Tacrolimus

Tacrolimus is an immunosuppressive drug. Its 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.

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 Fujisawa Pharmaceutical Company and is sold under the tradename Prograf®. It is sometimes referred to as FK506, 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 acts by reducing peptidyl-prolyl isomerase activity by binding to the immunophilin FKBP-12 (FK506 binding protein) creating a new complex. This inhibits 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.

Dermatological use

Protopic® or tacrolimas is a recent topical treatment of eczema, particularly atopic eczema. It suppresses inflammation in a similar way to steroids, but is not as powerful. It has few advantages over local steroids and has gained ground mainly because of undue fear of topical steroids, particularly in USA. It does have one important advantage, that it can be used directly on the face, where topical steroids cannot, as they thin the skin dramatically there. It has one major disadvantage, that if used over a wide area, it causes a burning sensation on the first one or two applications.

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 bacteria, Streptomyces tsukubaensis. 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 link

Prograf® prescribing information at Fujisawa

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