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

Marla C. Dubinsky, Huiying Yang, Philip V. Hassard, Ernest G. Seidman, Lori Y. Kam, Maria T. Abreu, Stephan R. Targan, Eric A. Vasiliauskas

Research output: Contribution to journalArticlepeer-review

443 Scopus citations


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 ≤ 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.

Original languageEnglish (US)
Pages (from-to)904-915
Number of pages12
Issue number4
StatePublished - Jan 1 2002
Externally publishedYes

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology


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