title: Relationship between azathioprine dosage, 6-thioguanine nucleotide levels, and therapeutic response in pediatric patients with IBD treated with azathioprine.
abstract: BACKGROUND
  Azathioprine (AZA) is commonly used to treat IBD either alone or in combination with mesalazine. However, there are relatively few studies concerning the relationship between AZA dose, thiopurine metabolite levels, and therapeutic response in pediatric patients treated with both AZA and mesalazine.
  
  
  METHODS
  We retrospectively investigated the relationship between AZA dose, thiopurine metabolite levels, and therapeutic response in 137 pediatric patients with IBD treated with AZA using multilevel analysis. Additional factors affecting metabolite levels and therapeutic response were also analyzed.
  
  
  RESULTS
  A positive correlation was observed between AZA dosage and 6-thioguanine nucleotide (6-TGN) level (P < 0.0001). Variant TPMT genotype (P < 0.001) and concomitant use of mesalazine (P < 0.001) were predictors of higher 6-TGN levels. Leukopenia (P = 0.025) and lymphopenia (P = 0.045) were associated with higher levels of 6-TGN. Poor AZA compliance affected median 6-TGN levels (P < 0.001). The frequency of patients with median 6-TGN levels >235 pmol per 8 × 10(8) red blood cells was the highest in the sustained therapeutic response group (P = 0.015). Age, sex, IBD type, and duration of AZA therapy did not influence 6-TGN levels or therapeutic effect.
  
  
  CONCLUSIONS
  AZA dosage is positively correlated with 6-TGN level. Higher 6-TGN levels are related to leukopenia, lymphopenia, and concurrent use of mesalazine. These results provide the rationale for monitoring metabolites to optimize drug dosing and minimize drug-related toxicity. In addition, maintenance of 6-TGN levels within a beneficial therapeutic range by direct monitoring should be helpful in attaining therapeutic efficacy, although this possibility should be verified in prospective studies.
authors: Departments of *Laboratory Medicine and Genetics, and †Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; ‡Department of Pediatrics, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea; and §Biostatistics Team, Samsung Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors: Mi-Na
authors: MN
authors: Lee
authors: Ben
authors: B
authors: Kang
authors: So Yoon
authors: SY
authors: Choi
authors: Mi Jin
authors: MJ
authors: Kim
authors: Sook Young
authors: SY
authors: Woo
authors: Jong-Won
authors: JW
authors: Kim
authors: Yon Ho
authors: YH
authors: Choe
authors: Soo-Youn
authors: SY
authors: Lee
mesh_terms: D000293:Adolescent; D001379:Azathioprine / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006150:Guanine Nucleotides / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000378:metabolism*; D008297:Male; D008780:Methyltransferases / Q000235:genetics; D016133:Polymerase Chain Reaction; D011379:Prognosis; D012189:Retrospective Studies; D013873:Thionucleotides / Q000378:metabolism*
chemical_list: D006150:Guanine Nucleotides; D007166:Immunosuppressive Agents; D013873:Thionucleotides; C003964:6-thioguanylic acid; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine