AZATHIOPRINE - CLINICAL-PHARMACOLOGY AND CURRENT INDICATIONS IN AUTOIMMUNE DISORDERS

Azathioprine remains one of the most important and widely prescribed d rugs for immunosuppression/immunomodulation in autoimmune disease over 30 years after its introduction. Extensive clinical experience with a zathioprine and steady progress in understanding its pharmacodynamic a nd pharmacokinetic characteristics provide a clear understanding of ho w this drug has gained importance in the treatment of autoimmune disea se. This review highlights advances in the understanding of the metabo lic fate of azathioprine and relates these to the efficacy and toxicit y profiles for the drug. Clinicians have been slow to appreciate advan ces in pharmacogenetics that relate to azathioprine and how the common genetic polymorphism affecting the catabolic enzyme thiopurine methyl transferase may have profound effects on the toxicity and efficacy of the drug, as demonstrated by the lack of reference to this work in pub lications relating to azathioprine. A current literature review has es tablished that this information has, to a significant degree, now reac hed the medical disciplines that use azathioprine, but there are still notable exceptions. The marked interpatient variability in azathiopri ne metabolism is of particular significance in the context of clinical trials, which may reach doubtful or invalid conclusions by failing to consider this in trial protocols. Azathioprine is licensed for the tr eatment of only a limited range of autoimmune disorders, which is prob ably a reflection on the age of the drug. Widening the licence for a d rug is both costly and time consuming, and it would make no commercial sense for manufacturers to do so, at this late stage of life, for aza thioprine. However, azathioprine is now so well established as an immu nomodulating drug in autoimmune disorders that it represents the gold standard by which other drugs are compared. A review of the literature shows that usage of azathioprine goes considerably beyond the short l ist of licensed indications, and in many disciplines usage is continui ng to increase as new immunotherapies are often too expensive or toxic to gain widespread acceptance. This review aims to provide on update on the clinical pharmacology of azathioprine and relate this to the cu rrent indications for usage in the treatment of autoimmune disorders.