title: Thiopurine maintenance therapy for ulcerative colitis: the clinical significance of monitoring 6-thioguanine nucleotide.
abstract: BACKGROUND
  6-Mercaptopurine (6-MP) is an effective maintenance medication in patients with ulcerative colitis (UC), but toxic effects like myelosuppression limit its clinical benefit. In the blood, 6-thioguanine (6-TGN) is formed from 6-MP and mediates the therapeutic efficacy and most of the toxicities of 6-MP. The level of 6-TGN depends on the activity of thiopurine methyltransferase (TPMT), inherited as 1 of its 3 polymorphic forms with low, moderate, or normal/high activity. Accordingly, the 6-MP dose needs to be pharmacogenetically guided.
  
  
  METHODS
  Patients with quiescent UC received 6-MP as maintenance therapy and 6-TGN was assayed as its concentrations in red blood cells (RBCs) done by high-performance liquid chromatography. In a preliminary investigation, 30 mg/day 6-MP (n = 50) was given orally over 12 weeks to determine the time course of blood 6-TGN level. Then 257 patients were given 6-MP at 15-80 mg/day in a stepwise manner based on RBC 6-TGN, white blood cell count, and body weight to monitor 6-MP efficacy and safety profiles.
  
  
  RESULTS
  At 30 mg/day 6-MP, RBC 6-TGN peaked over 4-8 weeks. In the main dosing study, the mean RBC 6-TGN level in patients who remained in remission during the 1-year observation time (n = 151) was 322.3 +/- 119.5 pmole/8 x 10(8) RBC versus 204.8 +/- 78.7 pmole/8 x 10(8) RBC in patients (n = 19) who relapsed (P < 0.001). Bone marrow suppression was seen almost exclusively at high 6-TGN concentration ranges. Further, a regression plot showed an inverse relationship between 6-TGN levels in RBC and TPMT enzyme activity.
  
  
  CONCLUSIONS
  By regularly measuring RBC 6-TGN in patients with quiescent UC receiving 6-MP as maintenance therapy, we could monitor bone marrow suppression as well as other toxic side effects. Potentially, this strategy should enable physicians to avoid thiopurine-related adverse effects and identify individuals who may benefit most from 6-MP maintenance therapy.
authors.affiliation: Centre for Gastroenterology and Inflammatory Bowel Disease Research, Hamamatsu South Hospital, Hamamatsu, Japan. hanai@hamamatsuminami.com
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hanai
authors.forename: Takayuki
authors.initials: T
authors.lastname: Iida
authors.forename: Ken
authors.initials: K
authors.lastname: Takeuchi
authors.forename: Osamu
authors.initials: O
authors.lastname: Arai
authors.forename: Fumitoshi
authors.initials: F
authors.lastname: Watanabe
authors.forename: Jinrou
authors.initials: J
authors.lastname: Abe
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Maruyama
authors.forename: Akihiko
authors.initials: A
authors.lastname: Oohata
authors.forename: Kentarou
authors.initials: K
authors.lastname: Ikeya
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kageoka
authors.forename: Ichita
authors.initials: I
authors.lastname: Miwa
authors.forename: Satou
authors.initials: S
authors.lastname: Yoshirou
authors.forename: Yoshisuke
authors.initials: Y
authors.lastname: Hosoda
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kubota
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001853:Bone Marrow / Q000187:drug effects; D001855:Bone Marrow Diseases / Q000139:chemically induced; D003093:Colitis, Ulcerative / Q000188:drug therapy*; D016903:Drug Monitoring; D004912:Erythrocytes / Q000737:chemistry / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D007937:Leukapheresis; D015122:Mercaptopurine / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D019804:Mesalamine / Q000627:therapeutic use; D008780:Methyltransferases / Q000032:analysis / Q000235:genetics; D008875:Middle Aged; D011239:Prednisolone / Q000627:therapeutic use; D013866:Thioguanine / Q000097:blood*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D019804:Mesalamine; D011239:Prednisolone; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D013866:Thioguanine