Azathioprine: state of the art in inflammatory bowel disease

The use of 6-mercaptopurine (6MP) and its prodrug azathioprine (AZA) for inflammatory bowel disease (IBD) has increased in recent years. The pharmacology, patient response in controlled trials, new formulations and routes of administration and safety for these agents are reviewed.

AZA is rapidly converted to 6MP, which is then further metabolized to the active metabolites, the 6-thioguanine nucleotides (6TGN). The half-life of 6TGN in erythrocytes is prolonged and weeks to months may be required to reach steady state. This prolonged time to 6TGN steady state may help explain the clinical observation that prolonged treatment (3-4 months) with 6MP/AZA for IBD is required before a therapeutic response occurs. CLINICAL RESPONSE: Controlled trials of 6MP (1.5 mg/kg/d) or AZA (1.0-3.0 mg/kg/d) support the following treatment indications for 6MP/AZA: inflammatory Crohn's disease; fistulizing Crohn's disease; steroid-sparing; and remission maintenance. Controlled trials of AZA (1.5-2.5 mg/kg/d) in UC have suggested efficacy for the indications of steroid sparing and remission maintenance, as well as a possible effect in chronically active disease. A therapeutic response appears to require > or = 17 weeks for most patients, and it has been suggested that a greater cumulative dose of AZA may result in increased likelihood of response to AZA. A recent pilot study suggested that administration of an i.v. loading dose of AZA (20-44 mg/kg over 36 h) may decrease the time to response in Crohn's disease patients treated with AZA, perhaps by administering a portion of the necessary cumulative dose more rapidly. Two recent pharmacokinetic studies demonstrated that use of a delayed release oral AZA formulation which delivers AZA directly to the ileocolon markedly reduces systemic absorption of AZA. This 'topical' or 'local' approach to AZA treatment of IBD holds the promise of equal or improved efficacy with a significant reduction in toxicity, and dose-ranging clinical trials with delayed release oral AZA are planned in the near future.

Side effects of AZA/6MP include pancreatitis, fever, nausea, leukopenia, infection, and hepatitis. It appears that the risk of malignancy during or following monotherapy with AZA/6MP for IBD is not increased relative to the general population.

AZA/6MP therapy is efficacious and reasonably safe for selected patients with IBD. Indications for treatment with AZA/6MP include refractory Crohn's disease, fistulizing Crohn's disease, steroid-dependent Crohn's disease, Crohn's disease remission maintenance, and possibly refractory UC, steroid dependent UC, and UC remission maintenance. The use of these immune modifier drugs in patients with IBD represents a significant therapeutic advance.