Gastroenterology

Gastroenterology

Volume 122, Issue 4, April 2002, Pages 904-915
Gastroenterology

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

https://doi.org/10.1053/gast.2002.32420Get rights and content

Abstract

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.

GASTROENTEROLOGY 2002;122:904-915

Section snippets

Patient population

All CD and UC patients followed at the Cedars-Sinai IBD Center (Los Angeles, CA), receiving at least 3 months of 6-MP/AZA therapy who had had serial 6-MP metabolite levels measured as part of routine clinical practice from January 1999 (when the test became commercially available) to April 2000, were identified by a laboratory log (n = 208). An investigator (M.C.D.), not directly implicated in the clinical care of these patients, retrospectively determined which individuals were failing

Patient population

A total of 51 IBD patients met all the criteria for final analysis. Fourteen of 51 patients (27%) responded to dose escalation. The remaining 37 failed to achieve adequate clinical benefit from 6-MP/AZA therapy upon reevaluation (Time 1). Baseline characteristics for both the responder and nonresponder groups are detailed in Table 1.Few significant baseline differences were observed between the 2 groups. Male gender, the use of corticosteroids at the initiation of 6-MP/AZA, and a higher

Discussion

The results of this study suggest that 6-MP metabolite profiles provide a biochemical explanation for 6-MP resistance in patients with IBD. In this study, only 14 of 51 patients failing 6-MP/AZA therapy at baseline achieved therapeutic efficacy in response to dose escalation. In these patients, clinical improvement coincided with a significant change in 6-TGN levels to a desired therapeutic range (Fig. 3, Fig. 4). Despite increased 6-MP/AZA doses, the remaining 37 patients continued to fail

Acknowledgements

The authors would like to thank Kai Yang for his assistance with the statistical analyses.

References (35)

  • AB Hawthorne et al.

    Randomized controlled trial of azathioprine withdrawal in ulcerative colitis

    BMJ

    (1992)
  • DC Pearson et al.

    Azathioprine and 6-mercaptopurine in Crohn's disease. A meta-analysis

    Ann Intern Med

    (1995)
  • W Sandborn et al.

    Azathioprine or 6-mercaptopurine or inducing remission of Crohn's disease

    Cochrane Database Syst Rev

    (2001)
  • AH Steinhart et al.

    6-Mercaptopurine and azathioprine for maintaining remission in ulcerative colitis

    Cochrane Database Syst Rev

    (2001)
  • M Dubinsky et al.

    6-MP metabolite levels correlate with clinical response and drug toxicity in adult IBD (abstr)

    Am J Gastroenterol

    (1999)
  • C Cuffari et al.

    6-Mercaptopurine metabolism in Crohn's disease: correlation with efficacy and toxicity

    Gut

    (1996)
  • L. Lennard

    The clinical pharmacology of 6-mercaptopurine

    Eur J Clin Pharmacol

    (1992)

    • Cited by (463)

    • Nucleoside-based anticancer drugs: Mechanism of action and drug resistance

      2023, Biochemical Pharmacology

    • Pharmacogenomics in gastroenterology

      2023, Pharmacogenomics: from Discovery to Clinical Implementation

    • Therapeutic drug monitoring in inflammatory bowel disease: A practical approach

      2024, Indian Journal of Gastroenterology

    • Severe azathioprine-induced liver injury 22 months after initiation of treatment

      2024, Drug and Therapeutics Bulletin

    • The Role of Pharmacogenetics in the Therapeutic Response to Thiopurines in the Treatment of Inflammatory Bowel Disease: A Systematic Review

      2023, Journal of Clinical Medicine

    • Implications of Tioguanine Dosing in IBD Patients with a TPMT Deficiency

      2023, Metabolites
    View all citing articles on Scopus
    ☆

    Address requests for reprints to: Marla C. Dubinsky, M.D. or Eric A. Vasiliauskas, M.D., Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, 8631 West Third Street, Suite 245E, Los Angeles, California 90048. e-mail: [email protected] or vasiliauskas@ csmc.edu; fax (310) 423-0147.

    ☆☆

    Dr. Targan is a co-founder of Prometheus Labs, and Dr. Seidman has a royalty agreement for the use of the 6-MP metabolite levels for the management of IBD with Prometheus Labs.

    View full text
    Copyright © 2002 American Gastroenterological Association. Published by Elsevier Inc. All rights reserved.