Use of allopurinol to optimize thiopurine immunomodulator efficacy in inflammatory bowel disease

The thiopurine immunomodulators azathioprine and 6-mercaptopurine are integral to the management of inflammatory bowel disease (IBD), particularly as corticosteroid-sparing and maintenance agents; however, up to 50% of patients do not adequately respond to these agents. Advances in pharmacogenomics and an increased understanding of thiopurine metabolism have led to the practice of measuring the thiopurine metabolites 6-thioguanine (6-TGN) and 6-methylmercaptopurine (6-MMP) to help achieve optimal immunomodulator dosages. Metabolite profiles are also useful for categorizing the reasons for thiopurine treatment failures. A desirable metabolite profile favors 6-TGN production over 6-MMP formation; however, a significant subgroup of IBD patients, perhaps 15%, preferentially metabolizes thiopurines toward the inefficacious and potentially hepatotoxic metabolite 6-MMP. The xanthine oxidase inhibitor allopurinol has been shown recently to advantageously switch thiopurine metabolism toward 6-TGN production in this subgroup of patients, and small studies have shown this switch to be safe and clinically beneficial. This article reviews evidence describing the use of allopurinol to optimize immunomodulator metabolism, provides careful practice guidelines to clinicians considering this strategy, and briefly discusses the potential mechanisms by which this favorable interaction occurs.