Drug Interactions Newsletter

Volume 1, Issue 12, 04/07/2009

Question

How does the interaction between allopurinol (Zyloprim®, Aloprim®) and the immunosuppressant, azathioprine (Imuran®; Azasan®) increase the risk of significant reductions in WBCs?

Answer

The use of azathioprine (Imuran®; Azasan®) is common for a number of conditions, some of which include the prevention of rejection of organ transplantation, inflammatory bowel disease (in particular Crohn's disease), rheumatoid arthritis, systemic lupus erythematosus (SLE), and several other immune mediated chronic diseases.(1-10)  While not intuitively related to azathioprine, allopurinol (Zyloprim®, Aloprim®) is used mainly for the prevention of gout attacks, treatment of tophi, treatment of calcium oxalate calculi, and elevated levels of uric acid in patients with leukemia, lymphoma and malignancies.(11)  In addition to these indications, the use of  allopurinol along with azathioprine based therapy has been done to improve outcomes in pediatric and adult patients with inflammatory bowel disease, prevention of rejection in organ transplantation, and reducing thiopurine-induced hepatotoxicity.(3-8) The rationale for the coadministration of allopurinol and azathioprine in these situations will be described in future newsletters.  Regardless of the reason for coadministration of allopurinol and azathioprine, their concomitant use should be done with caution and close monitoring or, possibly, not done at all.  What happens if allopurinol and azathioprine are used together?

The simple answer is that the patient incurs significant risk for potentially life threatening reductions in white blood cells (WBC).  This is especially true if the dose of azathioprine is not reduced.  A significant drug-drug interaction occurs that shunts azathioprine's primary route of metabolism to a pathway that favors the production of active metabolites that are also known to cause side effects.  These active metabolites are known to decrease replication and activation of WBCs while also inducing apoptosis (programmed cell death) of WBCs (see figure 1).(1,3,4,8,11-14)  The cumulative effect of this interaction can be a dramatic reduction in WBCs.  What is the mechanism of this drug-drug interaction and the resulting reduction in WBCs?.......To read the full answer please LOGIN or SUBSCRIBE NOW.