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The Mechanism and Drug Interaction - Allopurinol and Azathioprine and Risk of Bone Marrow Suppression

Summary:

  • While not commonly used together for the treatment of various chronic conditions, the concomitant use of allopurinol and azathioprine has been used to improve outcomes in pediatric and adult patients with inflammatory bowel disease, prevention of rejection in organ transplantation, and reducing thiopurine-induced hepatotoxicity.  Coadministration of these medications did require dose reductions and extra monitoring for life threatening reductions in WBC.
  • Allopurinol inhibits the enzyme xanthine oxidase (XO), which is one of 3 enzymes responsible for inactivating 6-mercaptopurine (active form of azathioprine).
  • Due to inhibition of XO, 6-mercaptopurine is shunted down another pathway which produces a greater amount of 6-thioguanine metabolites.  These metabolites are incorporated into the DNA resulting in a reduction in WBC replication/activation, as well as inhibition of the activity of Rac1 GTP which stimulates apoptosis of WBCs.
  • The coadministration of allopurinol and azathioprine (especially if doses are not reduced) can therefore result in life-threatening reductions in WBCs.

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Reviewers:
Jon D. Herrington, PharmD, BCPS, BCOP
Last Reviewed: October 2015

Explanation

  • 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, 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.

    Allopurinol and Azathioprine Drug Interaction

    What is the mechanism of this drug-drug interaction and the resulting reduction in WBCs?
    After oral administration and absorption, approximately 90% of azathioprine is converted to 6-mercaptopurine (6-MP).1,3,4,15  At this point, 6-MP can undergo metabolism by 1 of 3 different pathways; 2 of these pathways serve to inactivate 6-MP and produce metabolites that are largely inactive while the third pathway results in the production of active metabolites.  The 2 inactivating pathways are carried out separately by the enzymes thiopurine methyltransferase (TPMT) and xanthine oxidase (XO).  The inactivation pathway catalyzed by TMPT is straight forward, but unfortunately is subject to the influence of genetic polymorphism which will be covered in a future Pharmacogenetics Newsletter issue.12 The inactivating XO pathway is also straight forward in terms of converting 6-MP to the inactive metabolite 6-thiouracil.  However, anything that inhibits XO will shunt 6-MP down the pathway that results in the formation of the active 6-thioguanine (TGN) and 6-methyl-MP (MMP) metabolites.  This is where allopurinol interacts with azathioprine.    

    Allopurinol and its metabolite (oxipurinol) are both known inhibitors of xanthine oxidase.11  Normally, XO is needed to convert the purine base hypoxanthine to xanthine and xanthine to then uric acid.  Allopurinol is a structural analogue of hypoxanthine and binds to XO, thereby inhibiting its effect on purine metabolism.  Therefore, the coadministration of allopurinol with azathioprine results in an increased shunting of 6-MP down the pathway that forms 6-TGN metabolites.  These metabolites are then incorporated into DNA resulting in decreased WBC replication/activation and/or suppression of ras-related C3 botulinum toxin substrate 1 (Rac1) which can facilitate apoptosis (programmed cell death) of WBC's.14 

    The Details for Those Who Want Them:

    • Normally, CD28 costimulation of CD4+ T cells results in activation of Vav guanine nucleotide exchange factors (GEF), thereby resulting in the conversion of Rac1-bound GDP to Rac1-bound GTP.14  This, in turn, results in the activation of MEKK/IkB/NF-kB pathway and STAT-3 activation that ultimately enhances the amount of bcl-xL levels that provide an important "antiapoptotic" signal.  Therefore, anything that reduces the expression or activation of bcl-xL would increase the mitochondrial pathway of apoptosis.   This is one of the mechanisms for azathioprine (specifically the 6-TGN triphosphate metabolite) induced inhibition of WBCs.14 6-TGN triphosphate blocks the activation of Rac1-bound GDP to Rac1-bound GTP that is needed to activate the "antiapoptotic" pathway mentioned above. 

    In most studies where allopurinol was purposefully added to azathioprine regimens for improved efficacy, the dose of azathioprine was decreased to avoid life-threatening reductions in WBC.3,4,8  Despite this, some patients still experienced significant drops in neutrophil counts to <1,000 cells/mm3.4  This appears to be reversible with the discontinuation of therapy.4  Failing to recognize or monitor for this interaction, whether being done for synergy or for treatment of separate conditions, can increase the risk for life-threatening pancytopenia or myelotoxicity.  While no definitive data are available, it is assumed that febuxostat (Uloric) would cause the same drug interaction as allopurinol since it is also an inhibitor of XO.

    References:

    1. Azathioprine tablets (Azasan) product package insert.  Salix Pharmaceuticals, Inc., Wilmington, NC. 2003. 
    2. McGeown MG, Douglas JF, Donaldson RA et al.  Ten-year results of renal transplantation with azathioprine and prednisolone as only immunosuppression.  Lancet  1988;1:983-5.
    3. Sparrow MP, Hande SA, Friedman S et al.  Effect of allopurinol on clinical outcomes in inflammatory bowel disease nonresponders to azathioprine or 6-mercaptopurine.  Clin Gastroenterol Hepatol  2007;5:209-14.       
    4. Rahhal RM, Bishop WP.  Initial clinical experience with allopurinol-thiopurine combination therapy in pediatric inflammatory bowel disease.  Inflamm Bowel Dis  2008;14:1678-82.
    5. Chocair P, Duley J, Simmonds HA et al.  Low-dose allopurinol plus azathioprine/cyclosporine/prednisolone, a novel immunosuppressive regimen.  Lancet 1993;342:83-4.
    6. A, Evans C, Keevil B et al.  Effect of allopurinol on the metabolism of azathioprine in heart transplant patients.  Transplant Proc  1998;30:1127-9.
    7. Chocair PR, Duley JA, Cameron JS et al.  Does low-dose allopurinol, with azathioprine, cyclosporine and prednisolone, improve renal transplant immunosuppression?  Adv Exp Med Biol  1994;370:205-8.
    8. Ansari A, Elliott T, Baburajan B et al.  Long-term outcome of using allopurinol co-therapy as a strategy for overcoming thiopurine hepatotoxicity in treating inflammatory bowel disease.  Aliment Pharmacol Ther  2008;28:734-41.
    9. De Silva M, Hazleman BL.  Long-term azathioprine in rheumatoid arthritis: a double-blind study.  Ann Rheum Dis  1981;40:560-3.
    10. Ginzler E, Sharon E, Diamond H et al.  Long-term maintenance therapy with azathioprine in systemic lupus erythematosus. Arthritis Rheum 1975;18:27-34.
    11. Allopurinol tablets product package insert.  Watson Laboratories, inc.; Corona, CA.  January 2006. 
    12. Dubinsky MC, Lamothe S, Yang HY et al.  Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease.  Gastroenterology  2000;118:705-13.
    13. Lepage GA.  Basic biochemical effects and mechanism of action of 6-thioguanine.  Cancer Res  1963;23:1202-6.
    14. Tiede I, Fritz G, Strand S et al.  CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes.  J Clin Invest  2003;111:1133-45.
    15. Lennard L.  The clinical pharmacology of 6-mercaptopurine.  Eur J Clin Pharmacol  1992;43:329-39.

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MESH Terms & Keywords

  • Azathioprine, Imuran, Xanthine Oxidase Inhibitors, Allopurinol, Zyloprim, Aloprim, Bone Marrow Suppression, Drug Induced Reductions of White Blood Cells