Split-dose administration of thiopurine drugs: a novel and effective strategy for managing preferential 6-MMP metabolism

Aliment Pharmacol Ther. 2012 Sep;36(5):449-58. doi: 10.1111/j.1365-2036.2012.05206.x. Epub 2012 Jul 11.


Background: Mercaptopurine and azathioprine (AZA) are efficacious in treating IBD. 6-tioguanine (6-TGN) levels correlate with therapeutic efficacy, whereas high 6-methylmercaptopurine (6-MMP) levels are associated with hepatotoxicity and myelotoxicity. Some IBD patients exhibit dose-limiting preferential 6-MMP production, which may lead to undesired side effects and impact efficacy.

Aim: To review the outcomes of thiopurine split-dosing in patients with preferential 6-MMP metabolism.

Methods: A retrospective chart review of 179 IBD patients treated at the Cedars-Sinai IBD Center with AZA or mercaptopurine was performed. Preferential 6-MMP metabolisers with 6-MMP levels greater than 7000 pmol/8 × 10(8) erythrocytes who underwent split-dosing were identified and assessed for biochemical and clinical responses to these dose modifications.

Results: A total of 20 of 179 patients met the criteria for preferential 6-MMP metabolism and underwent thiopurine split-dosing. Dividing the total daily thiopurine dose led to a reduction in 6-MMP levels (11785 vs. 5324 pmol/8 × 10(8) erythrocytes; P < 0.0001) without negatively affecting clinical disease activity or 6-TGN levels (239 vs. 216 pmol/8 × 10(8) erythrocytes; P = N.S.) and led to resolution of 6-MMP associated side effects (elevated transaminases, leucopenia and flu-like symptoms) in all but two patients. After mean follow-up of 36 months, 12 patients remained in clinical remission on split-dose mercaptopurine. Five of the remaining eight patients escalated to anti-TNF therapy, two progressed to surgery, and one switched to tioguanine therapy.

Conclusion: Split-dose administration of mercaptopurine/AZA represents an alternative option in IBD patients with preferential 6-MMP metabolism who might otherwise require steroid exposure or escalation of therapy.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adolescent
  • Adult
  • Azathioprine / administration & dosage*
  • Dose-Response Relationship, Drug
  • Erythrocytes / drug effects
  • Erythrocytes / metabolism
  • Female
  • Humans
  • Immunosuppressive Agents / administration & dosage*
  • Inflammatory Bowel Diseases / drug therapy*
  • Inflammatory Bowel Diseases / metabolism
  • Male
  • Mercaptopurine / administration & dosage*
  • Mercaptopurine / analogs & derivatives*
  • Mercaptopurine / metabolism
  • Middle Aged
  • Retrospective Studies
  • Treatment Outcome
  • Young Adult


  • Immunosuppressive Agents
  • 6-methylthiopurine
  • Mercaptopurine
  • Azathioprine