Thiopurine maintenance therapy for ulcerative colitis: the clinical significance of monitoring 6-thioguanine nucleotide.
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.
Hanai
Hiroyuki
H
Centre for Gastroenterology and Inflammatory Bowel Disease Research, Hamamatsu South Hospital, Hamamatsu, Japan. hanai@hamamatsuminami.com
Iida
Takayuki
T
Takeuchi
Ken
K
Arai
Osamu
O
Watanabe
Fumitoshi
F
Abe
Jinrou
J
Maruyama
Yasuhiko
Y
Oohata
Akihiko
A
Ikeya
Kentarou
K
Kageoka
Masanobu
M
Miwa
Ichita
I
Yoshirou
Satou
S
Hosoda
Yoshisuke
Y
Kubota
Takahiro
T
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
D007166:Immunosuppressive Agents; D019804:Mesalamine; D011239:Prednisolone; D015122:Mercaptopurine; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D013866:Thioguanine