Teratogen update: azathioprine and 6-mercaptopurine.

Abstract

Azathioprine (AZA) and its active metabolite, 6-mercaptopurine (6-MP), are purine analogues that interfere with the synthesis of adenine and guanine ribonucleosides. These ribonucleosides are important precursors of DNA and RNA. Because AZA and 6-MP act predominantly on rapidly dividing cells such as the T lymphocytes, these drugs are not only cytotoxic but also immunosuppressive and anti-inflammatory. The effects are dose-related, small doses of either drug are anti-inflammatory, but larger doses are immunosuppressive and cytotoxic (Goldstein, ’87). 6-MP has been used in cancer chemotherapy, primarily in childhood and adult leukemias and usually in combination with other drugs. 6-MP is also used to treat autoimmune diseases, such as inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA) (Bermas and Hill, ’95; Ramsey-Goldman and Schilling, ’97). Initial oral doses for treatment of leukemia range between 2.5–5 mg/kg/d. For maintenance therapy of leukemia, doses range between 1.5–2.5 mg/kg/d. Similar doses (1.5–2.5 mg/kg/d) are used to treat IBD (Present et al., ’80; Botoman et al., ’98; USP DI, ’01), but the use of 6-MP as an immunosuppressant has been largely superseded by AZA, which has been shown to possess a better therapeutic index (Van Scoik et al., ’85; Goldstein, ’87; Chabner et al., ’96). AZA is no longer used as an antineoplastic agent (Ostensen, ’92), but is employed in the treatment of autoimmune disorders at doses between 1–2.5 mg/kg/d and at doses between 1–5 mg/kg/d as part of immunosuppressive regimens to prevent transplant rejection (Botoman et al., ’98; USP DI, ’01). The majority of patients affected by autoimmune diseases are women, in whom the peak incidence occurs between 16 and 55 years of age (Weterman, ’89; Brent et al., ’97; Esplin and Branch, ’97). Successful treatment with cytotoxic and immunosuppressant drugs such as AZA has greatly improved the feasibility of pregnancy in affected women, many of whom must continue to take the medications throughout gestation to prevent relapse. Similarly, women who become pregnant after organ transplantation continue immunosuppressive therapy to prevent rejection if they have been on immunosuppressive therapy before pregnancy. In some patients who become ill with an immunopathic or malignant disease while pregnant, treatment with 6-MP or AZA may be initiated during gestation. The use of cytotoxic immunosuppressants during pregnancy raises concern about possible adverse effects in the developing embryo or fetus, but the potential teratogenicity of AZA and 6-MP is difficult to evaluate in humans. These agents are used to treat patients who have severe illness, and it is often impossible to determine if adverse effects that occur in the embryo/fetus resulted from a particular treatment, the maternal illness, or some other factor (Brent et al., ’97). Also, because of the severity of the illness and the complications that ensue, combination therapy is common. Use of drug combinations as well as variations in dose further hamper efforts to attribute an observed adverse effect to a particular treatment. This article will review human and animal data regarding the pharmacology of 6-MP and AZA and their adverse effects on the embryo and fetus.