6-MP metabolite profiles provide a biochemical explanation for 6-MP resistance in patients with inflammatory bowel disease.
OBJECTIVE
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.
Dubinsky
Marla C
MC
Division of Gastroenterology and Genetics, Department of Medicine and Pediatrics, Cedars-Sinai Medical Center, UCLA, Los Angeles, California 90048, USA. dubinskym@csmc.edu
Yang
Huiying
H
Hassard
Philip V
PV
Seidman
Ernest G
EG
Kam
Lori Y
LY
Abreu
Maria T
MT
Targan
Stephan R
SR
Vasiliauskas
Eric A
EA
D000293:Adolescent; D000328:Adult; D000368:Aged; D001379:Azathioprine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D056486:Chemical and Drug Induced Liver Injury; D004351:Drug Resistance; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D008780:Methyltransferases / Q000378:metabolism; D008875:Middle Aged; D018579:Patient Selection; D017211:Treatment Failure
D007166:Immunosuppressive Agents; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine