title: 6-MP metabolite profiles provide a biochemical explanation for 6-MP resistance in patients with inflammatory bowel disease.
abstract: 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.
authors.affiliation: Division of Gastroenterology and Genetics, Department of Medicine and Pediatrics, Cedars-Sinai Medical Center, UCLA, Los Angeles, California 90048, USA. dubinskym@csmc.edu
authors.forename: Marla C
authors.initials: MC
authors.lastname: Dubinsky
authors.forename: Huiying
authors.initials: H
authors.lastname: Yang
authors.forename: Philip V
authors.initials: PV
authors.lastname: Hassard
authors.forename: Ernest G
authors.initials: EG
authors.lastname: Seidman
authors.forename: Lori Y
authors.initials: LY
authors.lastname: Kam
authors.forename: Maria T
authors.initials: MT
authors.lastname: Abreu
authors.forename: Stephan R
authors.initials: SR
authors.lastname: Targan
authors.forename: Eric A
authors.initials: EA
authors.lastname: Vasiliauskas
mesh_terms: 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
chemical_list: D007166:Immunosuppressive Agents; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine