Allopurinol enhanced thiopurine treatment for inflammatory bowel disease: safety considerations and guidelines for use

Abstract

SUMMARYWhat is known and objective: The thiopurine medications are standard inflammatory bowel disease treatments. Therapeutic failure is observed, however, often because of variable drug metabolism. Allopurinol can enhance the potency of thiopurine treatment. Our objective is to review the relevant literature, and our own experience, to determine if allopurinol enhancement of thiopurine treatment is a reasonable therapeutic strategy. Comment: Published reports of, and our own experience using, allopurinol-thiopurine combination therapy indicate that the addition of allopurinol will enhance thiopurine treatment in up to 60% of patients. There are risks to this approach, but with appropriate monitoring, these risks should approximate those observed with thiopurine therapy alone.

Role of Allopurinol in Optimizing Thiopurine Therapy in Patients with Autoimmune Hepatitis: A Review

“…Levels of thiopurine metabolites also need to be measured every 1-2 months till the target level of 6TG is achieved, and then every 6 monthly. 36,37 However as there is no established target therapeutic value of 6TG in the setting of AIH, the utility of repeated drug metabolite monitoring after the patients has achieved normalization of transaminases is not yet clear. The present evidence suggests that combination therapy of allopurinol and thiopurine can be tried as an option in patients with intolerance/non-response to thiopurines before shifting to second line therapy.…”

Update 2014

“…67,71 The exact mechanism of action of allopurinol in shifting metabolites toward the favored 6-TGN remains unclear; however, there are a few proposed mechanisms that revolve around the competing enzymatic pathways of 6-MP. 43,79,80 A study by Hoentjen et al involving 77 skewed thiopurine metabolizers switched to long-term combination therapy reported 12 patients (16%) with subsequent leukopenia. Direct inhibition of XO would be expected to shift conversion toward the remaining pathways subsequently increasing active metabolites.…”

“…The first mechanism involves the breakdown of 6-MP into inactive metabolite 6-thiouric acid by XO. 79,80 Although thiopurine alone has been described to carry a 6-to 8-fold increase in the risk of lymphoma compared with the general population, there have not been reports of lymphoma in existing studies using concomitant thiopurine and allopurinol therapy. The second mechanism involves the inhibition of TPMT that has also been proposed through increased production of metabolite 6-thioxanthine (6-TX) with allopurinol supplementation.…”

“…Direct inhibition of XO would be expected to shift conversion toward the remaining pathways subsequently increasing active metabolites. 71,[80][81][82] Regardless, close monitoring of regular blood counts is essential during combination therapy. This product inhibits TPMT directly in vivo, and increased urinary 6-TX levels were found in patients receiving combination therapy of AZA or 6-MP with allopurinol.…”

Pharmacology and Optimization of Thiopurines and Methotrexate in Inflammatory Bowel Disease

“…In fact, allopurinol actually was first introduced for combined use with thiopurines in the late 1950s in an effort to improve thiopurine efficacy [106]. This combination therapy was later shown to successfully reduce drug toxicity and potentially to recover the treatment response in selected patients [107][108][109], presumably by reducing 6-MeMP levels and increasing 6-TGN levels [108][109][110][111][112]. Thus, IBD patients who have discontinued thiopurines because of side effects might benefit by receiving 25-50 % of the original thiopurine dose combined with an allopurinol dose of 100 mg/day [109,113].…”