title: Evaluating the use of metabolite measurement in children receiving treatment with a thiopurine.
abstract: BACKGROUND
  Clinical response to thiopurine medication is related to the concentration of its metabolites. Proxy measures are traditionally used to assess dose adequacy. We present our experience of using tioguanine (previously known/formerly referred to as thioguanine) metabolite measurements in paediatric patients and evaluate their effect on clinical practice.
  
  
  OBJECTIVE
  To report our experience of using tioguanine metabolite measurements in paediatric patients and to evaluate their effects on clinical practice.
  
  
  METHODS
  The 6-tioguanine nucleotide (6-TGN) and 6-methylmercaptopurine (6-MMP) were measured in children prescribed thiopurine medication for at least 3 months. Data were collected on thiopurine methyl transferase (TPMT) genotype, drug dose, laboratory indices and management changes. Therapeutic 6-TGN levels were defined as 235-400 pmol/8 × 10(8) RBCs. Seventy individuals (30 males) with a median age of 15 years. Underlying diagnoses were 'IBD' (68/70) and two cases of eosinophilic colitis. Sixty-three were treated with azathioprine and seven with mercaptopurine. A total of 103 separate measurements were made.
  
  
  RESULTS
  On initial measurement, 68% of patients had 6-TGN levels outside therapeutic levels despite standard thiopurine dosing. Initial 6-TGN levels were significantly higher in patients with TPMT mutations. Toxicity occurred in seven cases. The 6-TGN levels were significantly higher in those with signs of marrow toxicity. The 6-TGN level correlated with WBC, leukocyte count, mean corpuscular volume (MCV) and ΔMCV; however, the ability of each of these to predict therapeutic 6-TGN levels was poor. After initial measurement, management was changed in 25/70 cases (36%).
  
  
  CONCLUSIONS
  6-TGN levels were therapeutic in a minority of those patients who were tested. Proxy measures perform poorly in predicting therapeutic 6-TGN levels. Measuring thiopurine metabolites is useful for dosage adjustment in children, and for the detection of potential toxicity.
authors.affiliation: Department of Gastroenterology, Hepatology and Nutrition, Royal Hospital for Sick Children, Glasgow, UK. lazarmstrong@doctors.org.uk
authors.forename: L
authors.initials: L
authors.lastname: Armstrong
authors.forename: J-A
authors.initials: JA
authors.lastname: Sharif
authors.forename: P
authors.initials: P
authors.lastname: Galloway
authors.forename: P
authors.initials: P
authors.lastname: McGrogan
authors.forename: J
authors.initials: J
authors.lastname: Bishop
authors.forename: R K
authors.initials: RK
authors.lastname: Russell
mesh_terms: D000293:Adolescent; D001379:Azathioprine / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005260:Female; D006150:Guanine Nucleotides / Q000097:blood*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D015212:Inflammatory Bowel Diseases / Q000097:blood / Q000188:drug therapy*; D008297:Male; D015122:Mercaptopurine / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use*; D008780:Methyltransferases / Q000378:metabolism; D012189:Retrospective Studies; D013873:Thionucleotides / Q000097:blood*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D006150:Guanine Nucleotides; D007166:Immunosuppressive Agents; D013873:Thionucleotides; C003964:6-thioguanylic acid; C010240:6-methylthiopurine; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine