Azathioprine Imuran

Structural Formula

= Carbon

Ball-and-Stick Model

= Sulfur

= Hydrogen

= Oxygen

= Nitrogen

= Sulfur

Year of discovery: Late 1950s (Wellcome Research Laboratories); Year of introduction: 1968; Drug category: Immunosuppressant; Main uses: Prevention of organ transplant rejection and treatment of severe rheumatoid arthritis; Other names: Azasan; Related drugs: Sirolimus (Rapamune), Mycophenolate mofetyl (Cellcept), FTY720.

Azathioprine is a potent immunosuppressant used to prevent rejection of organ transplants and to treat patients with severe, erosive rheumatoid arthritis not responsive to conventional treatment. It is also indicated for the treatment of other autoimmune diseases, including systemic lupus erythematosus, inflammatory myositis, and inflammatory bowel disease.

Azathioprine was discovered at Wellcome Research Laboratories by George Hitchings and Gertrude Elion in a pioneering study of the effect of DNA base analogs on rapidly dividing cells. In the early 1950s, several of these purine derivatives were tested at the Sloan-Kettering Institute against a wide range of rodent tumor and leukemia cell lines.

Adenine w

6-Mercaptopurine

Of special interest was the adenine analog, 6-mercaptopurine, which in clinical trials could produce complete remission of acute leukemia and substantially increased the life expectancy of terminally ill children. This compound was approved by the FDA for the treatment of leukemia in 1954. Subsequent research to improve on 6-mercaptopurine led to the development of azathioprine. Coincidentally, in 1954 a surgeon, Joseph Murray, performed the first successful organ transplant (kidney) between identical twins and theorized that transplantation between non-identical twins would be possible using immunosuppression. Shortly thereafter, Robert Schwartz and William Dameshek examined the effect of 6-mercaptopurine on the Immune response and demonstrated immunosuppression. Inspired by these findings, a British surgeon, Roy Calne, investigated the effect of 6-mercaptopurine on kidney transplants in dogs and found that the graft survival of the treated animals was longer than that of the controls. Further studies showed that azathioprine was superior to 6-mercaptopurine.1 Azathioprine was used in combination with prednisone (see page 44) for kidney transplants in humans in 1962.

Nobel Prizes in Medicine were awarded to Elion and Hitchings in 1988 and to Murray in 1990 for their research on immunosuppression and organ transplantation.

Azathioprine is a prodrug that is gradually cleaved in the body to 6-mercaptopurine, from which 6-thioguanine nucleotides are bio-synthesized.

6-Thioguanine

These compounds interfere with de novo DNA biosynthesis and inhibit T-cell proliferation. The major side effect of azathioprine is bone marrow suppression. Although still used extensively after four decades, azathioprine gradually is being displaced by a newer drug, mycophenolate mofetil, which is associated with less bone marrow suppression and fewer incidents of acute rejection (see page 123).2

t Science 1989. 244, 41-47; 2 Current and Future Immunosuppressive Therapies Following Transplantation 2001, 85-110; Refs. p. 173

PART IV. IMMUNOSUPPRESSIVE AGENTS

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