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 journalArticle

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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.

Original languageEnglish
Pages (from-to)904-915
Number of pages12
JournalGastroenterology
Volume122
Issue number4
StatePublished - Apr 11 2002
Externally publishedYes

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6-Mercaptopurine
thiopurine methyltransferase
Inflammatory Bowel Diseases
Azathioprine
6-thioguanylic acid
Therapeutics
Phenotype
6-methylthiopurine ribonucleoside-5'-phosphate

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Dubinsky, M. C., Yang, H., Hassard, P. V., Seidman, E. G., Kam, L. Y., Abreu, M. T., ... Vasiliauskas, E. A. (2002). 6-MP metabolite profiles provide a biochemical explanation for 6-MP resistance in patients with inflammatory bowel disease. Gastroenterology, 122(4), 904-915.

6-MP metabolite profiles provide a biochemical explanation for 6-MP resistance in patients with inflammatory bowel disease. / Dubinsky, Marla C.; Yang, Huiying; Hassard, Philip V.; Seidman, Ernest G.; Kam, Lori Y.; Abreu, Maria T; Targan, Stephan R.; Vasiliauskas, Eric A.

In: Gastroenterology, Vol. 122, No. 4, 11.04.2002, p. 904-915.

Research output: Contribution to journalArticle

Dubinsky, MC, Yang, H, Hassard, PV, Seidman, EG, Kam, LY, Abreu, MT, Targan, SR & Vasiliauskas, EA 2002, '6-MP metabolite profiles provide a biochemical explanation for 6-MP resistance in patients with inflammatory bowel disease', Gastroenterology, vol. 122, no. 4, pp. 904-915.
Dubinsky, Marla C. ; Yang, Huiying ; Hassard, Philip V. ; Seidman, Ernest G. ; Kam, Lori Y. ; Abreu, Maria T ; Targan, Stephan R. ; Vasiliauskas, Eric A. / 6-MP metabolite profiles provide a biochemical explanation for 6-MP resistance in patients with inflammatory bowel disease. In: Gastroenterology. 2002 ; Vol. 122, No. 4. pp. 904-915.
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AU - Dubinsky, Marla C.

AU - Yang, Huiying

AU - Hassard, Philip V.

AU - Seidman, Ernest G.

AU - Kam, Lori Y.

AU - Abreu, Maria T

AU - Targan, Stephan R.

AU - Vasiliauskas, Eric A.

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N2 - 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.

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