title: Thiopurine methyl-transferase activity and azathioprine metabolite concentrations do not predict clinical outcome in thiopurine-treated inflammatory bowel disease patients.
abstract: BACKGROUND
  Low thiopurine-methyl-transferase (TPMT) activity and high 6-thioguanine-nucleotide (6TGN) concentrations have been linked to therapeutic success in inflammatory bowel disease patients treated with thiopurines; however, this has not been implemented in clinical practice.
  
  
  OBJECTIVE
  To identify a therapeutic threshold value for TPMT or 6TGN concentrations, and their capability to predict treatment safety and efficacy.
  
  
  METHODS
  Prospective multicentre study including steroid-resistant/dependent patients starting thiopurines. The TPMT activity was determined at inclusion (>5 U/mL required). Azathioprine metabolites [6TGN, 6-methyl-mercaptopurine ribonucleotides (6MMP), and 6TGN/6MMP and 6TGN/TPMT ratios] were periodically monitored during steroid tapering and after withdrawal for 6 months or until a new flare occurred.
  
  
  RESULTS
  A total of 113 patients were analysed (62% clinical response). Areas under the receiver operating characteristic (ROC) curve (AUC) relating clinical response and metabolite levels at 2, 4 and 6 months after steroid withdrawal were less than 0.7. The AUCs relating final response and initial TPMT activity or metabolite concentrations at 2, 4, 8 and 16 weeks after starting thiopurines were less than 0.7. No cut-off point with worthwhile sensitivity/specificity was found. Eight (7%) patients developed thiopurine-related toxicity that could not be linked to TPMT activity or 6TGN levels.
  
  
  CONCLUSIONS
  Our results do not support determination of TPMT activity or 6TGN concentrations to predict treatment outcome, and no useful serum metabolites threshold value to adjust the drug's dose was identified.
authors: La Princesa and Instituto de Investigación Sanitaria Princesa, Madrid, Spain.
authors: Y
authors: Y
authors: González-Lama
authors: F
authors: F
authors: Bermejo
authors: A
authors: A
authors: López-Sanromán
authors: V
authors: V
authors: García-Sánchez
authors: M
authors: M
authors: Esteve
authors: J L
authors: JL
authors: Cabriada
authors: A G
authors: AG
authors: McNicholl
authors: R
authors: R
authors: Pajares
authors: F
authors: F
authors: Casellas
authors: O
authors: O
authors: Merino
authors: D
authors: D
authors: Carpio
authors: M I
authors: MI
authors: Vera
authors: C
authors: C
authors: Muñoz
authors: M
authors: M
authors: Calvo
authors: L M
authors: LM
authors: Benito
authors: L
authors: L
authors: Bujanda
authors: F J
authors: FJ
authors: García-Fernández
authors: E
authors: E
authors: Ricart
authors: D
authors: D
authors: Ginard
authors: M
authors: M
authors: Velasco
authors: J A
authors: JA
authors: Carneros
authors: N
authors: N
authors: Manceñido
authors: M
authors: M
authors: Calvo
authors: A
authors: A
authors: Algaba
authors: C
authors: C
authors: Froilan
authors: C
authors: C
authors: Cara
authors: J
authors: J
authors: Maté
authors: L
authors: L
authors: Abreu
authors: J P
authors: JP
authors: Gisbert
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D001379:Azathioprine / Q000097:blood*; D015415:Biomarkers / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006150:Guanine Nucleotides / Q000097:blood; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D015122:Mercaptopurine / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D008780:Methyltransferases / Q000097:blood*; D008875:Middle Aged; D011446:Prospective Studies; D012372:ROC Curve; D013873:Thionucleotides / Q000097:blood; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D015415:Biomarkers; D006150:Guanine Nucleotides; D007166:Immunosuppressive Agents; D013873:Thionucleotides; C488629:azathiopurine; C003964:6-thioguanylic acid; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine