title: Novel assay to improve therapeutic drug monitoring of thiopurines in inflammatory bowel disease.
abstract: OBJECTIVE
  The thiopurines are widely used in the treatment of inflammatory bowel disease, but are limited by poor dose-effect relationship. The objective was to assess the ability of a novel assay, determining the mono-, di-, and triphosphates, of thioguanine as well as methylthioinosine as individual metabolites in erythrocytes, to predict clinical outcome compared to a routine assay, determining metabolites as sums.
  
  
  METHODS
  Samples from 79 patients with Crohn's disease or ulcerative colitis treated with azathioprine or mercaptopurine were analysed by both assays. Clinical status was determined by the Harvey-Bradshaw and Walmsley indices. The genotypes of thiopurine methyltransferase (TPMT) and inosine triphosphatase were determined.
  
  
  RESULTS
  TPMT wild-type patients with thioguanine nucleotide (TGN) levels below the cut-off level were more likely to have active disease when TGN was measured by the novel assay (p=0.02), and when thioguanosine triphosphate (TGTP) was measured separately (p=0.01). When TGN was measured by the routine assay the correlation was not evident (p=0.12). Neither TGN levels nor TGTP correlated to disease activity in TPMT deficient patients. Patients with methyl thioinosine nucleotide (meTIN) levels above 1500 pmol/8×10^8 RBCs were more likely to have active disease (p=0.07). We observed good correlations between the mono-, di-, and triphosphates and their respective sums (R(2)>0.88).
  
  
  CONCLUSIONS
  The novel TGN assay was better in predicting clinical outcome compared to the routine assay, while determination of TGTP had no clinical advantage and TGTP ratio was not correlated to disease activity.
authors.affiliation: Division of Drug Research, Clinical Pharmacology, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Sweden. Electronic address: svante.vikingsson@liu.se.
authors.forename: Svante
authors.initials: S
authors.lastname: Vikingsson
authors.affiliation: Department of Gastroenterology, Skåne University Hospital, SE-22185 Lund, Sweden; Department of Medicine, Section of Gastroenterology and Hepatology, Danderyd Hospital, Stockholm, Sweden.
authors.forename: David
authors.initials: D
authors.lastname: Andersson
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden; Karolinska Institutet, Department of Medicine, SE-171 76 Stockholm, Sweden; GastroCentrum, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Sven
authors.initials: S
authors.lastname: Almer
authors.affiliation: Division of Drug Research, Clinical Pharmacology, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Sweden.
authors.forename: Curt
authors.initials: C
authors.lastname: Peterson
authors.affiliation: Department of Gastroenterology, Skåne University Hospital, SE-22185 Lund, Sweden.
authors.forename: Ulf
authors.initials: U
authors.lastname: Hindorf
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001379:Azathioprine / Q000097:blood / Q000627:therapeutic use*; D003430:Cross-Sectional Studies; D016903:Drug Monitoring / Q000379:methods; D004912:Erythrocytes / Q000737:chemistry*; D005260:Female; D020558:GTP Phosphohydrolases / Q000097:blood; D006150:Guanine Nucleotides / Q000097:blood; D006801:Humans; D007166:Immunosuppressive Agents / Q000097:blood / Q000627:therapeutic use*; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy*; D008297:Male; D015122:Mercaptopurine / Q000097:blood / Q000627:therapeutic use*; D008778:Methylthioinosine / Q000097:blood; D008875:Middle Aged; D013866:Thioguanine / Q000097:blood; D013868:Thioinosine / Q000031:analogs & derivatives / Q000097:blood; D013873:Thionucleotides / Q000097:blood; D055815:Young Adult
chemical_list: D006150:Guanine Nucleotides; D007166:Immunosuppressive Agents; D013873:Thionucleotides; D008778:Methylthioinosine; D013868:Thioinosine; C002344:6-methylthiopurine ribonucleoside-5'-phosphate; D015122:Mercaptopurine; D020558:GTP Phosphohydrolases; C022740:thioguanosine triphosphatase; D013866:Thioguanine; D001379:Azathioprine
keywords: Azathioprine; HPLC; Individualized medicine; Inflammatory bowel diseases; Purines; Thiopurine