Tacrolimus (also FK-506 or Fujimycin) is an immunosuppressive drug whose main use is after 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, severe refractory uveitis after bone marrow transplants, and the skin condition vitiligo. It was discovered in 1984 from the fermentation broth of a Japanese soil sample that contained the bacteria Streptomyces tsukubaensis. 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.

• Antineoplastic and Immunomodulating Agents
• Calcineurin Inhibitors
• Combined Inhibitors of CYP3A4 and P-glycoprotein
• Cytochrome P-450 CYP3A Inhibitors
• Cytochrome P-450 CYP3A4 Inhibitors
• Cytochrome P-450 CYP3A4 Substrates
• Enzyme Inhibitors
• Hyperglycemia-Associated Agents
• Immunologic Factors
• Immunosuppressive Agents
• Lactones
• Macrolides
• Myelosuppressive Agents
• P-glycoprotein/ABCB1 Inducers
• P-glycoprotein/ABCB1 Inhibitors
• P-glycoprotein/ABCB1 Substrates
• Polyketides

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.

• Graft Versus Host Disease (GVHD)
• Heart Transplant Rejection
• Kidney Transplant Rejection
• Liver Transplant Rejection
• Oral Lichen Planus
• Psoriasis
• Pyoderma Gangrenosum
• Rheumatoid Arthritis
• Severe Atopic Dermatitis
• Vitiligo
• Moderate Atopic dermatitis
• Refractory Atopic dermatitis
• Refractory Rheumatoid arthritis
• Severe Rheumatoid arthritis

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. Tacrolimus has also been shown to be effective in the topical treatment of eczema, particularly atopic eczema. It suppresses inflammation in a similar way to steroids, but is not as powerful. An important dermatological advantage of tacrolimus is that it can be used directly on the face; topical steroids cannot be used on the face, as they thin the skin dramatically there. On other parts of the body, topical steroid are generally a better treatment.

Absorption of tacrolimus from the gastrointestinal tract after oral administration is incomplete and variable. The absolute bioavailability in adult kidney transplant patients is 17±10%; in adults liver transplant patients is 22±6%; in healthy subjects is 18±5%. The absolute bioavailability in pediatric liver transplant patients was 31±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.

• 2.6 ± 2.1 L/kg [pediatric liver transplant patients]
• 1.07 ± 0.20 L/kg [patients with renal impairment, 0.02 mg/kg/4 hr dose, IV]
• 3.1 ± 1.6 L/kg [Mild Hepatic Impairment, 0.02 mg/kg/4 hr dose, IV]
• 3.7 ± 4.7 L/kg [Mild Hepatic Impairment, 7.7 mg dose, PO]
• 3.9 ± 1.0 L/kg [Severe hepatic impairment, 0.02 mg/kg/4 hr dose, IV]
• 3.1 ± 3.4 L/kg [Severe hepatic impairment, 8 mg dose, PO]

~99% bound to human plasma protein, primarily to albumin and alpha-1-acid glycoprotein. This is independent of concentration over a range of 5-50 ng/mL.

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%.

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.

• 0.040 L/hr/kg [healthy subjects, IV]
• 0.172 ± 0.088 L/hr/kg [healthy subjects, oral]
• 0.083 L/hr/kg [adult kidney transplant patients, IV]
• 0.053 L/hr/kg [adult liver transplant patients, IV]
• 0.051 L/hr/kg [adult heart transplant patients, IV]
  
• 0.138 ± 0.071 L/hr/kg [pediatric liver transplant patients]
• 0.12 ± 0.04 (range 0.06-0.17) L/hr/kg [pediatric kidney transplant patients]
• 0.038 ± 0.014 L/hr/kg [patients with renal impairment, 0.02 mg/kg/4 hr dose, IV]
• 0.042 ± 0.02 L/hr/kg [Mild Hepatic Impairment, 0.02 mg/kg/4 hr dose, IV]
• 0.034 ± 0.019 L/hr/kg [Mild Hepatic Impairment, 7.7 mg dose, PO]
• 0.017 ± 0.013 L/hr/kg [Severe hepatic impairment, 0.02 mg/kg/4 hr dose, IV]
• 0.016 ± 0.011 L/hr/kg [Severe hepatic impairment, 8 mg dose, PO]

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. LD₅₀=134-194 mg/kg (rat).

• Humans and other mammals

• Food, especially food with a high-fat content, decreases the rate and extent of absorption.
• The time of the meal affects tacrolimus bioavailability. Take tacrolimus capsules consistently everyday either with or without food.

1. Kino T, Hatanaka H, Hashimoto M, Nishiyama M, Goto T, Okuhara M, Kohsaka M, Aoki H, Imanaka H: FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics. J Antibiot (Tokyo). 1987 Sep;40(9):1249-55. [PubMed:2445721 ]
2. Pritchard DI: Sourcing a chemical succession for cyclosporin from parasites and human pathogens. Drug Discov Today. 2005 May 15;10(10):688-91. [PubMed:15896681 ]
3. Liu J, Farmer JD Jr, Lane WS, Friedman J, Weissman I, Schreiber SL: Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell. 1991 Aug 23;66(4):807-15. [PubMed:1715244 ]
4. Fukatsu S, Fukudo M, Masuda S, Yano I, Katsura T, Ogura Y, Oike F, Takada Y, Inui K: Delayed effect of grapefruit juice on pharmacokinetics and pharmacodynamics of tacrolimus in a living-donor liver transplant recipient. Drug Metab Pharmacokinet. 2006 Apr;21(2):122-5. [PubMed:16702731 ]
5. Hanifin JM, Paller AS, Eichenfield L, Clark RA, Korman N, Weinstein G, Caro I, Jaracz E, Rico MJ: Efficacy and safety of tacrolimus ointment treatment for up to 4 years in patients with atopic dermatitis. J Am Acad Dermatol. 2005 Aug;53(2 Suppl 2):S186-94. [PubMed:16021174 ]

• D11AH — Agents for dermatitis, excluding corticosteroids
• D11A — OTHER DERMATOLOGICAL PREPARATIONS
• D11 — OTHER DERMATOLOGICAL PREPARATIONS
• D — DERMATOLOGICALS

• L04AD — Calcineurin inhibitors
• L04A — IMMUNOSUPPRESSANTS
• L04 — IMMUNOSUPPRESSANTS
• L — ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS

• 84:92.00
• 92:00.00

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