Tacrolimus
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Image:Tacrolimus.png | |
| IUPAC chemical 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. | |
| CAS number 104987-11-3 | ATC code D11AX14, L04AA05 |
| Chemical formula | C44H69NO12·H2O |
| Molecular weight | 804.024 |
| Bioavailability | 20%, less after eating food rich in fat |
| Metabolism | Hepatic |
| Elimination half-life | 12-15 h. for transplantation patients (varies) |
| Excretion | Mostly faecal |
| Pregnancy category | C |
| Legal status | ? |
| Routes of administration | Intravenous, oral, cutaneously |
Tacrolimus (also FK-506 or Fujimycin) is a 23-membered macrolide lactone discovered in 1984 from the fermentation broth of a Japanese soil sample that contained the bacteria Streptomyces tsukubaensis. It is an immunosuppressive drug whose main use is after allogenic organ transplant to reduce the activity of the patient's immune system and so the risk of organ rejection.
It has similar immunosuppressive properties to cyclosporine, but is much more potent in equal volumes. Also like cyclosporine it has a wide range of adverse interactions, including that with grapefruit which increases plasma-tacrolimus concentration. Immunosuppression with tacrolimus was associated with a significantly lower rate of acute rejection compared with cyclisporine-based immunosuppression (30.7% vs 46.4%, respectively, P < .001) in one study. Template:Ref
It has been used in a topical preparation in the treatment of severe atopic dermatitis, as have cyclosporine and azathioprine with much less success. It has also been used after bone marrow transplants and for severe refractory uveitis.
The drug is owned by Astellas Pharma Inc. (Merging of Fujisawa Pharmaceutical Co.,Ltd. and Yamanouchi Pharmaceutical Co., Ltd as of April 1, 2005) and is sold under the tradename Prograf®. It is sometimes referred to as FK-506, an early name relating to its action. It was first approved by the FDA in 1994 for use in liver transplantation, this has been extended to include kidney, heart, small bowel, pancreas, lung, trachea, skin, cornea, and limb transplants.
Tacrolimus is a macrolide antibiotic. It reduces peptidyl-prolyl isomerase activity by binding to the immunophilin FKBP-12 (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. Although this activity is similar to cyclosporine studies have shown that the incidence of acute rejection is reduced by tacrolimus use over cyclosporine.
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.
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Dermatological use
Protopic® or tacrolimus is a recent topical treatment of eczema, particularly atopic eczema. It suppresses inflammation in a similar way to steroids, but is not as powerful. An important dermatological advantage of tacrolimus is that it can be used directly on the face; topical steroids cannot be used on the face, as they thin the skin dramatically there. On other parts of the body, topical steroid are generally a better treatment. 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.
Cancer risks
Tacrolimus and a related drug for eczema (pimecrolimus) are being suspected of carrying a cancer risk, though the matter is still a subject of controversy. Dermatologists agree that the drug should be used as a second-line remedy only after conventional methods of treatment have failed. 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.
History
Tacrolimus was discovered in 1987 by a Japanese team headed by T. Goto, T. Kino and H. Hatanaka; it was the first macrolide immunosuppressant discovered. Like cyclosporine, it was found in a soil fungus, although it is produced by a type of bacteria, Streptomyces tsukubaensis.Template:Ref The name tacrolimus is reportedly derived from 'Tsukuba macrolide immunosuppressant'. The chemical name for tacrolimus is:
[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.
As a monohydrate its empirical formula is C44H69NO12·H2O.
External links
- Prograf® prescribing information at Fujisawa
- Tacrolimus (Protopic Cream) FDA advisory page (for eczema treatment)
- Pimecrolimus (Elidel Cream) FDA adivisory page (for eczema treatment)
Notes
- Kino T, Hatanaka H, Hashimoto M et al. FK-506, a novelimmunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physicochemical and biological characteristics.J Antibiot (Tokyo) 1987; 40: 1249–1255. original reference
- Template:Note McCauley, J.Long-Term Graft Survival In Kidney Transplant Recipients.
- Template:Note Pritchard, David I. 2005. "Sourcing a chemical succession for cyclosporin from parasites and human pathogens". Drug Discovery Today 10[10]:688-691. Supports source organism, but not team information
- Liu J, Farmer JD, Lane WS, Friedman J, Weissman I, and Schreiber S. Calcineurin is a common target of cyclophilin-Cyclosporin A and FKBP-FK506 complexes. Cell 1991; 66: 807–815.de:Tacrolimus