Tacrolimus Education

Tacrolimus (TAC), previously known as FK-506, is a macrocyclic lactone antibiotic that was initially extracted in Japan from the soil microorganism, Streptomyces tsukubaensis, in 1984.^1,2 The drug, which is a calcineurin inhibitor, was granted approval by the U.S. Food and Drug Administration (FDA) for preventing rejection after liver (1994), kidney (1997), and heart transplants (2006).^1,3

Mechanism of Action
Tacrolimus, a potent inhibitor of T-lymphocyte proliferation, binds to the FK-binding protein (FKBP), which is an intracellular cytoplasmic immunophilin.² The tacrolimus-FKBP complex inhibits the calcium-dependent phosphatase, calcineurin, which leads to the inhibition of T-cell activation, resulting in immunosuppression.^{2, 4}

Clinical Indications
TACR, which is similar to cyclosporine, but 100 times more potent,⁵ is mainly indicated for the following:

• Prevention of transplant rejection
  1. As a substitute to cyclosporine for primary immunosuppression following solid organ transplantation²
  2. As a rescue therapy in patients with refractory rejection with cyclosporine treatment
• Prophylaxis against host-versus-graft disease
• Topical therapy for atopic dermatitis, scleroderma, and other eczematous diseases⁶
• Suppressing inflammation in inflammatory bowel disease, severe steroid-refractory or steroid-dependent ulcerative colitis, and Crohn’s disease.^7,8

Adverse Effects⁹

• Nephrotoxicity and neurotoxicity
• Lightheadedness and blurred vision
• Enhanced risk for developing cancer, diabetes mellitus, hypertension, dysrhythmias, and left ventricular hypertrophy with heart failure
• Other associated side effects such as weight gain, hair loss, itching, diarrhea, dyspepsia, vomiting, etc¹⁰

Drug Interactions
CYP3A gene and P-glycoprotein play a key role in tacrolimus metabolism. Administration of tacrolimus with other drugs or substances that are also metabolized by the same gene and protein can alter the blood concentrations of the drug.