Tacrolimus

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Tacrolimus , also known as fujimycin or FK506 , is an immunosuppressive drug used primarily after allogene organ transplants to reduce the risk of organ rejection. This achieves this by inhibiting the production of interleukin-2, a molecule that promotes the development and proliferation of T cells, which is essential for the body's (or adaptive) immune response. Tacrolimus is also used in the treatment of other T-cell mediated diseases such as eczema (applied to the skin in ointment), severe refractory uveitis after bone marrow transplantation, exacerbation of minimal change disease, Kimura disease, and vitiligo skin condition.

Chemically it is the 23-member lacton macrolide which was first discovered in 1987 from a fermented broth of Japanese soil samples containing bacteria Streptomyces tsukubaensis .

Video Tacrolimus

Medical use

Organ transplants

It has immunosuppressive properties similar to ciclosporin, but is much stronger. Immunosuppression with tacrolimus was associated with a much lower acute rejection rate than ciclosporin-based immunosuppression (30.7% vs 46.4%) in one study. Clinical outcomes were better with tacrolimus compared to ciclosporin during the first year of liver transplantation. Long-term results have not been fixed to the same level. Tacrolimus is usually prescribed as part of a post-transplant cocktail including steroids, mycophenolate, and IL-2 receptor inhibitors such as basiliximab. Dose is titrated to target blood levels.

Colitis ulcerativa

In recent years, tacrolimus has been used to suppress the inflammation associated with ulcerative colitis (UC), a form of inflammatory bowel disease. Although almost exclusively used in experimental cases alone, tacrolimus has been shown to be very effective in suppressing UC outbreaks.

Skin

As an ointment, tacrolimus is used in the treatment of eczema, especially atopic dermatitis. It suppresses inflammation in a similar way to steroids, and is as effective as mid-potency steroids. An important advantage of tacrolimus is that, unlike steroids, it does not cause skin thinning (atrophy), or other steroid-related side effects.

It is applied to active lesions until they are healed, but can also be used continuously in low doses (twice a week), and applied to thinner skin over the face and eyelids. Clinical trials up to one year have been performed. Recently it has also been used to treat segmental vitiligo in children, especially in the face area.

Maps Tacrolimus

Contraindications and precautions

Contraindications and precautions include:

• Breastfeeding
• Liver disease
• Immunosuppression
• Baby
• Infection
• Neoplastic disease, such as:
  • Skin cancer
  • Lung cancer
• Oliguria
• Pregnancy
• QT interval extension
• Sunlight (UV) lighting
• Grapefruit Juice

Topical use

• Change clothes
• Malignant lesions that are known or suspected
• Netherton syndrome or similar skin lesions
• Certain skin infections

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Side effects

By mouth or intravenous use

Side effects can be severe and include infections, heart damage, hypertension, blurred vision, liver and kidney problems (tacrolimus nephrotoxicity), hyperkalemia, hypomagnesemia, hyperglycemia, diabetes mellitus, itching, lung damage (sirolimus also causes lung damage) and various neuropsychiatric problems such as loss of appetite, insomnia, posterior reversible encephalopathy syndrome, confusion, weakness, depression, nightmares are alive, cramps, neuropathy, seizures, tremors, and catatonia.

In addition, it can potentially increase the severity of fungal conditions or existing infections such as herpes zoster or polyoma virus infection.

Carcinogenesis and mutagenesis

In people receiving immunosuppressants to reduce transplant transplant rejection, an increased risk of malignancy (cancer) is a known complication. The most common cancers are non-Hodgkin's lymphoma and skin cancer. The risk seems to be related to the intensity and duration of treatment.

Topical use

The most common side effects are associated with the use of topical tacrolimus ointment, especially if used over a large area, including burning or itching sensations in the initial application, with increased sensitivity to sunlight and heat in the affected area. Less common are flu-like symptoms, headache, cough, and burning eyes.

Cancer risk

Tacrolimus and related drugs for eczema (pimecrolimus) allegedly carry the risk of cancer, although this is still a controversy. The FDA issued a health warning in March 2005 for the drug, based on an animal model and a small number of patients. Until further human research yields more conclusive results, the FDA recommends that users be advised about the potential risks. However, current practice by British dermatologists does not consider this to be of significant real concern and they increasingly recommend the use of these new drugs.

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Interactions

Also like ciclosporin, it has various interactions. Tacrolimus is primarily metabolized by the cytochrome P450 liver enzyme system, and there are many substances that interact with this system and induce or inhibit the metabolic activity of the system.

Interactions include grapefruit that increases plasma concentrations of tacrolimus. Because infection is a major cause of morbidity and mortality in post-transplant patients, the most frequently reported interactions include interactions with anti-microbial drugs. Macrolide antibiotics include erythromycin and clarithromycin, as well as some newer antifungal groups, especially the azole group (fluconazole, voriconazole), increasing tacrolimus levels by competing for cytochrome enzymes.

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Pharmacology

Action mechanism

Tacrolimus is a macrolide calcineurin inhibitor. In T-cells, T-cell receptor activation usually increases intracellular calcium, which acts through calmodulin to activate calcineurin. Calcineurin then dephosphorylates the nuclear factor transcription factor of activated T-cells (NF-AT), which travels to the T-cell nucleus and increases the activity of coding genes for IL-2 and associated cytokines. Tacrolimus prevents dephosphorylation of NF-AT.

In detail, tacrolimus reduces peptidilprolyl isomerase activity by binding to immunophilin FKBP12 (FK506 binding protein), creating new complexes. This FKBP12-FK506 complex interacts with and inhibits calcineurin, thus inhibiting T-lymphocyte signal transduction and IL-2 transcription. Although this activity is similar to ciclosporin, the incidence of acute rejection is reduced by the use of tacrolimus over the use of ciclosporin. Although short-term immunosuppression of patient survival and graft is found to be similar between the two drugs, tacrolimus produces a more favorable lipid profile, and this may have important long-term implications given the prognostic effect of rejection on transplant survival.

Pharmacokinetics

Oral tacrolimus is slowly absorbed in the gastrointestinal tract, with a total bioavailability of 20 to 25% (but with variations from 5 to 67%) and the highest blood plasma concentration (Cmax) is achieved after one to three hours. Taking medication along with eating, especially those rich in fat, slows resorption and reduces bioavailability. In blood, tacrolimus is primarily bound to erythrocytes; only 5% were found in plasma, of which more than 98.8% were bound to plasma proteins.

The substance is metabolized in the liver, mainly through CYP3A, and in the intestinal wall. All metabolites found in the circulation are inactive. Biological half-life varies widely and appears to be higher for healthy people (mean 43 hours) than for patients with liver transplantation (12 hours) or kidney transplant (16 hours), due to differences in clearance. Tacrolimus is largely removed through the faeces in its metabolite form.

When applied locally to eczema, tacrolimus has little or no bioavailability.

Pharmacogenetic

The dominant enzyme responsible for tacrolimus metabolism is CYP3A5. The genetic variation in CYP3A5 that results in changes in the activity of CYP3A5 protein may affect the concentration of tacrolimus in the body. Specifically, homozygous individuals for G allele in single nucleotide polymorphism (SNP) rs776746 (also known as CYP3A5 * 3/* 3) have non-functional CYP3A5 proteins. G allele frequencies vary worldwide, from 4% in some African populations to 80-90% in Caucasian populations. In a large number of studies, homozygous individuals for the G allele have been shown to have higher tacrolimus concentrations and require lower drug doses, compared with individuals not homozygous for G alleles. Achieving target tacrolimus concentrations is important - if the levels are too low, the risk of transplant rejection, if the level is too high, there is a risk of drug toxicity. There is evidence to suggest that patient doses based on the rs776746 genotype can result in faster and more frequent achievement of target tacrolimus. However, there is a lack of consistent evidence as to whether doses based on genotype rs776746 results in better clinical outcomes (such as reduced risk of transplant rejection or drug toxicity), perhaps because patients taking tacrolimus should undergo therapeutic drug monitoring.

Studies have shown that genetic polymorphisms of genes other than CYP3A5, such as NR1I2 (PXR encoding), also significantly affect tacrolimus pharmacokinetics.

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History

Tacrolimus was discovered in 1987; it was one of the first macrolide immunosuppressants to be discovered, preceded by the discovery of rapamycin (sirolimus) on Rapa Nui (Easter Island) in 1975. It was produced by soil bacteria, Streptomyces tsukubaensis . The name tacrolimus comes from "Tsukuba macrolide immunosuppressant".

Tacrolimus was first approved by the Food and Drug Administration in 1994 for use in liver transplants; It has been expanded to include kidney, heart, small intestine, pancreas, lung, trachea, skin, cornea, bone marrow, and limb transplantation.

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Available form

The branded version of this drug is owned by Astellas Pharma, and sold under the trade name Prograf, given twice daily. A number of other manufacturers hold marketing authorizations for alternative brands of twice-daily formulations.

The once-daily formulation with marketing authorization includes Advagraf (Astellas Pharma) and Envarsus (marketed as Envarsus XR in the US by Veloxis Pharmaceuticals and marketed in Europe by Chiesi). This formulation is intended to reduce pharmacokinetic variation in blood levels and facilitate adherence with dosing.

Topical formulations are also marketed by Astellas Pharma under the name Protopic.

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Biosynthesis

Tacrolimus biosynthesis is a hybrid synthesis of both type 1 polymer synthase (MCC 1) and nonribosomal peptide synthase (NRPS). The research shows hybrid synthesis consists of ten module type 1 polymer synthase and one nonribosomal peptide synthase module. The synthetic enzyme for Tacrolimus is found in 19 gene groups called fkb. The 19 genes are fkbQ, fkbN, fkbM, fkbD, fkbA, fkbP, fkbO, fkbB, fkbC, fkbL, fkbH, fkbG, allD, allR, allK and allA.

There are several possible ways of Tacrolimus biosynthesis. The basic unit for biosynthesis is as follows: one molecule of 4, 5-dihydroxycyclohex-1-enecarboxylic acid (DHCHC) as a starter unit, four molyules of malonyl-CoA, five methylmalonyl-CoA molecules, one allylmalonyl-CoA molecule as an extension unit. However, two molyules of malonyl-CoA can be replaced by two molecules of methoxymalonyl CoA. After two molyules of malonyl-CoA are replaced, post-synthesis adjustment steps are no longer needed where two coA methoxymalonyl molecules are replaced. The biosynthesis of methoxymalonyl CoA to the Acyl Carrier protein is processed by five enzymes (fkbG, fkbH, fkbI, fkbJ, and fkbK). Allylmalonyl-CoA can also be replaced by propionylmalonyl-CoA.

The starter unit, DHCHC of chorismic acid is formed by the fkbO enzyme and is loaded onto the CoA-ligase domain (CoL). Then, the result depends on NADPH (ER) reduction. The three enzymes, fkbA, B, C enforce the process from the loading module to module 10, the final step of the MCC enzyme 1. fkbB is responsible for the synthesis of allylmalonyl-CoA or possibly propionylmalonyl-CoA in C21, which is an unusual step of the general MCC 1 As mentioned, if two methoxymalonyl COA molecules are replaced for two malonyl-CoA molecules, they will take place in modules 7 and 8 (C13 and C15), and the fkbA enzyme will enforce this process. After the last step (module 10) of the MCC 1, an L-Pipecolic acid molecule formed from L-Lysine and catalyzed via the fkbL enzyme is synthesized with the molecule of module 10. The L-Pipecolic acid synthesis process is NRPS enforced by the fkbP enzyme. After synthesizing the entire subunit, the molecule is cyclized. After cyclization, the pre-Tacrolimus molecule passes through post synthesis steps such as oxidation and S-Adenosyl methionine. Especially the fkbM enzyme is responsible for alcohol methylation targeting alcohol from DHCHC starter units (Carbon number 31 is described in brown), and the fkbD enzyme is responsible for C9 (described in green). After these adjustment steps, the Tacrolimus molecule becomes biologically active.

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See also

• Tohru Kino
• Stuart Schreiber
• Thomas Starzl
• FK1012, derivative

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References

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External links

• Tacrolimus level in the Liver-Indian Transplant Study by Dr.Pradeep Naik, Dr.Dharmesh Kapoor, Dr.DCS Reddy
• Prograf's prescribing information in Fujisawa
• Pimecrolimus (Elidel Cream) FDA adivisory page (for eczema treatment)
• Tacrolimus (FK506) product page from Fermentek
• US. National Drug Library: Drug Information Portal - Tacrolimus

Source of the article : Wikipedia