title: Routinely Established Skewed Thiopurine Metabolism Leads to a Strikingly High Rate of Early Therapeutic Failure in Patients With Inflammatory Bowel Disease.
abstract: BACKGROUND
  The conventional thiopurines azathioprine and mercaptopurine are considered maintenance immunosuppressive drugs of choice in the treatment of inflammatory bowel disease (IBD). Unfortunately, treatment is often discontinued because of adverse events (AEs) or refractoriness, retrospectively associated with the high levels of the thiopurine metabolites 6-methylmercaptopurine ribonucleotides (6-MMPR). Patients with a clinically "skewed" thiopurine metabolism may be particularly at risk for therapy failure. We determined the predictive value of this pharmacological phenomenon in patients with IBD during regular thiopurine therapy.
  
  
  METHODS
  Clinical effectiveness and tolerability of weight-based thiopurine therapy were determined in all patients with IBD displaying a skewed metabolism [ratio 6-MMPR/6-thioguanine nucleotide (6-TGN) >20]. All samples were routinely assessed between 2008 and 2012, as part of standard clinical follow-up after initiation of conventional thiopurine therapy.
  
  
  RESULTS
  Forty-one (84%) of 49 included patients with IBD discontinued thiopurines (55% female, 53% with Crohn disease) with a median duration of 14 weeks (range, 7-155). The majority of patients with a skewed metabolism discontinued thiopurines because of adverse events (55%) or refractoriness (12%). The most commonly observed adverse event was hepatotoxicity (18 patients, 37%). Median 6-TGN level was 159 pmol/8 × 10 RBC (range, 46-419), median 6-MMPR level was 11,020 pmol/8 × 10 RBC (range, 3610-43,670), and the median 6-MMPR/6-TGN ratio was 72 (range, 29-367). Thiopurine therapy failure was associated with a ratio above 50 (P < 0.03). Hepatotoxicity occurred more frequently in patients with an extremely skewed metabolism (6-MMPR/6-TGN ratio >100) (P < 0.01).
  
  
  CONCLUSIONS
  This study demonstrates that a routinely established skewed metabolism is a major risk factor for future thiopurine failure in patients with IBD. These observations imply that routine thiopurine metabolite measurements may be used as a prognostic tool to identify those patients with an aberrant-skewed metabolism at an early stage, possibly benefitting from therapy adjustments.
authors: Departments of *Gastroenterology and Hepatology, and †Pharmacy, VU University Medical Center, Amsterdam; and ‡Department of Internal Medicine, Geriatrics, and Gastroenterology, Atrium-ORBIS Medical Center, Heerlen-Sittard-Geleen, the Netherlands.
authors: Joany E
authors: JE
authors: Kreijne
authors: Margien L
authors: ML
authors: Seinen
authors: Abraham J
authors: AJ
authors: Wilhelm
authors: Gerd
authors: G
authors: Bouma
authors: Chris J
authors: CJ
authors: Mulder
authors: Adriaan A
authors: AA
authors: van Bodegraven
authors: Nanne K H
authors: NK
authors: de Boer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001379:Azathioprine / Q000009:adverse effects / Q000378:metabolism* / Q000627:therapeutic use; D015331:Cohort Studies; D003093:Colitis, Ulcerative / Q000188:drug therapy*; D003424:Crohn Disease / Q000188:drug therapy*; D005260:Female; D005500:Follow-Up Studies; D006150:Guanine Nucleotides / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use; D008297:Male; D015122:Mercaptopurine / Q000009:adverse effects / Q000378:metabolism* / Q000627:therapeutic use; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D013868:Thioinosine / Q000031:analogs & derivatives / Q000378:metabolism; D013873:Thionucleotides / Q000378:metabolism; D017211:Treatment Failure; D055815:Young Adult
chemical_list: D006150:Guanine Nucleotides; D007166:Immunosuppressive Agents; D013873:Thionucleotides; C003964:6-thioguanylic acid; D013868:Thioinosine; C002344:6-methylthiopurine ribonucleoside-5'-phosphate; D015122:Mercaptopurine; D001379:Azathioprine