Tacrolimus: Wikis

  
  

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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

Identifiers
CAS number 104987-11-3
ATC code D11AH01 L04AD02
PubChem 656830
DrugBank APRD00276
ChemSpider 4976056
Chemical data
Formula C 44H69NO12  
Mol. mass 804.018 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability 20%, less after eating food rich in fat
Protein binding 75-99%
Metabolism Hepatic CYP3A4
Half life 11.3 h (range 3.5-40.6 h)
Excretion Mostly faecal
Therapeutic considerations
Pregnancy cat. C
Legal status
Routes Topical, oral, iv

Tacrolimus (also FK-506 or Fujimycin) is an immunosuppressive drug whose main use is after allogeneic organ transplant to reduce the activity of the patient's immune system and so lower the risk of organ rejection. It reduces T-cell and interleukin-2 (IL-2) activity. It is also used in a topical preparation in the treatment of severe atopic dermatitis (eczema), severe refractory uveitis after bone marrow transplants, 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 bacteria Streptomyces tsukubaensis.

Contents

History

Tacrolimus was discovered in 1984 by a Japanese team headed by T. Goto, T. Kino and H. Hatanaka; it was among the first macrolide immunosuppressants discovered, preceded by the discovery of rapamycin (sirolimus) on Rapa Nui (Easter Island) in 1975.[1] Like cyclosporin, it was found in a soil fungus, although it is produced by a type of bacterium, Streptomyces tsukubaensis.[2 ] The name tacrolimus is derived from 'Tsukuba macrolide immunosuppressant'.[3]

The drug is owned by Astellas Pharma Inc., and is sold under the tradenames Prograf, Advagraf, and Protopic. It is sometimes referred to as FK-506. It 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.

Pharmacology

Tacrolimus is chemically known as a macrolide. It 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-lymphocyte signal transduction and IL-2 transcription.[4] Although this activity is similar to cyclosporin, studies have shown that the incidence of acute rejection is reduced by tacrolimus use over cyclosporin.[5] 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.[6]

Indications

Immunosuppression following transplantation

It has similar immunosuppressive properties to ciclosporin, but is much more potent in equal volumes. Also like ciclosporin it has a wide range of adverse 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. 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.[5] Clinical outcome is better with tacrolimus than with emulsified ciclosporin during the first year of liver transplantation.[7]

Use in treating ulcerative colitis

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.[8][9]

Dermatological use

As an ointment (Protopic), tacrolimus is a recent addition 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 may therefore be used continuously on the body (clinical trials of up to one year in length have occurred), and applied to the thinner skin over the face and eyelids. Recently it has also been used to treat segmental vitiligo in children,especially on the face.[10]

The most common adverse events associated with the use of Protopic included the sensation of skin burning, itching, flu-like symptoms, and headache. The use of Protopic should be avoided on known or suspected malignant lesions. The use of Protopic 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. Protopic should not be used with occlusive dressings (http://www.protopic.com/).

Contraindications and precautions

Side effects

From oral and intravenous administration

Side effects can be severe and include blurred vision, liver and kidney problems (it is nephrotoxic), seizures, tremors, hypertension, hypomagnesemia, diabetes mellitus, hyperkalemia, itching, insomnia, confusion, loss of appetite, hyperglycemia, weakness, depression, cramps, and neuropathy, as well as potentially increasing the severity of existing fungal or infectious conditions such as herpes zoster or polyoma viral infections.

From topical use

A common side effect of tacrolimus ointment, if used over a wide area, is to cause a burning or itching sensation on the first one or two applications. Less common side effects include flu-like symptoms, headache, cough and burning eyes.[12]

Cancer risks

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.[13]

References

  1. ^ 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): 1249–55. PMID 2445721.  
  2. ^ 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. ^ Ponner, B, Cvach, B (Fujisawa Pharmaceutical Co.): Protopic Update 2005
  4. ^ 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): 807–15. doi:10.1016/0092-8674(91)90124-H. PMID 1715244.  
  5. ^ a b McCauley, Jerry (2004-05-19). "Long-Term Graft Survival In Kidney Transplant Recipients". Slide Set Series on Analyses of Immunosuppressive Therapies. Medscape. http://www.medscape.com/viewarticle/474429. Retrieved 2006-06-06.  
  6. ^ 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: 3025–3028. doi:10.1016/j.transproceed.2005.08.040.  
  7. ^ 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: 1119–1125. doi:10.1016/S0140-6736(02)11196-2.  
  8. ^ 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 Gastroenterol 101: 1048–1056. doi:10.1111/j.1572-0241.2006.00524.x. PMID 16573777.  
  9. ^ Baumgart DC, MacDonald JK, Feagan BG (2008). "Tacrolimus (FK506) for induction of remission in refractory ulcerative colitis.". Cochrane Database Syst Rev 16: CD007216. doi:10.1002/14651858.CD007216. PMID 18646177.  
  10. ^ Nanette B. Silverberg, Peggy Lin, Lisa Travis, Jeanne Farley-Li, Anthony J. Mancini, Annette M. Wagner, Sarah L. Chamlin and Amy S. Paller(Nov.2004)."Tacrolimus ointment promotes repigmentation of vitiligo in children: A review of 57 cases". Journal of the American Academy of Dermatology, Volume 51, Issue 5,Pages 760-766.
  11. ^ 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): 122–5. doi:10.2133/dmpk.21.122. PMID 16702731.  
  12. ^ 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.  
  13. ^ N H Cox and Catherine H Smith (December 2002). "Advice to dermatologists re topical tacrolimus" (DOC). Therapy Guidelines Committee. British Association of Dermatologists. http://www.bad.org.uk/healthcare/guidelines/Advice_re_topical_tacrolimus.doc.  

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