic dermatitis(eczema), severe refractoryuveitisafterbone marrowtransplants, exacerbations ofminimal change disease, and the skin conditionvitiligo.It is a 23-memberedmacrolidelactonediscovered in 1984 from the fermentation broth of aJapanesesoilsample that contained thebacteriaStreptomyces tsukubaensis. It reducesinterleukin-2(IL-2) production byT-cells.Contents[hide] 1History 2Availability 3Mechanism of action 4Indications 4.1Immunosuppression following transplantation 4.1.1Interactions 4.2Ulcerative colitis 4.3Dermatological use 5Side effects 5.1From oral and intravenous administration 5.1.1Carcinogenesis and mutagenesis 5.2From topical use 5.2.1Cancer risks 6Contraindications and precautions 7Use as a biological research tool 8References 9External linksHistory[edit]Tacrolimus was discovered in 1984; it was among the first macrolide immunosuppressants discovered, preceded by the discovery ofrapamycin(sirolimus) onRapa Nui(Easter Island) in 1975.[1]It is produced by a type of soil bacterium,Streptomyces tsukubaensis.[2]The name tacrolimus is derived from 'Tsukubamacrolide immunosuppressant'.[3]Tacrolimus was first approved by theFood and Drug Administration(FDA) in 1994 for use inliver transplantation; this has been extended to include kidney, heart, small bowel, pancreas, lung, trachea, skin, cornea, bone marrow, and limb transplants.Availability[edit]The branded version of the drug is owned byAstellas Pharma, and is sold under the trade namesPrografgiven twice daily,Advagraf, a sustained release formulation allowing once daily dosing, andProtopic(Eczemusin Pakistan by Brookes Pharma), the topical formulation.[4]Advagraf is available in 0.5, 1, 3 and 5mg capsules, the ointment is concentrations of 0.1% and 0.03%.A second once-daily formulation of tacrolimus is in Phase 3 clinical trials in the U.S. and Europe. This formulation also has a smoother pharmacokinetic profile that reduces the peak-to-trough range in blood levels compared to twice-daily tacrolimus.[5]Data from the first Phase 3 trial in stable kidney transplant patients showed that this once-daily formulation was non-inferior in efficacy and safety compared to twice-daily tacrolimus.[6]A second Phase 3 trial in de novo patients is ongoing.[7]Mechanism of action[edit]Tacrolimus is chemically known as amacrolide. In T-cells, activation of the T-cell receptor normally increases intracellular calcium, which acts via calmodulin to activatecalcineurin. Calcineurin then dephosphorylates the transcription factor NF-AT (nuclear factor of activated T-cells), 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.[8]In detail, Tacrolimus reduces peptidyl-prolyl isomerase activity by binding to the immunophilinFKBP12(FK506 binding protein) creating a new complex. This FKBP12-FK506 complex interacts with and inhibitscalcineurinthus inhibiting both T-lymphocytesignal transduction and IL-2 transcription.[9]Although this activity is similar tociclosporin, studies have shown that the incidence of acute rejection is reduced by tacrolimus use over ciclosporin.[10]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.[11]Indications[edit]Immunosuppression following transplantation[edit]It has similar immunosuppressive properties to ciclosporin, 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.[10]Clinical outcome is better with tacrolimus than with ciclosporin during the first year of liver transplantation.[12][13]Long term outcome has not been improved to the same extent. Tacrolimus is normally prescribed as part of a post-transplant cocktail includingsteroids,mycophenolateandIL-2 receptorinhibitors. Dosages are titrated to target blood levels. Typical starting doses for once daily tacrolimus are 0.15-0.20mg/kg body weight.Interactions[edit]Also like ciclosporin it has a wide range of interactions, including that withgrapefruitwhich increases plasma-tacrolimus concentration. Several of the newer class of antifungals, especially of the azole class (fluconazole, posaconazole) also increase drug levels by competing fordegradative enzymes.Ulcerative colitis[edit]In recent years, tacrolimus has been used to suppress the inflammation associated withulcerative colitis, a form ofinflammatory bowel disease. Although almost exclusively used in trial cases only, tacrolimus has shown to be significantly effective in the suppression of outbreaks of UC.[14][15]Dermatological use[edit]

Tacrolimus 0.1%See also:Medications used in treatment of eczemaAs anointment, tacrolimus is used in the treatment ofeczema, particularlyatopic dermatitis. It suppresses inflammation in a similar way tosteroids, 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 (atrophy), or other steroid related side-effects.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]. Clinical trials of up to one year have been conducted. Recently it has also been used to treat segmentalvitiligoin children, especially in areas on the face.[16]Side effects[edit]From oral and intravenous administration[edit]Side effects can be severe and include infection, cardiac damage,hypertension, blurred vision, liver andkidneyproblems (tacrolimusnephrotoxicity),[17]hyperkalemia,hypomagnesemia,hyperglycemia,diabetes mellitus,itching, lung damage (sirolimusalso causes lung damage),[18]and various neuropsychiatric problems such as loss of appetite,insomnia,Posterior reversible encephalopathy syndrome, confusion, weakness, depression, cramps, neuropathy,seizures,tremors, andcatatonia.[19]In addition it may potentially increase the severity of existing fungal or infectious conditions such asherpes zosterorpolyomaviral infections.Carcinogenesis and mutagenesis[edit]In people receiving immunosuppressants to reduce transplant graft rejection, an increase risk of malignancy is a recognised complication. The most common cancers arenon-Hodgkin's lymphomaand skin cancers. The risk appears to be related to the intensity and duration of treatment.From topical use[edit]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. Less common areflu-like symptoms, headache and cough and burning eyes.[20]The use of topical tacrolimus ointments should be avoided on known or suspected malignant lesions. The use of tacrolimus on patients withNetherton's syndromeor similar skin diseases is not recommended. Patients should minimize or avoid natural or artificial sunlight exposure. Skin infections should be cleared prior to application, and there may be an increased risk of certain skin infections. Tacrolimus should not be used with occlusive dressings.Cancer risks[edit]Further information:Eczema#MedicationsTacrolimus and a related drug for eczema (pimecrolimus) 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 byUKdermatologists is not to consider this a significant real concern and they are increasingly recommending the use of these new drugs.[21]Contraindications and precautions[edit] Breast-feeding Hepaticdisease Immunosuppression Infants Infection Intravenous administration Neoplasticdisease, such as: Skin cancer Lung cancer Occlusive dressing Oliguria Pregnancy QT prolongation Sunlight(UV) exposure Grapefruitjuice[22]Use as a biological research tool[edit]FK1012, a derivative of tacrolimus, is used as a research tool inchemically induced dimerizationapplications. The proteinFKBPdoes not normally form dimers but can be caused to dimerize in the presence of this drug. Genetically engineered proteins based on FKBP can be used to manipulate protein localization, signalling pathways and protein activation.[23]References[edit]1. Jump up^Kino T, Hatanaka H, Hashimoto M, Nishiyama M, Goto T, Okuhara M, Kohsaka M, Aoki H, Imanaka H (1987). "FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics.".J Antibiot (Tokyo)40(9): 124955.PMID2445721.2. Jump up^Pritchard D (2005). "Sourcing a chemical succession for cyclosporin from parasites and human pathogens.".Drug Discov Today10(10): 68891.doi:10.1016/S1359-6446(05)03395-7.PMID15896681.Supports source organism, but not team information3. Jump up^Ponner, B, Cvach, B (Fujisawa Pharmaceutical Co.): Protopic Update 20054. Jump up^Healthy Ontario: Tacrolimus topical ointment5. Jump up^Alloway RR, Germain M, Osama Gaber, A, Bodziak KA, Mulgaonkar SP, Gohh RY, Kaplan B, Katz E, Beckert M, Gordon RD, A Phase II Open-Label, Multi-Center Prospective, Conversion Study in Stable Kidney Transplant Patients to Compare the Pharmacokinetics of LCP-Tacro Tablets Once-A-Day to Prograf Capsules Twice-A-Day. American Transplant Congress, 20086. Jump up^http://files.shareholder.com/downloads/ABEA-4J4LWA/1008134289x0x477697/e60eb3d4-849c-41e2-95f3-d8a1eaea3b56/LCP_News_2011_6_21_English_Releases.pdf7. Jump up^Clinicaltrials.gov identifier: NCT011879538. Jump up^William F. Ganong.Review of medical physiology(22nd ed.). Lange medical books. p.530.ISBN0-07-144040-2.9. Jump up^Liu J, Farmer J, Lane W, Friedman J, Weissman I, Schreiber S (1991). "Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes.".Cell66(4): 80715.doi:10.1016/0092-8674(91)90124-H.PMID1715244.10. ^Jump up to:abMcCauley, Jerry (2004-05-19)."Long-Term Graft Survival In Kidney Transplant Recipients".Slide Set Series on Analyses of Immunosuppressive Therapies.Medscape. Retrieved 2006-06-06.11. Jump up^M.M. Abou-Jaoude, R. Naim, J. Shaheen, N. Naufal, S. Abboud, M. AlHabash, M. Darwish, A. Mulhem, A. Ojjeh, and W.Y. Almawi (2005). "Tacrolimus (FK506) versus cyclosporin microemulsion (Neoral) as maintenance immunosuppresion therapy in kidney transplant recipients.".Transplantation Proceedings37(7): 30253028.doi:10.1016/j.transproceed.2005.08.040.PMID16213293.12. Jump up^Elizabeth Haddad, Vivian McAlister, Elizabeth Renouf, Richard Malthaner, Mette S. Kjaer, and Lise Lotte Gluud (2006)."Cyclosporin versus Tacrolimus for Liver Transplanted Patients". In McAlister, Vivian.Cochrane Database of Systematic Reviews4(CD005161): CD005161.doi:10.1002/14651858.CD005161.pub2.PMID17054241.13. Jump up^J.G. O'Grady, A. Burroughs, P. Hardy, D. Elbourne, A. Truesdale, and The UK and Ireland Liver Transplant Study Group (2002). "Tacrolimus versus emulsified cyclosporin in liver transplantation: the TMC randomised controlled trial".Lancet360(9340): 11191125.doi:10.1016/S0140-6736(02)11196-2.PMID12387959.14. Jump up^Baumgart DC, Pintoffl JP, Sturm A, Wiedenmann B, Dignass AU (2006). "Tacrolimus is safe and effective in patients with severe steroid-refractory or steroid-dependent inflammatory bowel disease--a long-term follow-up".Am J Gastroenterol101(5): 10481056.doi:10.1111/j.1572-0241.2006.00524.x.PMID16573777.15. Jump up^Baumgart DC, MacDonald JK, Feagan BG (2008). "Tacrolimus (FK506) for induction of remission in refractory ulcerative colitis". In Baumgart, Daniel C.Cochrane Database Syst Rev16(3): CD007216.doi:10.1002/14651858.CD007216.PMID18646177.16. Jump up^Silverberg, NB; Lin, P; Travis, L; Farley-Li, J; Mancini, AJ; Wagner, AM; Chamlin, SL; Paller, AS (2004). "Tacrolimus ointment promotes repigmentation of vitiligo in children: a review of 57 cases.".Journal of the American Academy of Dermatology51(5): 7606.doi:10.1016/j.jaad.2004.05.036.PMID15523355.17. Jump up^Naesens M, Kuypers DR, Sarwal M (2009). "Calcineurin inhibitor nephrotoxicity".Clin. J. Am. Soc. Nephrol.4(2): 481509.doi:10.2215/CJN.04800908.PMID19218475.18. Jump up^Miwa Y, Isozaki T, Wakabayashi K,et al.(2008). "Tacrolimus-induced lung injury in a rheumatoid arthritis patient with interstitial pneumonitis".Mod Rheumatol18(2): 20811.doi:10.1007/s10165-008-0034-3.PMID18306979.19. Jump up^O'Donnell MM, Williams JP, Weinrieb R, Denysenko L (2007)."Catatonic mutism after liver transplant rapidly reversed with lorazepam".Gen Hosp Psychiatry29(3): 2801.doi:10.1016/j.genhosppsych.2007.01.004.PMID17484951.20. Jump up^Hanifin JM, Paller AS, Eichenfield L, Clark RA, Korman N, Weinstein G, Caro I, Jaracz E, Rico MJ; US Tacrolimus Ointment Study Group (2005). "Efficacy and safety of tacrolimus ointment treatment for up to 4 years in patients with atopic dermatitis".J Am Acad Derm53(2 suppl 2): S18694.doi:10.1016/j.jaad.2005.04.062.PMID16021174.21. Jump up^N H Cox and Catherine H Smith (December 2002)."Advice to dermatologists re topical tacrolimus"(DOC).Therapy Guidelines Committee. British Association of Dermatologists.22. Jump up^Fukatsu S, Fukudo M, Masuda S, Yano I, Katsura T, Ogura Y, Oike F, Takada Y, Inui K (2006). "Delayed effect of grapefruit juice on pharmacokinetics and pharmacodynamics of tacrolimus in a living-donor liver transplant recipient".Drug Metab Pharmacokinet21(2): 1225.doi:10.2133/dmpk.21.122.PMID16702731.23. Jump up^Fegan, A; White, B; Carlson, JC; Wagner, CR (2010 Jun 9). "Chemically controlled protein assembly: techniques and applications.".Chemical reviews110(6): 331536.doi:10.1021/cr8002888.PMID20353181.External links[edit] Tacrolimus levels in Liver Transplants-Indian Study by Dr.Pradeep Naik,Dr.Dharmesh Kapoor, Dr.DCS Reddy Prograf prescribing information at Fujisawa Pimecrolimus (Elidel Cream) FDA adivisory page (for eczema treatment) Tacrolimus (FK506)product page fromFermentek U.S. National Library of Medicine: Drug Information Portal - Tacrolimus[show] v t eOtherdermatologicalpreparations (D11)

[show] v t eImmunomodulators:Immunosuppressive drugs/Immunosuppressants(L04)

Categories: Macrolides Immunosuppressants Chemical compounds found in Streptomyces speciesNavigation menu Create account Log in Article Talk Read Edit View historyTop of Form

Bottom of Form Main page Contents Featured content Current events Random article Donate to WikipediaInteraction Help About Wikipedia Community portal Recent changes Contact pageToolboxPrint/exportLanguages Deutsch Espaol Franais Bahasa Indonesia Italiano Magyar Nederlands Polski Suomi Svenska Trke Edit links This page was last modified on 13 October 2013 at 11:2Text is available uDeskripsiLatar belakangTacrolimus (FK506) dan siklosporin (siklosporin A, CSA) adalah landasan agen imunosupresif diberikan kepada penerima transplantasi organ padat untuk mencegah dan mengobati penolakan allograft.Penemuan siklosporin pada 1970-an, dan masuknya ke koleksi imunosupresan pada awal tahun 1980, adalah sebuah terobosan besar di bidang kedokteran.Siklosporin adalah yang paling sukses obat anti-penolakan sampai saat ini, dan secara radikal meningkatkan kesempatan untuk bertahan hidup untuk penerima transplantasi.Pada tahun 1994, Food and Drug Administration (FDA) menyetujui tacrolimus, alternatif yang efektif untuk siklosporin [Artikel:15041303].Sejak itu, tacrolimus dan siklosporin telah menjadi obat imunosupresif utama untuk transplantasi organ padat.TheAmerika Serikat Organ Pengadaan dan Jaringan Transplantasi dan Registry Ilmiah Penerima Transplantasimenunjukkan bahwa pada tahun 2011, 86% dari 16.055 pasien yang menerima transplantasi ginjal diberi resep tacrolimus pada debit, dan 2,4% diberi resep siklosporin.Satu tahun setelah transplantasi, 84% dan 4% dari pasien menerima tacrolimus dan terapi siklosporin, masing-masing.Perbedaan global ada dalam penggunaan tacrolimus dan siklosporin: 2008 angka dariAustralia & New Zealand Dialisis dan Transplantasi Registrymenunjukkan bahwa 61% dari 391 pasien Australia yang menerima cangkok donor ginjal almarhum diberi resep tacrolimus, dan 35% diberi resep siklosporin.Pada satu tahun pasca transplantasi, angka-angka ini berubah menjadi 55% dan 33% untuk tacrolimus dan siklosporin, masing-masing.Tacrolimus dan siklosporin juga diresepkan untuk hati, usus, paru-paru dan penerima transplantasi jantung, dan dapat digunakan untuk mengelola kondisi parah autoimun, seperti dermatitis atopik [Artikel:15175770,14522634] dan rheumatoid arthritis [Artikel:15187241,8448639].Tacrolimus dan siklosporin berbeda dalam struktur kimianya: siklosporin adalah endecapeptide siklik [Artikel:8513650], sementara tacrolimus adalah makrosiklik lakton [Artikel:8588225].Namun, mereka bertindak dengan cara yang sama.Keduanya adalah inhibitor kalsineurin, mekanisme utama aksi mereka melibatkan penghambatan fosfatase penting ini [Artikel:15041303].Tacrolimus menunjukkan efek yang mirip dengan siklosporin, tetapi pada konsentrasi 100 kali lebih rendah [Artikel:2.445.722].Meskipun perbedaan-perbedaan dalam potensi, tacrolimus dan siklosporin keduanya menunjukkan tingkat kelangsungan hidup yang sangat baik untuk cangkok di banyak studi banding (dirangkum dalam Maeset al.[Artikel:15041305]).Namun, beberapa penelitian telah menunjukkan bahwa penggunaan tacrolimus dikaitkan dengan tingkat penolakan allograft rendah dibandingkan dengan siklosporin [Artikel:16686762,15741208,16157605].FarmakodinamikDalam limfosit, tacrolimus dan siklosporin mengerahkan imunosupresi oleh beberapa jalur, termasuk menghambat kalsineurin dan c-Juni N-terminal kinase (JNK) dan jalur p38, dan mendorong peningkatan ekspresi transforming growth factor-1 (TGF-1).Mayoritas studi tentang efek farmakodinamik tacrolimus dan siklosporin telah berfokus pada peran mereka dalam sel T.Keterlibatan natural killer (NK) sel dalam penolakan transplantasi sangat tidak didefinisikan dengan baik, namun, kedua obat telah ditemukan untuk menghambat degranulasi sel pembunuh alami secara dosis-tergantung [Artikel:20967261].Aksi kalsineurin dan NFATSetelah memasuki sel T, baik siklosporin dan tacrolimus mengikat dengan afinitas tinggi untuk protein yang dikenal sebagai immunophilins.Siklosporin mengikat terutama untuk cyclophilin A (dikodekan olehPPIAgen), yang cyclophilin utama yang ditemukan dalam sel-sel T, dan tacrolimus mengikat protein FK-mengikat, khususnya FKBP12 (dikodekan olehFKBP1Agen).Kedua immunophilins berinteraksi dengan kalsineurin dalam tidak adanya ligan.Namun, afinitas immunophilin untuk kalsineurin ditingkatkan pada pengikatan obat, mengakibatkan penghambatan aktivitas protein [Artikel:7529175].Kalsineurin adalah fosfatase kalmodulin-tergantung, yang dirangsang selama aktivasi sel T oleh rantai peristiwa yang melibatkan kalsium dan kalmodulin [Artikel:11015619,1377362].Setelah diaktifkan, itu berasosiasi dengan dan dephosphorylates anggota faktor nuklir sel T aktif (NFAT) keluarga, sehingga mengaktifkan protein ini [Artikel:10878286,7479966].Setelah aktivasi, protein NFAT mentranslokasi ke inti [Artikel:7479966], di mana asosiasi dengan faktor transkripsi lain, seperti anggota aktivator protein-1 (AP-1) keluarga, dan mengikat DNA untuk mempromosikan transkripsi interleukin- 2 (IL-2) [Artikel:10970869].Hal ini juga mengikat ke situs promotor pada berbagai macam gen sitokin lainnya, termasuk untuk interleukin-4 (IL-4), interleukin-10 (IL-10) dan interleukin-17 (IL-17) [Artikel:20103781].Penghambatan kalsineurin, oleh karena itu, mencegah kemampuannya untuk dephosphorylate dan mengaktifkan NFAT, mempengaruhi transkripsi sitokin penting dalam respon imun.Dampak dari obat pada transkripsi IL-2 mungkin adalah yang terbaik mekanisme ditangani, dan ini sitokin tertentu memainkan peran besar dalam respon imun, termasuk pemeliharaan sel T peraturan dan diferensiasi dan kelangsungan hidup CD4 + dan CD8 + sel T [Article:22343569].Selain NFAT dan-1 AP anggota keluarga, faktor nuklir kappa-light-chain-penambah sel diaktifkan B (NF-kB) juga terlibat dalam induksi IL-2 transkripsi [Artikel:2497518,7546397,20103781].NF-kB adalah nama yang diberikan kepada sekelompok faktor transkripsi dimer yang mengikat sebagai homo atau heterodimer, dan mengerahkan baik efek positif dan negatif pada gen transkripsi [Artikel:22302935].Secara umum, NF-kB memiliki dampak besar terhadap perkembangan, homeostasis, kelangsungan hidup, dan fungsi sel T [Artikel:21199863].Ini memiliki berbagai macam target gen dalam sel T, dan di samping IL-2 juga terlibat dalam regulasi sitokin seperti tumor necrosis factor-beta (TNF) [Artikel:2.104.232] dan interferon-gamma (IFN) [ Artikel:9374532].Kalsineurin juga terlibat dalam aktivasi NF-kB.Ini secara tidak langsung menginduksi degradasi senyawa yang dikenal sebagai IB, yang terikat aktif NF-kB dan bertindak sebagai protein hambat, mencegah NF-kB dari bergaul dengan gen target nuklirnya.Blokade aktivitas kalsineurin oleh kedua obat sehingga mempengaruhi kemampuan NF-kB untuk mengerahkan aksinya pada gen sistem kekebalan tubuh [Artikel:8112299,21199863].Aksi jalur JNK dan p38Meskipun efek tacrolimus dan siklosporin pada kalsineurin adalah mungkin mekanisme terbaik-dipelajari, kedua obat juga diduga terlibat dalam penghambatan protein mitogen-diaktifkan kinase (MAPK) jalur.The MAPK adalah kaskade sinyal yang terlibat dalam berbagai proses, khususnya dalam sel sistem kekebalan [Artikel:17473844].Ini terdiri dari tiga protein kinase: MAPK, MAPKK dan MAPKK-K.MAPKK-K phosphorylates dan mengaktifkan MAPKK, yang pada gilirannya phosphorylates dan mengaktifkan MAPK [Artikel:11274345].Ada tiga MAPK sub kelompok yang berbeda - ERK, JNK dan p38 [Artikel:17473844].Kedua cyclosporine dan tacrolimus (dalam kompleks dengan immunophilins mereka) telah ditunjukkan untuk menghambat JNK (MAPK8) dan p38 (MAPK14) jalur, tetapi tidak jalur ERK.Sebuah studi di Jurkat limfosit T menunjukkan penurunan tingkat kedua JNK dan protein p38 bawah administrasi siklosporin atau tacrolimus [Artikel:11258483].JNK dan p38 diaktifkan melalui MAPK kaskade sinyal oleh sel T dan CD28 co-stimulasi reseptor [Artikel:9.575.191], dan pada saat aktivasi, translokasi ke nukleus di mana mereka dapat memenuhi berbagai peran mereka [Artikel:12077368].Ini termasuk mengatur aktivitas AP-1 anggota [Artikel:7.622.446], yang terlibat dalam mempromosikan transkripsi IL-2 [Artikel:10970869] dan sitokin lain [Pasal:9.468.273].Memang, blokade jalur p38 dan JNK ditunjukkan untuk mencegah ekspresi gen IL-2 [Artikel:9.575.191].Jalur JNK dan aktivasi p38 melalui berbagai kinase dapat dilihat pada gambar, dan dua obat dianggap menghambat jalur hulu dari tingkat MAPKK-K, sebagai siklosporin dan tacrolimus memiliki keduanya telah terlihat menghambat aktivasi dari MAPKK -K dikenal sebagai MAP3K1 [Artikel:11258483].Hal ini tidak percaya bahwa kalsineurin terlibat dalam mekanisme ini, karena inhibitor kalsineurin telah terlihat untuk memblokir aktivasi NFAT, tetapi tidak JNK atau p38 jalur dalam sel T [Artikel:11258483].Aksi TGF-1TGF-1 merupakan sitokin penting untuk pengaturan sel sistem kekebalan tubuh.Ini adalah anggota dari keluarga TGF-, yang juga termasuk TGF-2 dan TGF-3.TGF- telah terbukti dapat menghambat proliferasi sel T IL-2-tergantung [Artikel:8.423.782], serta mengerahkan berbagai efek imunosupresif lain dalam sel T [Artikel:11905837].In vivostudi pada pasien dengan stadium akhir penyakit ginjal yang menjalani transplantasi telah menunjukkan peningkatan TGF-beta1 mRNA dan protein ekspresi setelah pengobatan dengan siklosporin [Artikel:10071036], danin vitrostudi tacrolimus dalam sel T juga menunjukkan peningkatan yang signifikan dalam tingkat mRNA dan protein setelah pemberian obat [Artikel:9484745].Namun, mekanisme yang obat ini mempengaruhi tingkat TGF-1 masih harus dijelaskan.Hal ini juga penting untuk dicatat bahwa beberapa studi telah menemukan bukti yang menunjukkan bahwa baik tacrolimus atau siklosporin mampu mempengaruhi protein TGF-1 atau tingkat mRNA pada konsentrasi di mana IL-2 produksi berhasil dihambat [Artikel:12588317,15716327].Oleh karena itu, pada tahap ini, tidaklah mungkin untuk menyatakan secara definitif apakah kedua obat mempengaruhi tingkat TGF-1.Namun, penting untuk dicatat bahwa seiring dengan terlibat dalam sistem kekebalan tubuh, TGF-1 juga memiliki sifat fibrogenic yang dapat mengarah pada pengembangan nefrotoksisitas [Artikel:19218475].Sebuah studi pada pasien transplantasi ginjal menemukan bahwa ekspresi mRNA TGF-1 dalam biopsi ginjal meningkat pada pasien dengan baik nefrotoksisitas tacrolimus atau siklosporin, dibandingkan dengan mereka yang dipamerkan penolakan akut.Hal ini menunjukkan bahwa peningkatan kadar protein dapat menyebabkan nefrotoksisitas sering dikaitkan dengan obat-obatan [Artikel:12427154].PharmacogenomicsMayoritas studi farmakogenetik pada tacrolimus dan siklosporin telah berfokus pada efek dari varian dalamCYP3A4,CYP3A5danABCB1gen karena peran sentral enzim dan transporter yang mereka kode untuk bermain di tacrolimus dan siklosporin disposisi.Namun, beberapa studi telah meneliti pengaruh polimorfisme nukleotida tunggal (SNP) dalam gen pengkodean pregnane X reseptor (NR1I2), yang mengatur ekspresi beberapa gen termasukCYP3AdanABCB1[Artikel:2.309.580].Selain itu, beberapa studi telah meneliti SNP dalamPORgen, yang mengkode untuk CYP450 oksidoreduktase, sebuah protein yang bertanggung jawab untuk mentransfer elektron dari NADPH ke CYP450 enzim, memungkinkan kegiatan mereka [Artikel:11371558].Beberapa studi juga telah melihat variasi dalam gen TGF-1 (TGFB1), yang cyclophilin A gen (PPIA), danCYP2C8gen, CYP2C8 terlibat dalam metabolisme asam arakidonat (AA) menjadi asam epoxyeicosatrienoic (EETs), metabolit terlibat dalam mempertahankan fungsi ginjal normal.Meskipun berbagai studi ini, hanya3 *alel (rs776746) dalamCYP3A5gen telah menunjukkan asosiasi yang kuat dengan tacrolimus farmakokinetik.Bukti yang konsisten sangat sedikit yang muncul untuk faktor yang mempengaruhi tacrolimus farmakodinamik atau farmakokinetik dan farmakodinamik siklosporin.Keseluruhan inkonsistensi dari studi ini mungkin terkait dengan variabilitas etnis, sejumlah kecil pasien, tes farmakokinetik non-spesifik, variasi ketika hasil diukur, dan dampak genotipe donor - khususnya dalam studi nefrotoksisitas pada pasien transplantasi ginjal atau studi farmakokinetik pada pasien transplantasi hati.Penelitian yang lebih besar dan meta-analisis yang mengambil etnis dan genotipe donor ke rekening dapat membantu menyelesaikan beberapa variabilitas ini.Penulis:Julia M. Barbarino, Christine E. Staatz dan Raman Venkataramanan.

Kutipan:Barbarino Julia M, Staatz Christine E, Venkataramanan Raman, Klein Teri E, Altman Russ B. "Ringkasan PharmGKB: siklosporin dan tacrolimus jalur"Pharmacogenetics dan genomik(2013).Jika Anda ingin mereproduksi ini diagram jalur PharmGKB, silakan mengakui hak cipta untuk PharmGKB dan menyatakan bahwa izin telah diberikan oleh PharmGKB dan Stanford University.Juga, silakan kirim email singkat untukfeedback@pharmgkb.orguntuk menginformasikan kepada kami yang diagram jalur yang Anda gunakan dan untuk tujuan apa.

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Terapi Kategori: Nyeri, agen anti-inflamasi dan imunomodulasi

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