Review Question - QID 101430

6-mercaptopurine is degraded to an inactive metabolite by xanthine oxidase. Allopurinol is an inhibitor of xanthine oxidase, thereby increasing mercaptopurine toxicity.

6-mercaptopurine (6-MP) is a purine analog that inhibits de novo purine synthesis. The drug is converted to an active metabolite by hypoxanthine guanine phosphoribosyl transferase (HGPRTase) in the purine salvage pathway. The clinical usage of 6-MP includes treatment of leukemias, such as ALL, non-Hodgkins lymphoma, and immunosuppression. Toxic side effects of 6-MP include GI disturbances, hepatotoxicity, and myelosuppression.

McLeod reviews common drug-drug interactions in oncology. He finds that 6-MP is metabolized by both thiopurine methyltransferase and xanthine oxidase to inactivate metabolites. In a patient already receiving allopurinol, which is a xanthine oxidase inhibitor, subsequent administration of 6-MP leads to significantly elevated 6-MP plasma concentration levels.

Wilkins et al. describe a clinically important use of 6-MP in the treatment of inflammatory bowel disease, more specifically Crohn's disease. The anti-inflammatory effects of 6-MP are ideal for management of moderate to severe Crohn's disease. In patients concomitantly taking allopurinol, dosing of 6-MP should be reduced to compensate for the drug-drug interaction described above.

Illustration A depicts the purine salvage pathway; note that allopurinol acts to inhibit xanthine oxidase, leading to increased levels of purine metabolites.

Incorrect answers:
Answer 1: Leucovorin (folinic acid) can be used to reverse methotrexate-induced myelosuppresion.
Answer 2: Dexrazoxane is an iron-chelator used to prevent cardiotoxicity in doxorubicin and daunorubicin treatment.
Answer 3: Mesna is an organosulfur compound that binds toxic metabolites of cyclophosphamide and ifosamide, reducing hemorrhagic cystitis and hematuria in patients receiving these drugs.
Answer 5: Amifostine is a free radical scavenger used to prevent nephrotoxicity associated with cisplatin and carboplatin treatment.