Azathioprine: clinical pharmacology and current indications in autoimmune disorders.
Azathioprine remains one of the most important and widely prescribed drugs for immunosuppression/immunomodulation in autoimmune disease over 30 years after its introduction. Extensive clinical experience with azathioprine and steady progress in understanding its pharmacodynamic and pharmacokinetic characteristics provide a clear understanding of how this drug has gained importance in the treatment of autoimmune disease. This review highlights advances in the understanding of the metabolic fate of azathioprine and relates these to the efficacy and toxicity profiles for the drug. Clinicians have been slow to appreciate advances in pharmacogenetics that relate to azathioprine and how the common genetic polymorphism affecting the catabolic enzyme thiopurine methyltransferase may have profound effects on the toxicity and efficacy of the drug, as demonstrated by the lack of reference to this work in publications relating to azathioprine. A current literature review has established that this information has, to a significant degree, now reached the medical disciplines that use azathioprine, but there are still notable exceptions. The marked interpatient variability in azathioprine 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 treatment of only a limited range of autoimmune disorders, which is probably a reflection on the age of the drug. Widening the licence for a drug 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 azathioprine. However, azathioprine is now so well established as an immunomodulating 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 list of licensed indications, and in many disciplines usage is continuing to increase as new immunotherapies are often too expensive or toxic to gain widespread acceptance. This review aims to provide an update on the clinical pharmacology of azathioprine and relate this to the current indications for usage in the treatment of autoimmune disorders.
Anstey
A
A
Department of Dermatology, Royal Gwent Hospital, Newport, Wales.
Lear
J T
JT