Tacrolimus (C44H69NO12) is an exogenous solid at room temperature. Tacrolimus belongs to the macrolide lactams, a class of phenylpropanoids and polyketides within the organic compounds. With an average molecular weight of 804.02 g/mol, Tacrolimus is a heavy molecule. It is used as an immunosuppressive drug to reduce immune system activity and the risk of organ rejection following organ transplants. Additionally, it is used in topical preparations for the treatment of vitiligo, severe atopic dermatitis, and severe refractory uveitis after bone marrow transplants.
This compound acts by binding to the immunophilin FKBP-12, reducing peptidyl-prolyl isomerase activity and creating a complex that inhibits calcineurin, which inhibits IL-2 transcription and T-lymphocyte signal transduction. Its recorded protein targets include Protein phosphatase 3 catalytic subunit alpha (PPP3CA) and peptidyl-prolyl cis-trans isomerase FKBP1A. Exposure routes include topical, oral, and intravenous administration. It is found in dermatological preparations, immunosuppressants, and antennas.
belongs to the class of organic compounds known as macrolide lactams. These are cyclic polyketides containing both a cyclic amide and a cyclic ester group.
Absorption of tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable. The absolute bioavailability in adult kidney transplant patients is 17Њ±10%; in adults liver transplant patients is 22Њ±6%; in healthy subjects is 18Њ±5%. The absolute bioavailability in pediatric liver transplant patients was 31Њ±24%. Tacrolimus maximum blood concentrations (Cmax) and area under the curve (AUC) appeared to increase in a dose-proportional fashion in 18 fasted healthy volunteers receiving a single oral dose of 3, 7, and 10 mg. When given without food, the rate and extent of absorption were the greatest. The time of the meal also affected bioavailability. When given immediately after a meal, mean Cmax was reduced 71%, and mean AUC was reduced 39%, relative to the fasted condition. When administered 1.5 hours following the meal, mean Cmax was reduced 63%, and mean AUC was reduced 39%, relative to the fasted condition.
Mechanism of Toxicity
The mechanism of action of tacrolimus in atopic dermatitis is not known. While the following have been observed, the clinical significance of these observations in atopic dermatitis is not known. It has been demonstrated that tacrolimus inhibits T-lymphocyte activation by first binding to an intracellular protein, FKBP-12. A complex of tacrolimus-FKBP-12, calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin is inhibited. This prevents the dephosphorylation and translocation of nuclear factor of activated T-cells (NF-AT), a nuclear component thought to initiate gene transcription for the formation of lymphokines. Tacrolimus also inhibits the transcription for genes which encode IL-3, IL-4, IL-5, GM-CSF, and TNF-, all of which are involved in the early stages of T-cell activation. Additionally, tacrolimus has been shown to inhibit the release of pre-formed mediators from skin mast cells and basophils, and to downregulate the expression of FceRI on Langerhans cells.
LD50=134-194 mg/kg (rat).
Metabolism
Hepatic, extensive, primarily by CYP3A4. The major metabolite identified in incubations with human liver microsomes is 13-demethyl tacrolimus. In in vitro studies, a 31-demethyl metabolite has been reported to have the same activity as tacrolimus.
Route of Elimination: In man, less than 1% of the dose administered is excreted unchanged in urine. When administered IV, fecal elimination accounted for 92.6±30.7%, urinary elimination accounted for 2.3±1.1%.
Half Life: The elimination half life in adult healthy volunteers, kidney transplant patients, liver transplants patients, and heart transplant patients are approximately 35, 19, 12, 24 hours, respectively. The elimination half life in pediatric liver transplant patients was 11.5±3.8 hours, in pediatric kidney transplant patients was 10.2±5.0 (range 3.4-25) hours.
No indication of carcinogenicity to humans (not listed by IARC).
Uses/Sources
For use after allogenic organ transplant to reduce the activity of the patient's immune system and so the risk of organ rejection. 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. It has also been used in a topical preparation in the treatment of severe atopic dermatitis.
Minimum Risk Level
Not Available
Health Effects
Not Available
Symptoms
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.
Pan Sup Chang, Hoon Cho, “Water soluble polymer-tacrolimus conjugated compounds and process for preparing the same.” U.S. Patent US5922729, issued April, 1997.
