title: A skewed thiopurine metabolism is a common clinical phenomenon that can be successfully managed with a combination of low-dose azathioprine and allopurinol.
abstract: OBJECTIVE
  A skewed thiopurine metabolism is a phenomenon associated with both poor treatment response and toxicity. Our aim was to evaluate the frequency of this phenomenon and the relationship to thiopurine methyltransferase (TPMT) function.
  
  
  METHODS
  All thiopurine metabolite measurements in adult patients (n=4033) between January 2006 and April 2012 were assessed to evaluate the occurrence of a skewed metabolism and the relationship to TPMT genotype and activity.
  
  
  RESULTS
  A skewed metabolism was observed in 14% of all patients. It only developed in patients with a normal TPMT genotype, but was observed at all TPMT activity levels within the normal range (9.1-24.2 U/ml RBC). Two cases that illustrate typical clinical scenarios of a skewed metabolism and the effect of combination treatment with low-dose azathioprine and allopurinol are presented.
  
  
  CONCLUSIONS
  A skewed metabolism is a common clinical phenomenon in patients with a normal TPMT function, which can develop at all TPMT activity levels within the normal range. We suggest that metabolite measurements should be considered in patients not responding to treatment and in those with hepatotoxicity or myelotoxicity in order to detect a skewed metabolism, since this phenomenon can be successfully managed by a combination of low-dose azathioprine and allopurinol.
authors.affiliation: Division of Drug Research/Clinical Pharmacology, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Malin Lindqvist
authors.initials: ML
authors.lastname: Appell
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Wagner
authors.forename: Ulf
authors.initials: U
authors.lastname: Hindorf
mesh_terms: D000328:Adult; D000493:Allopurinol / Q000008:administration & dosage*; D001379:Azathioprine / Q000008:administration & dosage*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D016166:Free Radical Scavengers / Q000008:administration & dosage*; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy*; D008297:Male; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D013866:Thioguanine / Q000097:blood
chemical_list: D016166:Free Radical Scavengers; D007166:Immunosuppressive Agents; D000493:Allopurinol; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D013866:Thioguanine; D001379:Azathioprine