6-MP metabolite profiles provide a biochemical explanation for 6-MP resistance in patients with inflammatory bowel disease

Gastroenterology. 2002 Apr;122(4):904-15. doi: 10.1053/gast.2002.32420.


Background & aims: Approximately 40% of inflammatory bowel disease (IBD) patients fail to benefit from 6-mercaptopurine (6-MP)/azathioprine (AZA). Recent reports suggest 6-thioguanine nucleotide (6-TGN) levels (>235) independently correlate with remission. An inverse correlation between 6-TGN and thiopurine methyltransferase (TPMT) has been described. The objectives of this study were to determine whether dose escalation optimizes both 6-TGN levels and efficacy in patients failing therapy because of subtherapeutic 6-TGN levels and its effect on TPMT.

Methods: Therapeutic efficacy and adverse events were recorded at baseline and upon reevaluation after dose escalation in 51 IBD patients. 6-MP metabolite levels and TPMT activity were recorded blinded to clinical information.

Results: Fourteen of 51 failing 6-MP/AZA at baseline achieved remission upon dose escalation, which coincided with significant rises in 6-TGN levels. Despite increased 6-MP/AZA doses, 37 continued to fail therapy at follow-up. Dose escalation resulted in minor changes in 6-TGN, yet a significant increase in 6-methylmercaptopurine ribonucleotides (6-MMPR) (P < or = 0.01) and 6-MMPR:6-TGN ratio (P < 0.001). 6-MMPR rises were associated with dose-dependent hepatotoxicity in 12 patients (24%). TPMT was not influenced by dose escalation.

Conclusions: Serial metabolite monitoring identifies a novel phenotype of IBD patients resistant to 6-MP/AZA therapy biochemically characterized by suboptimal 6-TGN and preferential 6-MMPR production upon dose escalation.

Publication types

  • Clinical Trial

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Azathioprine / administration & dosage
  • Azathioprine / adverse effects
  • Azathioprine / pharmacokinetics
  • Chemical and Drug Induced Liver Injury
  • Drug Resistance
  • Female
  • Humans
  • Immunosuppressive Agents / administration & dosage
  • Immunosuppressive Agents / adverse effects
  • Immunosuppressive Agents / pharmacokinetics*
  • Inflammatory Bowel Diseases / drug therapy*
  • Inflammatory Bowel Diseases / enzymology
  • Male
  • Mercaptopurine / administration & dosage
  • Mercaptopurine / adverse effects
  • Mercaptopurine / pharmacokinetics*
  • Methyltransferases / metabolism
  • Middle Aged
  • Patient Selection
  • Treatment Failure


  • Immunosuppressive Agents
  • Mercaptopurine
  • Methyltransferases
  • thiopurine methyltransferase
  • Azathioprine