A team from Canada and the USA determined whether 6-mercaptopurine (6-MP) metabolite profiles provide a biochemical explanation for 6-MP resistance in patients with inflammatory bowel disease (IBD).
Approximately 40% of IBD patients fail to benefit from 6-MP/azathioprine (AZA).
Recent reports suggest 6-thioguanine nucleotide (6-TGN) levels independently correlate with remission.
An inverse correlation between 6-TGN and thiopurine methyltransferase (TPMT) has been described.
The researchers 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.
A total of 51 IBD patients were included in the study.
|IBD patients resistant to 6-MP/AZA therapy:|
- Suboptimal 6-TGN levels
- Preferential 6-MMPR production
| Gastroenterology |
Therapeutic efficacy and adverse events were recorded at baseline and upon re-evaluation after dose escalation.
6-MP metabolite levels and TPMT activity were recorded blinded to clinical information.
Some 14 of 51 failing 6-MP/AZA at baseline achieved remission upon dose escalation. This coincided with significant rises in 6-TGN levels.
Despite increased 6-MP/AZA doses, the authors found that 37 patients 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) and 6-MMPR:6-TGN ratio.
6-MMPR rises were associated with dose-dependent hepatotoxicity in 12 patients (24%).
The team researchers found that TPMT was not influenced by dose escalation.
Dr Marla C. Dubinsky, of the Cedars-Sinai Medical Center, University of California in Los Angeles, USA, concluded on behalf of fellow colleagues, "Serial metabolite monitoring identifies a novel phenotype of IBD patients resistant to 6-MP/AZA therapy.
"These individuals are biochemically characterized by suboptimal 6-TGN and preferential 6-MMPR production upon dose escalation."