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FK506 (Tacrolimus)

Tacrolimus, previously known as FK506, is an immunosuppressive drug derived from Streptomyces tsulenbaensis. Tacrolimus inhibits calcineurin, which is a calcium and calmodulin dependent phosphatase. Inhibition of phosphatase activityleads to reduced transcriptional activation of cytokine genes for interleukin (IL)-2, tumor necrosis factor (TNF)-alpha, IL-3, IL-4, CD40L, granulocyte-macrophage colony-stimulating factor, and interferon-gamma. Ultimately, T cell activation and proliferation are reduced.

Tacrolimus is approximately 100 times more potent than cyclosporine and is used clinically for primary and rescue therapy of solid organ transplants. Tacrolimus is available in oral and intravenous formulations. The intravenous form should be used only if enteral administration is not possible due to its potential for greater toxicity. Immediate release capsules are taken at 12-hour intervals Most centers start calcineurin inhibitor therapy just before transplantation or within the first 24 hours of transplantation.

The dose and target concentrations vary with the type of transplant. The product information recommends the following for tacrolimus initiation:

  • 0.1 mg/kg/day in kidney transplant recipients who also receive mycophenolate mofetil plus an interleukin (IL)-2 receptor antagonist
  • 0.2 mg/kg/day in kidney transplant recipients treated with azathioprine rather than mycophenolate mofetil
  • 0.1 to 0.15 mg/kg/day in adult liver transplant recipients
  • 0.075 mg/kg/day in adult heart transplant recipients

Tacrolimus is absorbed in the small intestine and peak blood concentrations occur after 1.5 to 8.0 hours. Absorption and metabolism may vary with race and ethnicity due to differences in the frequency of polymorphisms in the CYP3A5 gene among African American, Hispanic, and Caucasian transplant recipients.Tacrolimus absorption is decreased if administered after a fatty meal and should be taken on an empty stomach, if possible

Tacrolimus is lipophilic and most of the absorbed drug is taken up by erythrocytes in the blood and then accumulates in the lung, spleen, heart, kidney and pancreas. Tacrolimus is extensively metabolized by cytochrome P-450 CYP3A enzymes in the liver. One of the metabolites of tacrolimus possesses equal immunosuppressive potency to the parent drug.

Tacrolimus is excreted in the bile. The elimination half-life from whole blood is approximately 12 hours for immediate release tacrolimus and 31 +/- 8 hours after extended release capsules. Liver dysfunction prolongs the half-life of tacrolimus.

FK506 has a narrow therapeutic window between adequate immunosuppression and toxicity. The most frequent side effect is nephrotoxicity, followed by hyperkalemia, hyperglycemia, GI upset, and neurotoxicity.

Tacrolimus should be monitored using 12- and 24-hour trough concentrations for the immediate-release and extended-release preparations, respectively. Trough blood levels are useful in guiding dosage adjustments to achieve optimal immunosuppression while minimizing toxicity.

Tacrolimus reaches a steady state concentration after four to six doses. Blood concentrations should be checked two to three days after starting tacrolimus and after any dose change. Typically, after transplant, concentrations are measured every one or two days while hospitalized. After discharge, levels should be measured once or twice weekly for the first month; then weekly until three months post transplantation; then every two weeks until six months posttransplant; and then monthly. More frequent measurements may be required if drugs that affect tacrolimus metabolism are added or withdrawn. Dose adjustments can be assessed two to three days after an adjustment.

Preferred therapeutic ranges may vary by transplant type, transplant protocol, and concomitant medications.During the first four weeks following transplant an optimal response is obtained when the trough blood level is in the range of 15 to 20 ng/mL. Metabolism increases as renal and hepatic functions normalize and a steady state is reached two weeks or more after transplant. At that time, optimal trough blood concentrations are generally between 3.0 and 8.0 ng/mL.

Since tacrolimus is a substrate for cytochrome P-450 3A4/5 (CYP3A4/5) enzymes, any drug or chemical that is metabolized by these enzymes or that affects metabolism by these enzymes can potentially interact with calcineurin inhibitors. Furanocoumarins are chemicals present in grapefruit and grapefruit juice. They are potent inhibitors of cytochrome P-450 3A4 enzymes and can increase tacrolimus levels.

Drugs found to increase tacrolimus levels include diltiazem, verapamil, clotrimazole, fluconazole, ketoconazole, voriconazole, clarithromycin, erythromycin, nelfinavir, and ritonavir. Decreased tacrolimus levels have been found with coadministration of rifampicin, phenytoin, carbamazepine, phenobarbital, octreotide, and St John's wort.

Since 90% of tacrolimus is in erythrocytes, whole blood is the preferred specimen for analysis of trough concentrations. Specimen requirement is one lavender top (EDTA) tube of blood. Tacrolimus can be measured by immunoassay or liquid chromatography/mass spectrometry. Immunoassay measures both parent drug and some metabolites whereas LCMS measures parent drug only. Therefore, immunoassay levels tend to be higher than those measured by LCMS.


Scott LJ, McKeage K, Keam SJ, et al: Tacrolimus: a further update of its use in the management of organ transplantation. Drugs 2003;63(12):1247-1297.

Alak AM. Measurement of tacrolimus (FK506) and Its metabolites: A review of assay development and application in therapeutic drug monitoring and pharmacokinetic studies. Ther Drug Monit. 1997; 19(3):338-351. 

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