Tacrolimus is used for the prophylaxis of organ rejection in adult and pediatric patients who have received allogeneic liver, kidney, heart, or lung transplantation in combination with other immunosuppressants.
Tacrolimus is a calcineurin inhibitor. In T cells, activation of the T cell receptor normally leads to an increase in intracellular calcium, which acts via calmodulin to activate calcineurin. Calcineurin then dephosphorylates the transcription factor nuclear factor of activated T cells (NF-AT), which migrates into the nucleus of the T cell and increases the activity of genes encoding IL-2 and related cytokines. Tacrolimus prevents dephosphorylation of NF-AT, inhibiting the body's adaptive immune response.
Oral bioavailability is approximately 25%. Approximately 99% of tacrolimus is bound to plasma proteins, primarily serum albumin and acid alpha-1-glycoprotein. Tacrolimus is metabolized predominantly by CYP3A4 and secondarily by CYP3A5 in the liver. In humans, less than 1% of the administered dose is excreted unchanged in the urine. Cheb excretion via feces accounts for more than 90%. Plasma half-life can be highly variable, ranging from 4 to 40 hours.
In addition to tacrolimus, many other drugs are also degraded by the enzyme CYP3A4. Therefore, when taken concomitantly with these drugs, the risk for interactions and increased adverse effects is greatly increased.
Substances with an increased risk for interactions include:
- Macrolide antibiotics such as erythromycin and clarithromycin.
- Grapefruit juice
- Fluconazole and voriconazole
- HIV protease inhibitors
- HCV protease inhibitors
- Phenytoin or phenobarbital