Allopurinol is used to prevent gout attacks. Its active metabolite oxypurinol inhibits xanthine oxidase as a suicide substrate. A patient on allopurinol who requires 6-mercaptopurine (6-MP) for leukemia will experience:
- A Reduced efficacy of 6-MP due to allopurinol diverting 6-MP through the salvage pathway
- B Severe 6-MP toxicity because xanthine oxidase inhibition prevents 6-MP catabolism, markedly increasing its plasma levels ✓
- C Enhanced 6-MP efficacy without toxicity because allopurinol inhibits thiopurine S-methyltransferase
- D No interaction because 6-MP is metabolized exclusively by TPMT, not xanthine oxidase
Correct answer: B. Severe 6-MP toxicity because xanthine oxidase inhibition prevents 6-MP catabolism, markedly increasing its plasma levels
Explanation
6-Mercaptopurine is catabolized by xanthine oxidase to 6-thiouric acid (inactive). When xanthine oxidase is inhibited by allopurinol, 6-MP cannot be catabolized, causing its accumulation to toxic levels that may cause bone marrow suppression and hepatotoxicity. The standard recommendation is to reduce 6-MP dose by 66–75% when co-administered with allopurinol. Thiopurine S-methyltransferase (TPMT) is another inactivation pathway but does not compensate fully for xanthine oxidase inhibition.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.