Article: Tacrolimus

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	L04AA05 D11AX14
PubChem	656830
DrugBank	APRD00276
Chemical data
Formula	C44H69NO12·H2O
Mol. weight	804.018 g/mol
Pharmacokinetic data
Bioavailability	20%, less after eating food rich in fat
Protein binding	75-99%
Metabolism	Hepatic CYP3A4
Half life	11.3 hours (range 3.5-40.6 hours)
Excretion	Mostly faecal
Therapeutic considerations
Pregnancy cat.	C
Legal status
Routes	Topical, oral, iv

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 is also used in a topical preparation in the treatment of severe atopic dermatitis (often called "eczema"), as have cyclosporin and azathioprine with much less success. It has also been used after bone marrow transplants and for severe refractory uveitis.

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.^[1] Like ciclosporin, it was found in a soil fungus, although it is produced by a type of bacteria, Streptomyces tsukubaensis.^[2] The name tacrolimus is reportedly derived from 'Tsukuba macrolide immunosuppressant'.

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 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, and limb transplants.

Pharmacology

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.^[3] Although this activity is similar to ciclosporin studies have shown that the incidence of acute rejection is reduced by tacrolimus use over cyclosporine.

Indications

Immunosuppresion 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. 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.^[4]

Dermatological use

As a cream (Protopic®), tacrolimus is a recent addition in the treatment of eczema, particularly atopic eczema. It suppresses inflammation in a similar way to steroids, but is not as powerful. An important advantage of tacrolimus is that unlike steroids, it does not cause skin thinning (atrophy). It may therefore be used continuously on the body and applied to the thinner skin over the face. On other parts of the body, topical steroids are generally a better treatment^{[citation needed]}, and considerably cheaper.

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.

Cancer risks

Further information: Eczema#Immunomodulators

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. Whereas 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.^[5]

Dermatologists agree that the drug should be used as a second-line remedy only after conventional methods of treatment have failed.

Footnotes

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. PMID 15896681. Supports source organism, but not team information
3. ^ 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. PMID 1715244.
4. ^ McCauley, Jerry (2004-05-19). Long-Term Graft Survival In Kidney Transplant Recipients. Slide Set Series on Analyses of Immunosuppressive Therapies. Medscape. Retrieved on 2006-06-06.
5. ^ N H Cox and Catherine H Smith (December 2002). Advice to dermatologists re topical tacrolimus. (DOC) Therapy Guidelines Committee. British Association of Dermatologists.