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 IUPAC nomenclature is a system of naming chemical compounds and of describing the science of chemistry in general. ...
Identifiers
CAS number	104987-11-3
ATC code	L04AA05 D11AX14
PubChem	656830
DrugBank	APRD00276
Chemical data
Formula	C44H69NO12
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 hours (range 3.5-40.6 hours)
Excretion	Mostly faecal
Therapeutic considerations
Pregnancy cat.	A CAS registry numbers are unique numerical identifiers for chemical compounds, polymers, biological sequences, mixtures and alloys. ... The Anatomical Therapeutic Chemical Classification System is used for the classification of drugs. ... A section of the Anatomical Therapeutic Chemical Classification System. ... A section of the Anatomical Therapeutic Chemical Classification System. ... PubChem is a database of chemical molecules. ... The DrugBank database available at the University of Alberta is a unique bioinformatics and cheminformatics resource that combines detailed drug (i. ... A chemical formula is an easy way of expressing information about the atoms that constitute a particular chemical compound. ... For other uses, see Carbon (disambiguation). ... This article is about the chemistry of hydrogen. ... General Name, symbol, number nitrogen, N, 7 Chemical series nonmetals Group, period, block 15, 2, p Appearance colorless gas Standard atomic weight 14. ... This article is about the chemical element and its most stable form, or dioxygen. ... The molecular mass (abbreviated Mr) of a substance, formerly also called molecular weight and abbreviated as MW, is the mass of one molecule of that substance, relative to the unified atomic mass unit u (equal to 1/12 the mass of one atom of carbon-12). ... The simplified molecular input line entry specification or SMILES is a specification for unambiguously describing the structure of chemical molecules using short ASCII strings. ... In pharmacology, bioavailability is used to describe the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. ... A drugs efficacy may be affected by the degree to which it binds to the proteins within blood plasma. ... Drug metabolism is the metabolism of drugs, their biochemical modification or degradation, usually through specialized enzymatic systems. ... Cytochrome P450 3A4 (abbreviated CYP3A4) (EC 1. ... The biological half-life of a substance is the time required for half of that substance to be removed from an organism by either a physical or a chemical process. ... The kidneys are important excretory organs in vertebrates. ... The pregnancy category of a pharmaceutical agent is an assessment of the risk of fetal injury due to the pharmaceutical, if it is used as directed by the mother during pregnancy. ...
Legal status
Routes	Topical, oral, iv

Tacrolimus (also FK-506 or Fujimycin) 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 ("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. The regulation of therapeutic goods, that is drugs and therapeutic devices, varies by jurisdiction. ... In pharmacology and toxicology, a route of administration is the path by which a drug, fluid, poison or other substance is brought into contact with the body. ... An intravenous drip in a hospital Intravenous therapy or IV therapy is the administration of liquid substances directly into a vein. ... Immunosuppression is the medical suppression of the immune system. ... This article does not cite any references or sources. ... “Transplant” redirects here. ... A scanning electron microscope image of a single neutrophil (yellow), engulfing anthrax bacteria (orange). ... Transplant rejection occurs when the immune system of the recipient of a transplant attacks the transplanted organ or tissue. ... For the beetle, see Exema. ... Uveitis specifically refers to inflammation of the middle layer of the eye, termed the uvea but in common usage may refer to any inflammatory process involving the interior of the eye. ... For the Dir en grey album, see The Marrow of a Bone. ... Not to be confused with alphos, a form of leprosy once called vitiligo. ... The macrolides are a group of drugs (typically antibiotics) whose activity stems from the presence of a macrolide ring, a large lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, are attached. ... A lactone is a cyclic ester in organic chemistry. ... Loess field in Germany Surface-water-gley developed in glacial till, Northern Ireland For the American hard rock band, see SOiL. For the System of a Down song, see Soil (song). ... Phyla Actinobacteria Aquificae Chlamydiae Bacteroidetes/Chlorobi Chloroflexi Chrysiogenetes Cyanobacteria Deferribacteres Deinococcus-Thermus Dictyoglomi Fibrobacteres/Acidobacteria Firmicutes Fusobacteria Gemmatimonadetes Lentisphaerae Nitrospirae Planctomycetes Proteobacteria Spirochaetes Thermodesulfobacteria Thermomicrobia Thermotogae Verrucomicrobia Bacteria (singular: bacterium) are unicellular microorganisms. ...

History

Tacrolimus was discovered in 1987 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 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'. Year 1987 (MCMLXXXVII) was a common year starting on Thursday (link displays 1987 Gregorian calendar). ... The macrolides are a group of drugs (typically antibiotics) whose activity stems from the presence of a macrolide ring, a large lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, are attached. ... Sirolimus is a relatively new immunosuppressant drug used to prevent rejection in organ transplantation, and is especially useful in kidney transplants. ... Easter Island and its location Easter Island (Polynesian: Rapa Nui (Great Rapa), Spanish: Isla de Pascua) is an island in the south Pacific Ocean belonging to Chile. ... Ciclosporin (INN), cyclosporine or cyclosporin (former BAN), is an immunosuppressant drug. ... Tsukuba (Japanese: つくば市 Tsukuba-shi) is a planned city located in Ibaraki Prefecture, Japan. ...

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, 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, bone marrow, and limb transplants. Astellas Pharma Inc. ... “FDA” redirects here. ...

Pharmacology

Tacrolimus is chemically known as a macrolide. 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 cyclosporin, studies have shown that the incidence of acute rejection is reduced by tacrolimus use over cyclosporin.^{[citation needed]} The macrolides are a group of drugs (typically antibiotics) whose activity stems from the presence of a macrolide ring, a large lactone ring to which one or more deoxy sugars, usually cladinose and desosamine, are attached. ... Calcineurin (CN) is a protein phosphatase also known as protein phosphatase 2B (PP2B). ... A scanning electron microscope (SEM) image of a single human lymphocyte. ... ...

Indications

Immunosuppresion following transplantation

It has similar immunosuppressive properties to cyclosporin, but is much more potent in equal volumes. Also like cyclosporin 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 cyclosporin-based immunosuppression (30.7% vs 46.4%) in one study.^[4] Binomial name Macfad. ...

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. In medicine, inflammatory bowel disease (IBD) is a group of inflammatory conditions of the large intestine and, in some cases, the small intestine. ...

Dermatological use

See also: Immunomodulators in the treatment of eczema For the beetle, see Exema. ...

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.^[5] An ointment is a viscous semisolid preparation used topically on a variety of body surfaces. ... For the beetle, see Exema. ... This article is about the chemical family of steroids. ... Atrophy is the partial or complete wasting away of a part of the body. ...

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

• breast-feeding
• hepatic disease
• immunosuppression
• infants
• infection
• intravenous administration
• neoplastic disease
• occlusive dressing
• oliguria
• pregnancy
• QT prolongation
• skin cancer
• sunlight (UV) exposure
• grapefruit juice^[6]

A breastfeeding infant Breastfeeding is the practice of a woman feeding an infant (or sometimes a toddler or a young child) with milk produced from her mammary glands, usually directly from the nipples. ... The liver is an organ in vertebrates including humans. ... “Baby” redirects here. ... An infection is the detrimental colonization of a host organism by a foreign species. ... ... Oliguria and anuria are the decreased or absent production of urine, respectively. ... This article is about human pregnancy in biological females. ... Skin cancer is a malignant growth on the skin which can have many causes. ... Prism splitting light High Resolution Solar Spectrum Sunlight in the broad sense is the total spectrum of the electromagnetic radiation given off by the Sun. ... Note: Ultraviolet is also the name of a 1998 UK television miniseries about vampires. ...

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. The kidneys are the organs that filter wastes (such as urea) from the blood and excrete them, along with water, as urine. ... This article is about epileptic seizures. ... For the film see Tremors (film). ... For other forms of hypertension, see Hypertension (disambiguation). ... For the disease characterized by excretion of large amounts of very dilute urine, see diabetes insipidus. ... Hyperkalemia is an elevated blood level (above 5. ... For other uses, see Itch (disambiguation). ... This article is about the sleeping disorder. ... Hyperglycemia, hyperglycaemia, or high blood sugar is a condition in which an excessive amount of glucose circulates in the blood plasma. ... The varicella-zoster virus (VZV), also known as human herpesvirus 3 (HHV-3), is one of the eight herpesviruses known to affect humans (and other vertebrates). ... Species See text Polyomavirus is the sole genus of viruses within the family Polyomaviridae. ...

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.^[7]

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.^[8] For the beetle, see Exema. ... Pimecrolimus is an immunomodulating agent used in the treatment of atopic dermatitis. ...

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

References

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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)
• Offers more information on possible cancer risks of Protopic (Tacrolimus)
• Tacrolimus (FK506) product page from Fermentek