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Tacrolimus

Tacrolimus 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 tacrolimus


Tacrolimus 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 effects
Most 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 information References:

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

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Tacrolimus From Wikipedia, the free encyclopedia This article needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (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] oxaazacyclotricosine1,7,20,21(4H,23H) -tetrone, monohydrate Clinical data Pregnancy cat. Legal status Routes C Prescription only Topical, oral, iv

Pharmacokinetic data Bioavailability Protein binding Metabolism Half-life Excretion Identifiers CAS number ATC code PubChem DrugBank ChemSpider UNII 104987-11-3 D11AH01 L04AD02 CID 6473866 DB00864 4976056 Y5L2157C4J 20%, less after eating food rich in fat 75-99% Hepatic CYP3A4 11.3 h (range 3.5-40.6 h) Mostly faecal

ChEMBL Chemical data Formula Mol. mass SMILES[show] InChI[show]

CHEMBL269732

C44H69NO12 804.018 g/mol

(what is this?) (verify) Tacrolimus (also FK-506 or fujimycin, trade names Prograf, Advagraf, Protopic) is an immunosuppressive drug that is mainly used afterallogeneic organ transplant to reduce the activity of the patient's immune system and so lower the risk of organ rejection. It is also used in a topical preparation in the treatment of atopic dermatitis (eczema), severe refractory uveitis after bone marrow transplants, exacerbations ofminimal change disease, and the skin condition vitiligo. It is a 23-membered macrolide lactone discovered in 1984 from the fermentation broth of a Japanese soil sample that contained the bacteriaStreptomyces tsukubaensis. It reduces interleukin2 (IL-2) production by T-cells. Contents [hide]

1 History 2 Availability 3 Mechanism of action 4 Indications


o

4.1 Immunosuppression following transplantation

4.1.1 Interactions

o o

4.2 Ulcerative colitis 4.3 Dermatological use

5 Side effects

5.1 From oral and intravenous administration

5.1.1 Carcinogenesis and mutagenesis

5.2 From topical use

5.2.1 Cancer risks

6 Contraindications and precautions 7 Use as a biological research tool 8 References 9 External links

History[edit] Tacrolimus was discovered in 1984; it was among the first macrolide immunosuppressants discovered, preceded by the discovery of rapamycin(sirolimus) on Rapa Nui (Easter Island) in 1975.[1] It is produced by a type of soil bacterium, Streptomyces tsukubaensis.[2] The name tacrolimus is derived from 'Tsukuba macrolide immunosuppressant'.[3] Tacrolimus was first approved by the Food and Drug Administration (FDA) in 1994 for use in liver 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 by Astellas Pharma, and is sold under the trade names Prograf given twice daily, Advagraf, a sustained release formulation allowing once daily dosing, and Protopic (Eczemus in Pakistan by Brookes Pharma), the topical formulation.[4] Advagraf is available in 0.5, 1, 3 and 5 mg 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 a macrolide. In T-cells, activation of the T-cell receptor normally increases intracellular calcium, which acts via calmodulin to activate calcineurin. 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 immunophilin FKBP12 (FK506 binding protein) creating a new complex. This FKBP12-FK506 complex interacts with and inhibits calcineurin thus inhibiting both T-lymphocytesignal transduction and IL-2 transcription.[9] Although this activity is similar to ciclosporin, studies have shown that the incidence of acute rejection is reduced by tacrolimus use over ciclosporin.[10] Although shortterm 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 including steroids, mycophenolate and IL-2 receptor inhibitors. Dosages are titrated to target blood levels. Typical starting doses for once daily tacrolimus are 0.15-0.20 mg/kg body weight. Interactions[edit] Also like ciclosporin it has a wide range of interactions, including that with grapefruit which increases plasma-tacrolimus concentration. Several of the newer class of antifungals, especially of the azole class (fluconazole, posaconazole) also increase drug levels by competing for degradative enzymes. Ulcerative colitis[edit] In recent years, tacrolimus has been used to suppress the inflammation associated with ulcerative colitis, a form of inflammatory 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 eczema As an ointment, tacrolimus is used in the treatment of eczema, particularly atopic dermatitis. It suppresses inflammation in a similar way to steroids, 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 segmental vitiligo in 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 and kidney problems (tacrolimus nephrotoxicity),[17] hyperkalemia, hypomagnesemia,hyperglycemia, diabetes mellitus, itching, lung damage (sirolimus also 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, and catatonia.[19] In addition it may potentially increase the severity of existing fungal or infectious conditions such as herpes zoster or polyoma viral 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 are non-Hodgkin's lymphoma and 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 are flu-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 with Netherton's syndrome or 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#Medications Tacrolimus 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 by UK dermatologists 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 Hepatic disease Immunosuppression Infants Infection Intravenous administration Neoplastic disease, such as:

Skin cancer Lung cancer

Occlusive dressing Oliguria Pregnancy QT prolongation Sunlight (UV) exposure Grapefruit juice[22]

Use as a biological research tool[edit] FK1012, a derivative of tacrolimus, is used as a research tool in chemically induced dimerization applications. The protein FKBP does 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. PMID 2445721. 2. Jump up^ Pritchard D (2005). "Sourcing a chemical succession for cyclosporin from parasites and human pathogens.". Drug Discov Today 10 (10): 688 91. doi:10.1016/S1359-6446(05)03395-7.PMID 15896681. Supports source organism, but not team information 3. Jump up^ Ponner, B, Cvach, B (Fujisawa Pharmaceutical Co.): Protopic Update 2005 4. Jump up^ Healthy Ontario: Tacrolimus topical ointment 5. 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, 2008 6. Jump up^ http://files.shareholder.com/downloads/ABEA4J4LWA/1008134289x0x477697/e60eb3d4-849c-41e2-95f3d8a1eaea3b56/LCP_News_2011_6_21_English_Releases.pdf 7. Jump up^ Clinicaltrials.gov identifier: NCT01187953 8. Jump up^ William F. Ganong. Review of medical physiology (22nd ed.). Lange medical books. p. 530. ISBN 0-07-144040-2. 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.". Cell 66 (4): 80715.doi:10.1016/0092-8674(91)90124-H. PMID 1715244. 10. ^ Jump up to:a b McCauley, 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 Proceedings 37 (7): 3025 3028. doi:10.1016/j.transproceed.2005.08.040. PMID 16213293.

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 Reviews 4 (CD005161): CD005161. doi:10.1002/14651858.CD005161.pub2. PMID 17054241. 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". Lancet 360 (9340): 11191125. doi:10.1016/S0140-6736(02)111962. PMID 12387959. 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 steroiddependent inflammatory bowel disease--a long-term follow-up". Am J Gastroenterol 101 (5): 10481056. doi:10.1111/j.15720241.2006.00524.x. PMID 16573777. 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 Rev 16 (3): CD007216. doi:10.1002/14651858.CD007216. PMID 18646177. 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 Dermatology 51 (5): 7606. doi:10.1016/j.jaad.2004.05.036. PMID 15523355. 17. Jump up^ Naesens M, Kuypers DR, Sarwal M (2009). "Calcineurin inhibitor nephrotoxicity". Clin. J. Am. Soc. Nephrol. 4 (2): 481 509. doi:10.2215/CJN.04800908. PMID 19218475. 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 Rheumatol 18 (2): 20811. doi:10.1007/s10165-008-0034-3. PMID 18306979. 19. Jump up^ O'Donnell MM, Williams JP, Weinrieb R, Denysenko L (2007). "Catatonic mutism after liver transplant rapidly reversed with lorazepam". Gen Hosp Psychiatry 29 (3): 2801.doi:10.1016/j.genhosppsych.2007.01.004. PMID 17484951. 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 Derm 53 (2 suppl 2): S186 94. doi:10.1016/j.jaad.2005.04.062. PMID 16021174. 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 Pharmacokinet 21 (2): 1225. doi:10.2133/dmpk.21.122. PMID 16702731. 23. Jump up^ Fegan, A; White, B; Carlson, JC; Wagner, CR (2010 Jun 9). "Chemically controlled protein assembly: techniques and applications.". Chemical reviews 110 (6): 331536. doi:10.1021/cr8002888.PMID 20353181. 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 from Fermentek U.S. National Library of Medicine: Drug Information Portal - Tacrolimus

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Tacrolimus (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. The Amerika Serikat Organ Pengadaan dan Jaringan Transplantasi dan Registry Ilmiah Penerima Transplantasi menunjukkan 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 dari Australia & New Zealand Dialisis dan Transplantasi Registry menunjukkan 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 Maes et al. [Artikel: 15041305 ]). Namun, beberapa penelitian telah menunjukkan bahwa penggunaan tacrolimus dikaitkan dengan tingkat penolakan allograft rendah dibandingkan dengan siklosporin [Artikel: 16686762 , 15741208 , 16157605 ]. Farmakodinamik Dalam 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 NFAT

Setelah memasuki sel T, baik siklosporin dan tacrolimus mengikat dengan afinitas tinggi untuk protein yang dikenal sebagai immunophilins. Siklosporin mengikat terutama untuk cyclophilin A (dikodekan oleh PPIA gen), yang cyclophilin utama yang ditemukan dalam sel-sel T, dan tacrolimus mengikat protein FK-mengikat, khususnya FKBP12 (dikodekan oleh FKBP1A gen). 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 (IL4), 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 (NFkB) 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 p38 Meskipun efek tacrolimus dan siklosporin pada kalsineurin adalah mungkin mekanisme terbaikdipelajari, 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 MAPKKK. 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-1 TGF-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 vivo studi 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 ], dan in vitro studi 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 ]. Pharmacogenomics Mayoritas studi farmakogenetik pada tacrolimus dan siklosporin telah berfokus pada efek dari varian dalam CYP3A4 , CYP3A5 dan ABCB1 gen 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 termasukCYP3A dan ABCB1 [Artikel: 2.309.580 ]. Selain itu, beberapa studi telah meneliti SNP dalam POR gen, 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 ), dan CYP2C8 gen, CYP2C8 terlibat dalam metabolisme asam arakidonat (AA) menjadi asam epoxyeicosatrienoic (EETs), metabolit terlibat dalam mempertahankan fungsi ginjal normal. Meskipun berbagai studi ini, hanya 3 * alel ( rs776746 ) dalam CYP3A5 gen 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: Kutipan: Julia M. Barbarino, Christine E. Staatz dan Raman Venkataramanan.

Barbarino Julia M, Staatz Christine E, Venkataramanan Raman, Klein Teri E, Altman Russ B. " Ringkasan tacrolimus jalur " Pharmacogenetics dan genomik (2013).

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