Tacrolimus Prograf

Structural Formula Ball-and-Stick Model Space-filling Model

Year of discovery of immunosuppressant activity: 1987 (Fujisawa, later Astellas); Year of introduction: 1994; Drug category: Immunosuppressant; Main uses: Prevention of organ transplant rejection and treatment of eczema; Other brand names: FK-506, Fujimycin, Protopic; Related drugs: Cyclosporin (Neoral), Sirolimus (Rapamune).

Tacrolimus (FK506) is an immunosuppressant used for the prevention of graft rejection after transplantation and also for the topical treatment of eczema. The advantage of tacrolimus over steroids in dermatological use is that it does not cause thinning of the skin.1

The sequence of discovery, mechanism of action, and application of tacrolimus resembles in many ways that for cyclosporin (see page 124). Tacrolimus is a microbially produced macrolide that was isolated in 1984 as a result of an antibiotic screening program at Fujisawa Pharmaceuticals in Japan. In 1987, it was discovered that it also exhibits potent immunosuppressive activity. As with cyclosporin, the immunosuppression was due to the inhibition of T-cell activation. Tacrolimus exerts its effect by binding to an intracellular protein, FK506 binding protein-12 (FKBP-12), which further complexes with calcineurin, Ca and calmodulin, a small Ca2+ binding protein. The ternary complex of tacrolimus, FKBP-12 and calcineurin is depicted in the figure below.2 Whereas free calcineurin is an active phosphatase that causes T-cell activation, the complex with FK506 and FKBP-12 is inactive.

The first human trials with tacrolimus were conducted at the University of Pittsburgh in 1989. It was approved for human immunosuppression in 1994. Tacrolimus is superior to cyclosporin in improving graft survival and preventing acute rejection after kidney or liver transplantation. Individuals receiving tacrolimus require lower doses of steroids, but are at higher risk of developing diabetes mellitus.3

A related macrolide antibiotic, sirolimus (rapamycin) was discovered at Ayers Laboratories in Canada in the early 1970s. Originally, sirolimus was developed as an antifungal agent, but due to its powerful immunosuppressive properties it was advanced as an immunosuppressant by the successor company, Wyeth. Sirolimus was first approved for use in kidney transplantation in 1999, and Is sold under the name Rapamune. Sirolimus binds to FKBP-12, but unlike tacrolimus, this complex does not affect calcineurin. Instead, it binds to a kinase enzyme, the mammalian target of rapamycin (mTOR), causing inhibition of cytokine-induced T-cell proliferation.

0 0 OHO-Y OCKj

Sirolimus (Rapamuneā„¢)

1. Transplant. 2004, 77, S41-S43; 2. Cell 1995, 82, 507-522 (1TC0); 3. Principles of Drug Development in Transplant. Autoimmun. 1996, 159-163; Refs. p. 173

0 0 OHO-Y OCKj

Calcineurin

FKBP-12

Calcineurin

Ternary complex of tacrolimus.

Ternary complex of tacrolimus.

Calcineurin

FKBP-12

Calcineurin

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