Tacrolimus is a potent calcineurin inhibitor and immunosuppressive drug mainly used to prevent the rejection of transplanted organs like the kidney, liver, or heart. It works by suppressing the immune system, specifically T cells, to stop them from attacking the new organ. In addition to preventing transplant rejection, tacrolimus is also used topically to treat moderate to severe atopic dermatitis (eczema) and off-label for various autoimmune conditions. Discovered in 1984 by a Japanese research team, tacrolimus was originally named FK-506 and isolated from the bacterium Streptomyces tsukubaensis.
BRAND NAMES
Prograf.
Protopic.
Hecoria.
Astagraf XL.
Envarsus XR.
These are available in several formulations for different medical purposes, including oral capsules, oral granules, extended-release tablets and capsules, intravenous (IV) injection, and topical ointment. Use it exactly as prescribed on the label, at the same time each day.
MECHANISM OF ACTION
Tacrolimus is a calcineurin inhibitor with immunosuppressive properties. It works by binding to an intracellular protein called FK506-binding protein (FKBP), forming a complex that blocks the phosphatase activity of calcineurin. This inhibition prevents T-lymphocyte activation and the transcription of key cytokine genes, such as interleukin-2 (IL-2), thereby reducing immune response and limiting T-cell proliferation.
PHARMACOKINETICS
Absorption
Tacrolimus is absorbed inconsistently and incompletely, with an average oral bioavailability of around 25%. This makes achieving a stable and consistent therapeutic blood level a major challenge, especially for organ transplant recipients. A complex interplay of genetic, physiological, and environmental factors influences how the drug is absorbed.
Distribution
Based on plasma concentration: Approximately 30 L/kg.
Based on whole blood concentration: Much lower, around 1.0 to 1.5 L/kg.
Metabolism
Tacrolimus is mainly metabolized by the CYP3A4 and CYP3A5 enzymes in the liver and intestines. A specific single nucleotide polymorphism, known as the CYP3A53 genotype, has a significant impact on the drug’s bioavailability. Individuals who are homozygous for CYP3A53 have reduced metabolic activity, resulting in higher blood levels of tacrolimus compared to those who carry the CYP3A5*1 allele.
Excretion
Tacrolimus is mainly eliminated through the bile into the feces, with less than 1% excreted unchanged in the urine.
PHARMACODYNAMICS
Tacrolimus is a powerful immunosuppressant that works by inhibiting calcineurin, a phosphatase critical for activating T-lymphocytes, thereby preventing the body's immune system from attacking a transplanted organ. The drug's effectiveness is influenced by the patient's individual genetic makeup, particularly variations in metabolizing enzymes.
ADMINISTRATION
Tacrolimus administration varies by formulation, and you must take it exactly as prescribed by a healthcare provider. Immediate-release capsules (Prograf) are typically taken twice daily, 12 hours apart, and can be taken with or without food, as long as it's done consistently. Extended-release capsules (Astagraf XL) and tablets (Envarsus XR) should be taken once daily on an empty stomach.
DOSAGE AND STRENGTH
Oral immediate-release (IR) formulation: Start with 0.075 mg/kg/day, divided into two doses administered every 12 hours.
IV: Initially 0.01 mg/kg/day as a continuous infusion.
DRUG INTERACTIONS
Tacrolimus is associated with numerous drug interactions that can significantly affect its blood concentration, potentially resulting in underexposure or overexposure—both of which may lead to serious outcomes such as organ rejection or toxicity. Major interacting drug classes include antifungals, antibiotics, calcium channel blockers, and certain HIV medications. Additionally, grapefruit juice can raise tacrolimus levels and should be avoided.
FOOD INTERACTIONS
Tacrolimus has significant food interactions, particularly with grapefruit and grapefruit juice, which can elevate drug levels and increase the risk of toxicity. Other citrus fruits like pomelo, as well as certain herbs and teas—including pomegranate juice, turmeric, ginger, and various herbal supplements—may also influence tacrolimus concentrations. It's important to take tacrolimus on a consistent schedule, either with or without food, to maintain stable blood levels.
CONTRAINDICATIONS
Tacrolimus is contraindicated for anyone with a hypersensitivity to the drug, other macrolides, or any of the product's components. Grapefruit, St. John's Wort, live vaccines, and concurrent use of cyclosporine are also contraindicated for systemic tacrolimus due to potentially dangerous drug interactions. Topical tacrolimus should not be used in children under two, immunocompromised patients, or on malignant skin lesions or active viral and bacterial infections.
SIDE EFFECTS
Tacrolimus, a powerful immunosuppressant, can cause a wide range of side effects.
Nervous system: Tremors (shakiness, especially in the hands), headaches, and trouble sleeping (insomnia).
Gastrointestinal: Diarrhea, nausea, stomach pain, vomiting, and constipation.
Metabolic: High blood sugar (hyperglycemia), increased cholesterol levels, and elevated potassium levels.
Kidney damage.
Myocardial hypertrophy.
QT prolongation.
Thrombotic microangiopathy.
OVER DOSE
Overdose or sustained high tacrolimus levels can cause dose-dependent toxic effects on multiple organ systems.
Nephrotoxicity.
Hyperglycemia and diabetes.
Cardiovascular issues.
Gastrointestinal effects.
Tremors, headaches, confusion, dizziness, and insomnia.
Seizures, coma.
Posterior Reversible Encephalopathy Syndrome (PRES).
TOXICITY
Tacrolimus toxicity occurs when blood levels of the immunosuppressant medication become too high, often due to a narrow therapeutic window, variable absorption, or drug-drug interactions. Toxicity can impact several organ systems, with the kidneys and central nervous system being the most commonly affected. Close monitoring of blood levels is essential to prevent or manage this condition.
