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Gastroenterology. 2002 Apr;122(4):904-15.

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

Author information

1
Division of Gastroenterology and Genetics, Department of Medicine and Pediatrics, Cedars-Sinai Medical Center, UCLA, Los Angeles, California 90048, USA. dubinskym@csmc.edu

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 < 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.

PMID:
11910342
DOI:
10.1053/gast.2002.32420
[Indexed for MEDLINE]

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