Tacrolimus is an immunosuppressive drug discovered in 1984 by the Fujisawa Pharmaceutical Co., Ltd. It has been shown to be effective for the treatment of organ rejection following transplantation. The results of
clinical trials with liver and kidney have been published. Clinical studies are continuing for a variety of indications. Tacrolimus binds to a family of proteins termed FK506 (tacrolimus) binding proteins (FKBPs) The formation of a larger pentameric complex comprised of FKBP, tacrolimus, calmodulin and calcineurins A and B results in the inhibition of the phosphatase activity of calcineurin. The action of transcription factors requiring dephosphorylation for transport to the cell nucleus are thus inhibited leading to blockage of T-cell proliferation and function.
Tacrolimus may be administered IV or orally. Absorption from the gastrointestinal tract is variable and irregular. Pharmacokinetic studies with tacrolimus have shown that there are large inter- and intra-individual
differences in its kinetics in organ transplant patients. Tacrolimus is extensively metabolized in the liver and small intestine microsomes utilizing the cytochrome P-450 enzymes. Nine different metabolites of tacrolimus have been identified; several of the metabolites have been found and tested in whole blood.
The use of tacrolimus is associated with serious toxic side effects, primarily nephrotoxicity. At the present time it is not clear whether the nephrotoxicity of tacrolimus is the result of parent drug, metabolites, or a combination of both. Other adverse side effects include neurotoxicity, hypertension, insomnia, and nausea.