A Nudge in the Right Direction: Shaping the Metabolic Fate of Thiopurines for Therapeutic Gain

Gertrude B. Elion and George H. Hitchings were awarded the Nobel Prize for Physiology or Medicine in 1988 in recognition of their pioneering work on discovering “important principles for drug treatment.” These coworkers unraveled the complexity of nucleic acid metabolic pathways and, in doing so, developed the concept that DNA synthesis could be perturbed by drugs that are structural analogues of endogenous purine or pyrimidine nucleosides.¹ Initially, the thiopurines 6-mercaptopurine and later azathioprine were developed and shown to have potent anti-cancer and immunosuppressive effects. Elion and Hitchings also developed allopurinol, another purine nucleoside analogue that did not have anti-cancer properties but became a very useful treatment for gout.² It was quickly realized that administration of allopurinol enhanced the pharmacologic effects of azathioprine or 6-mercaptopurine, resulting in profound bone marrow suppression.³ This drug-drug interaction is well-known and has traditionally been regarded as a contraindication to coadministration of allopurinol with thiopurines or at least an indication for reduction of the dose of thiopurine by about 50%–75%. In this issue of Clinical Gastroenterology and Hepatology, Sparrow et al have turned this generally unfavorable drug-drug interaction on its head. They propose that the addition of allopurinol to the drug regimen of patients with inflammatory bowel disease unresponsive to usual doses of thiopurine drugs results in clinical improvement. In this therapeutic strategy, allopurinol is being used to tailor the metabolic fate of azathioprine or 6-mercaptopurine to maximize the production of active metabolites.