The Role of Tacrolimus

What Is Tacrolimus?

Tacrolimus (or FK506) is a fermentation product isolated from Streptomyces spp. As a macrolide antibiotic with potent immunosuppressive properties, it is mainly used clinically as an immunosuppressant for the treatment of rejection after organ transplantation. Tacrolimus has been widely used in the treatment of acute and chronic rejection of liver, kidney and bone marrow transplants since its introduction to the market, and has become the first-line drug for the treatment of rejection after liver and kidney transplantation in clinical practice. The drug is colourless crystal at room temperature, soluble in methanol, ethanol, acetone, ethyl acetate, chloroform or ether, insoluble in hexane or petroleum ether, insoluble in water, with high stability under different storage conditions.

Figure 1. Tacrolimus chemical structure
(Source: Iannitti T, et al. 2010)

Tacrolimus Mechanism of Action

Tacrolimus usually causes profound suppression of T cells. Its immunosuppressive effects are mediated by binding to its receptor, the immunophilin FK506-binding protein-12 (FKBP-12). The tacrolimus-FKBP-12 complex in turn inhibits the Ca²⁺/calmodulin-activated protein phosphatase calcineurin in T-cells, hence the classification of tacrolimus as a calcineurin inhibitor (CNI).

Figure 3. Inhibition of T cells by tacrolimus
(Source: Broen JCA, et al. 2020)

When tacrolimus acts as a CNI, the mechanism is very similar to that of cyclosporin A (CsA). The calmodulin-dependent serine/threonine phosphatase activity of calcineurin is inhibited when tacrolimus interacts with its cytosolic receptor. During an active immune response and under physiological conditions, calcineurin dephosphorylates a transcription factor called nuclear factor of activated T cells (NFAT). In turn, dephosphorylated NFAT is translocated to the nucleus and initiates gene transcription through interactions with other transcription factors, leading to T-cell proliferation and production of cytokines such as interleukin (IL)-2. The dephosphorylation of NFAT is inhibited by tacrolimus, which prevents T cells from obtaining key cytokines such as IL-2, leading to severe suppression of T cells. This mechanism is conserved in human T cells and fungal cells such as yeast, so tacrolimus also has antifungal activity.

Figure 4. Involvement of tacrolimus in the Calcineurin/Nuclear factor of T cells signaling pathway
(Source: Saffari TM, et al. 2019)

In addition to its role in immunity, the calcineurin/NFAT signaling pathway plays a key role in a variety of vertebrate developmental systems, including the nervous system. This signaling pathway plays an important role in several processes in the adult nervous system, including myelin formation, synaptic plasticity, neuronal cell survival, proliferation, migration and differentiation. Tacrolimus is a potent neuroprotective agent in the central nervous system. Neuronal damage due to cerebral ischaemia triggers N-methyl-D-aspartate (NMDA) receptor overactivation in response to glutamate stimulation, which leads to calcineurin-mediated dephosphorylation of nitric oxide synthase (NOS). Elevated NOS activity plays a role in excitotoxic neuronal death. Thus, the neuroprotective effect of tacrolimus may be to reduce NOS-mediated neurotoxicity by inhibiting calcineurin. It has also been suggested that the prophylactic effect of tacrolimus on ischaemic brain damage is achieved by de novo synthesis of anti-apoptotic protein synthesis rather than inhibition of calcineurin.

Tacrolimus Side Effects

Tacrolimus has a narrow therapeutic window, low concentrations are prone to graft rejection, high concentrations can cause toxic reactions, and serious adverse reactions will directly affect its clinical use. In addition, tacrolimus has been shown to cause hypertension, hyperkalaemia and an increased risk of tumours and infections. Neutropenia and acute haematopoietic arrest have been observed with tacrolimus use, and regular doses may also lead to hyperimmunosuppression, gingival hyperplasia, and haemolytic urotoxic syndrome. The exact mechanisms that lead to these adverse reactions require further study.

Long-term use of tacrolimus can lead to tacrolimus-induced chronic nephrotoxicity (TICN), which manifests itself as structural, progressive, and irreversible renal injury, severely affecting organ function and long-term survival in transplant recipient patients. The risk of TICN increases as the duration of medication increases. Tacrolimus can cause damage to all three important components of the kidney, with specific pathologies such as small arteriolar vitrification, tubular atrophy, tubulointerstitial fibrosis and glomerulosclerosis.

Clinical therapeutic monitoring of tacrolimus is essential in view of its potent secondary effects, including nephrotoxicity, neurotoxicity, diabetic effects, infections and risk of malignancy. The purpose of this therapeutic drug monitoring (TDM) is to avoid an increased risk of rejection due to underexposure or an increased risk of toxicity due to overexposure. By closely monitoring the patient's blood concentration, blood creatinine, urine output and liver function, and paying attention to the timing of tacrolimus administration and dosage adjustment, thus reducing the occurrence of adverse reactions.

Tacrolimus ELISA Kits

Tacrolimus Antigens

Tacrolimus Antibodies